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Cardiology TODAY

VOLUME XXI No. 6NOVEMBER-DECEMBER 2017

PAGES 213-252

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EDITORIALLearning Medicine – Does Pedagogy Need a Paradigm Shift ? 215OP YADAVA

REVIEW ARTICLEThe Cardioprotection: Recent Research and Concepts 217VINOD NIKHRA

REVIEW ARTICLEPrehypertension: What to Do? 225A.K. PANCHOLIA

REVIEW ARTICLEAlgorithm of Management of Type-2 Diabetes — India Specific 230RAJEEV CHAWLA, SHALINI JAGGI

REVIEW ARTICLEIatrogenic Hypertension: How to Approach? 236VITULL K. GUPTA, MEGHNA GUPTA, VARUN GUPTA

Cardiology Today VOL.XXI NO. 6 NOVEMBER-DECEMBER 2017 213

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REVEW ARTICLEHypertensive Crisis: Clinical Recognition and Treatment Approaches 240T GOVINDAN UNNI

ECG OF THE MONTHST-Segment Depression 245SR MITTAL

PICTORIAL CMEGiant Thrombus in Inferior Vena Cava 251MONIKA MAHESHWARI

VOLUME INDEXTable of Contents 252

214 Cardiology Today VOL. XXI NO. 6 NOVEMBER-DECEMBER 2017


Learning Medicine – Does Pedagogy need a Paradigm Shift ?

EDITORIAL

Lately, there has been a brouhaha raised on government’s proposal to introduce a bridge course for practitioners of alternative medicine and dental surgery to practice allopathic medicine. A similar hue and cry was raised earlier against a BSc course in community health, to encourage and develop a workforce for rural deployment. Whether these are a well intended protests - based on the perception that delivery of quality medicine will be aff ected, or is it that the medical profession, especially at the grass root level, is feeling threatened and that’s why the reaction, is not the issue I intend addressing. However, this does beg a collateral question - How much learning is required by a medical practitioner and how should that learning be dispensed?

With an ecclesiastical boomerang in the availability of medical information and data, it is universally appreciated that no single individual can learn and retain a signifi cant portion of that information. Do we need to know the molecular basis of every physiological process in the human body, or microscopic and ultra structural changes occurring in every disease pathology, to be able to dispense clinical medicine and that too at the grass root level? Should rare pathologies and syndromes, be taught in medical school at under graduate level, and infact a more disruptive thought - Should we at all have didacted lecture-based theoretical teaching in our medical curriculum? Infact University of Vermont’s off er, ‘Become a doctor, no lectures required’ has already generated a lot of debate and controversy.1 They propose moving away from traditional lecture-based medical education to a problem-based learning through a team-based approach. Now that the medical information and knowledge is available at the tips of the fi nger, and at the click of a button, should one be coerced into learning and memorizing it, or should one only be goaded into rather simpler techniques of how to access this knowledge, when needed? In the latter situation, the students can be better initiated into soft skills of medicine, basic clinical signs and the use of technology at practical level, rather than didacted lectures. In any case, the traditional system has failed, as can be gauzed by the attendance of students for these content heavy, power point slides based, monotonous one way transfer of knowledge, which hardly ever, if at all, reaches the target destination – brain and the intellect. De Jong et al. suggest that according to the cognitive load theory, our brains are limited in the amount of information they can process at a time.2 ‘60 slides in 45 minutes may seem like an effi cient way to teach, but it is unlikely to be an effi cient way to learn’.1

In an interesting article by Brown et al., very aptly titled, ‘Make it stick: the science of successful learning,’ they impress on the fact that the students may be ‘deceived by the elusion of knowing and the fallacy of the understanding.’ When confronted

DR. OP YADAVACEO and Chief Cardiac Surgeon

National Heart Institute,New Delhi


with a real- world problem, they would fi nd themselves lacking in the application of that knowledge and shall realize, sooner than later, that their knowledge is superfi cial at best.3 It is with this background that Schwartzstein and Roberts, in a perspective published in New England Journal of Medicine recently, bat for self-directed learning, which although can be facilitated by the instructor, but must be driven in a large part by the student himself.1 ‘Acquisition of information occurs largely outside the classroom: by principles derived from cognitive science, factual content is presented in study assignments that aren’t overwhelmingly long, and the content is interspersed with questions or problems to ensure that students can assess their level of understanding’.1 Its not that these activities are not labour intensive, but are more interesting and probably more eff ective for learning and retaining knowledge.3 This form of education is likely to be more appealing to this generation, who are digitally friendly and computer savvy. Classical teaching virtually constricts the brain and the thought process, which remains confi ned to the notes taken in the classroom. As against, open-ended learning incites the mind to think laterally and alternatively – a fact verifi ed even in a randomized controlled trial, which showed this form of learning to be more engaging and thought provoking.4 So instead of a senior professor standing in front of a huge classroom and delivering a one-way sermon, the time has come, when smaller groups with mentors attached, sit down at odd hours, odd times, in odd places to discuss both structured and unstructured topics and initiate into the students the quest for knowledge, which he then seeks himself through his eff orts and returns back to the group with doubts and queries and for problem-solving.

Looking forwards, we must evolve with the marching times and keep pace, even in our medical education. We will be served well being reminded constantly, ‘…..avoid zealotry concerning pedagogical approaches, including the insistence that team-based learning methods must adhere to specifi c criteria, or that no deviation from pure problem-based learning is allowed. We can often serve our students best by fusing elements of various methods, such as team-based or case-based learning and interactive large-group learning sessions, rather than feeling obliged to adhere to a particular format’.1

REFERENCES1. Schwartzstein RM, Roberts DH. Saying Goodbye to lectures in Medical School - Paradigm shift or passing fad. N Engl J Med.

2017;DOI:10.1056/NEJMp1706474.2. de Jong T. Cognitive load theory, educational research, and instructional design: some food for thought. Instr Sci 2010;

38:105-34.3. Brown PC, Roediger HL III, McDaniel MA. Make it stick: the science of successful learning. Cambridge, MA: Harvard

University Press, 2014.4. Krupat E, Richards JB, Sullivan AM, Fleenor TJ Jr, Schwartzstein RM. Assessing the effectiveness of case-based collaborative

learning via randomized controlled trial. Acad Med 2016;91: 723-9.

Cardiology Today VOL. XXI NO. 6 NOVEMBER-DECEMBER 2017 217

The Cardioprotection: Recent Research and Concepts

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VINOD NIKHRAKeywords cardioprotection acute coronary syndrome myocardial infarction stunned myocardium hibernating myocardium viable myocardium cardioprotective antioxidant defense fl avonoids coenzyme Q10 heat shock proteins calorie restriction

Dr. Vinod Nikhra is Senior Consultant (Physician) and the teaching faculty at Hindu Rao Hospital, Delhi

AbstractThe heart is made up of millions of myocardial cells that contract and relax to pump blood adequately to various body organs. In turn, it is itself dependent on oxygen and nutrients on vascular supply. All adaptive and compensatory measures including lifestyle interventions and related treatment modalities contributing directly or indirectly to the strengthening of heart and myocardial preservation are cardioprotective.The severity of myocardial damage following coronary occlusion leading to the acute coronary syndrome is not predetermined at the onset of ischemia but can modify by therapeutic interventions applied just before, during or immediately after the ischemic episode. Several important phenomena related to myocardial ischemic injury following ACS/MI have been identifi ed. These events provide an understanding of the pathophysiology involved, the state of myocardium stunned or hibernating but viable, and potential cardioprotective strategies.There are several barriers and lags to translating the experimentally effective cardioprotective interventions into clinically useful therapies, existing at preclinical and clinical levels. But, despite the limitations, the fi eld of cardioprotection appears to be promising, and several modalities have been proved clinically useful. The appropriate therapies can reduce the incidence of ACS/MI, modify favorably the size of a myocardial infarct as well as the ensuing decompensated myocardial function and heart failure.The recent research is focussed on identifying novel strategies to recover the damaged and dysfunctional yet viable myocardium, improve symptomatology and reduce CV mortality. There are drugs which can activate specifi c protective biomolecules and minimize ongoing damage to the heart and vasculature. These drugs can potentially preserve the myocardium and its functional ability, and delay the onset of heart failure, improve QOL and prolong survival.


THE CONCEPT AND MODALITIES OF CARDIOPROTECTION The body tissues need a continuous supply of oxygen and nutrients, and the human life depends on the rhythmical beating of the heart to pump adequately, the blood which is a vehicle for oxygen and nutrients. The heart, is made up of millions of muscle cells that all contract and relax to achieve this goal, and themselves dependent on oxygen and nutrients on vascular supply.

All adaptive and compensatory measures, including lifestyle inter-ventions and related treatment modalities that directly or indirectly contribute to the strengthening of heart and myocardial preservation, can be called ῾cardioprotective᾿.1 The benefi ts of these interventions which protect the heart from oxygen and nutrients starvation and resultant injury/apoptosis of heart muscle cells extend beyond preventing acute coronary syndrome (ACS)/myocardial infarction (MI). They also reduce the severity of disease, in-hospital adverse outcomes, and complications like heart failure in those who develop acute coronary syndrome ACS/MI.

Despite a substantial improvement in blood pressure and lipid profi le management with improved availability and increased use of antihypertensive and lipid-lowering drugs, events of ACS/MI do occur. In case of ACS/MI, there arises the need for the salvation of ischemic myocardium. During or immediately following ACS/MI, cardioprotection include various modalities that preserve function and viability of myocardium by preventing or reducing the ongoing myocardial damage.

Thus, the overall modalities for cardioprotection can be: 1. Physiological adaptive measures like

healthy lifestyle changes.2

2. Treatment of hypertension, dyslipidemia, CVDs, and HF with therapeutic agents such as ACE inhibitors, angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), Beta blockers, statins, diuretics and antiplatelet agents like aspirin and clopidogrel. On the precaution side, the data

suggest that regular, but not intermittent, use of NSAIDs inhibit the clinical benefi ts of aspirin.3

3. Therapeutic approaches include measures that serve to provide an adequate myocardial energy supply and implemented just before an ischemic event (preconditioning, PC), during an ischemic event (pre-conditioning, PerC) and immediately after the event and during reperfusion (postconditioning, PostC). They also include modalities which improve or compensate for unfavorable factors like structural remodeling left ventricular hypertrophy (LVH) and heart failure (HF).

4. Pharmaceuticals for cardioprotection: There are novel compounds which supposedly repair the myocardial damage and improve the physiological function of the heart. They include Co-enzyme Q10, resveratrol, fl avonoids and other plant-derived products, and specifi c peptides which have been proved to be cardioprotective in animal and human research studies.

PATHOPHYSIOLOGY OF MYOCARDIAL INJURY AND CARDIOPROTECTIONThe importance of limiting myocardial infarct size following ischemia/reperfusion injury is almost fi ve decades old. In 1971, Maroko, Kiekshus, Sobel, Watanbe, Covell, Ross and Braunwald highlighted, in a thought breaking paper, that the extent and severity of tissue damage after coronary occlusion were not predetermined at the onset of ischemia but could be modifi ed by therapeutic interventions applied during the ischemic episode.4 In 1974, this concept led to a signifi cant therapeutic breakthrough with Braunwald and Maroko themselves suggesting to test clinical therapies designed to limit myocardial infarct size.5 Over last few decades, several essential phenomena have been identifi ed related to myocardial ischemic injury manifesting as ACS and MI. These phenomena provide an understanding of the pathophysiology involved and potential cardioprotective strategies.

Stunned/Hibernating Myocardium and PreconditioningThe myocardial hibernation is related to the stunned myocardium. In stunned myocardium, there is reduced post-ischemic contractile function, which can be viewed as a reversible injury. The dysfunction due to hibernating myocardium can be considered to be an adaptive response.

The ongoing ischemia with reduced baseline coronary blood fl ow or repetitive cycles of ischemia/reperfusion leads to stunning, which subsequently results in hibernating myocardium with reduced contractile function and baseline blood fl ow.6 Thus, the cumulative eff ect of stunning is a progression to hibernation. The report by Shen et al. underlines the artifi cial distinction between stunning, hibernation, and preconditioning.7

Nitroglycerin induces delayed protection against ischemic ECG alterations, contractile dysfunction and pain sensation, and cyclosporin A in experiments, inhibits opening of the mitochondrial permeability transition pore (MPTP) and attenuates reperfusion injury in patients with ACS/MI. Infarct size reduction characterizes ischemic preconditioning.8

In animal experiments in pigs, six cycles of severe coronary stenosis with subsequent reperfusion did not induce necrosis but did result in profound contractile dysfunction. Repetitive coronary stenosis also resulted in the upregulation of potentially protective proteins and reduced infarct size from complete coronary occlusion and reperfusion.9 Thus, a protocol of cumulative stunning induced the phenotype of hibernating myocardium that was preconditioned.

Changes in Myocardial Mitochondria• NO - the Trigger and Mediator The interaction of NO with

mitochondria is vital in eff ecting cardioprotection. The studies using mice with cardiomyocyte-specifi c constitutive overexpression of inducible NOS (iNOS) confi rm the NO hypothesis of delayed

REVIEW ARTICLE


preconditioning as initially proposed by Bolli, et al.10 This discovery is a milestone in the pathophysiology of myocardial ischemia and molecular basis of the late phase of myocardial preconditioning (PC). The mechanism of late PC is of considerable therapeutic interest. In studies, the classic MPTP inhibitor cyclosporin A-induced diff erent eff ects by increased ROS formation on reperfusion but improved functional recovery.11

NO at low concentration increases ventricular function12 and matches myocardial oxygen consumption to contractile function in the short-term hibernating myocardium.13 Exogenous NO triggers are preconditioning, whereas endogenous NO is both a trigger (through endothelial NOS) and a mediator (through iNOS) of delayed ischemic preconditioning. Also, ischemic postconditioning uses NO as a signal.

• The Protein Kinase Activation Some protein kinases are activated

at multiple levels during ischemia/ reperfusion.14 Adenosine activates G-protein–coupled receptors, which in turn activates bradykinin and receptors for peptides such as natriuretic peptides, leading to activation of phosphoinositide 3 kinase (PI3K). PI3K activates endothelial NOS and NO formation and mitochondrial ATP-dependent K channel (KATP), resulting in p38 mitogen-activated kinase and PKC activation and priming of MPTP for the opening.

The second program is recruited during early reperfusion with ischemic preconditioning and postconditioning. Activation of G-protein–coupled receptors results in activation of the reperfusion injury salvage kinase (RISK). RISK involves the parallel activation of the PI3K/Akt and p70 ribosomal protein S6 kinase (p70S6K) and glycogen synthase kinase 3β (GSK3β) activation and the ultimate inhibition of MPTP opening.

The third program is recruited with

acute ischemic preconditioning, delayed ischemic preconditioning, and ischemic postconditioning.15 After activation of glycoprotein 130 (gp130) receptors or TNF-α receptors, the Janus-activated kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is activated with projection to mitochondria.

• The Mitochondrial KATP and MPTP

Apart from ATP production and its role in cell function and survival, mitochondria are decisive organelle for cell death by apoptosis, autophagy, and necrosis. Conversely, they are also crucial for protection from cell death through several kinases (PKC, PKG, GSK3β) and NO. During early reperfusion, ROS formation from various sources, including the respiratory chain, is primarily augmented. Reversible inhibition of complex I by S-nitration (NO-mediated modifi cation of thiols) is cardioprotective by limiting excess ROS formation during reperfusion.

Mitochondrial Adenosine Triphosphate-sensitive Potassium (KATP) channels are causally involved in ischemic preconditioning and postconditioning. Mitochondrial KATP channel opening induces potassium and accompanying water fl ux along the electrochemical gradient, resulting in matrix swelling. The infl ux of potassium also triggers modest ROS formation by respiratory chain complex I, activating, in turn, PKC and p38 mitogen-activated protein kinase.16 NO induces mitochondrial KATP opening through a mechanism yet not defi ned. Connexin is present at the inner mitochondrial membrane of cardiomyocytes and appears to regulate the gating of mitochondrial KATP channels.

Mitochondrial Permeability Transition Pore (MPTP) is a large-conductance mega-channel which in physiological conditions, is predominantly closed. The opening of the pore is favored by

high concentrations of Ca++, ROS, inorganic phosphate, and NO and a reduction of the inner membrane potential, all of which occur during ischemia and reperfusion. The opening of the MPTP results in depolarization of the membrane potential and matrix swelling. Cyclosporin A inhibits MPTP opening and attenuates reperfusion injury.

Antioxidant DefenceThe apparent paradox that characterizes both ischemic preconditioning and postconditioning is that a little ischemia/reperfusion before or after sustained ischemia/reperfusion protects. Whereas high levels of ROS are detrimental to cardiomyocytes, moderate levels of ROS function as signaling molecules for cardioprotection by activating protein kinases. Likewise, inhibition of MPTP opening is cardioprotective, but the transient opening of MPTP is required for cardioprotection. MPTP opening depends on NO. Low levels of NO prevent MPTP opening, whereas high NO levels accelerate MPTP opening and cytochrome C release.17

CARDIOPROTECTIVE INTERVENTIONSCardioprotective therapies off er potential usefulness in various settings, including the CABG procedure. But, by and large, the protection of myocardium in the setting of MI remains an unfulfi lled promise.18 There are some potentially cardioprotective therapies at the research level and some of which have shown promise in clinical studies.

AMISTAD I and AMISTAD II (Acute Myocardial Infarction Study of Adenosine to determine the effi cacy of IV adenosine in combination with either streptokinase or tissue plasminogen activator (tPA) in limiting the size infarct) had demonstrated a marked reduction in the size of anterior wall infarctions when adenosine was administered at the time of reperfusion. Administration of adenosine before, during, and after aortic clamping, also


reduces the incidence of perioperative infarction and improves a composite end-point consisting of the need for mechanical or inotropic support, infarction, or death.

The benefi cial eff ect of the KATP channel opener and nitric oxide donor, nicorandil has shown benefi ts when administered at the time of reperfusion in patients with AMI.19 Potassium channel openers or agonists represent a novel new class of compounds in the treatment of a range of cardiovascular disorders, including angina pectoris. Nicorandil is the only clinically available potassium channel opener with antianginal effi cacy.

Nicorandil confers benefi ts through a dual action: opening the mitochondrial KATP channels leading to preconditioning of the myocardium and a nitrate-like eff ect.20 Results from various studies have also confi rmed its role in the treatment of acute coronary syndromes. The recent studies have demonstrated its effi cacy in myocardial protection against ischemia‐reperfusion.21 The nicorandil administration during cardiopulmonary bypass provides enhanced myocardial protective eff ects against ischemia‐reperfusion in patients undergoing coronary artery bypass grafting.

The inhibitors of sodium/hydrogen (Na+/H+) exchange protect the ischemic myocardium in cardiac surgery. In the GUARDIAN trial, pre-treatment with the Na+/H+ exchange inhibitor cariporide resulted in a signifi cant reduction in the primary end-point - death and AMI at 36 days after CABG.22 A later larger trial, EXPEDITION trial also demonstrated prospectively the ability of the drug to reduce the incidence of perioperative AMI in CABG surgery.23 The drug limited myocardial ischemia/reperfusion injury in humans, but there was an unexpected increase in the incidence of stroke.

The timing of Na+/H+ inhibitor administration appears to be a key

factor in clinical cardioprotection.24 Both in GUARDIAN and in EXPEDITION Iviab, the infusion of cariporide was started before the onset of ischemia. Whereas, administration of the Na+/H+ exchange inhibitor eniporide at the time of reperfusion in patients with AMI (ESCAMI trial) failed to show a reduction in infarct size or an improvement in clinical outcome. Thus, though Cariporide has proved to be cardioprotective in high-risk CABG patients, its neurologic eff ects preclude its use at present.

GIK infusion has been found to reduce mortality in acute MI in a meta-analysis of studies and recent trials in patients undergoing therapeutic recanalization. In the setting of cardiac arrest, mild hypothermia has also been demonstrated to improve survival rates by various studies.

Barriers to Applying Experimental Interventions into Clinical TherapiesThere are various barriers and lags to translating the experimentally eff ective cardioprotective interventions into clinically useful therapies, which exist at the preclinical and at the clinical levels. There is a lack of adequate communication and coordination between those performing preclinical evaluations, those designing clinical studies, the medical service providers, and those developing therapeutically available interventions. Also, there is a neglect of both the primary and clinical researchers to carefully consider issues related to the eventual clinical application and modalities suitable for the clinical practice.

The barriers at the Preclinical Level:

• Lack of Clinical Reproducibility: Various preclinical studies relating to cardioprotection in experimental models have yielded inconsistent results. If they cannot be reproduced in the highly controlled experimental setting, they cannot be applied to the complex and less controllable clinical setting. This lack of reproducibility

appears to result from numerous factors including comorbid conditions like diabetes, hypercholesterolemia, hypertension, LVH and other variables like age, nutritional status, etc. The experimental models provide simplifi ed version and do not refl ect the complex multifactorial interactions that modulate myocardial ischemia in vivo and thus may have limited clinical eff ectiveness.

• Lack of emphasis on effi cacy: The majority of basic studies focus on understanding molecular and cellular mechanisms of injury and protection. They often neglect or put less emphasis on the potential clinical effi cacy of the interventions tested.

• Failure to disseminate negative results: The ‘positive’ results receive greater publicity than ‘negative’ results distorting the overall objectivity and effi cacy of a potentially useful cardioprotective discovery.

The barriers at the Clinical Level:• Clinical studies have complex

variables: In the patients presenting with ACS/AMI, specifi c data may be challenging to establish like the exact duration of ischemia, the ischemia continuous or intermittent, size of the region at risk, the presence of coronary collateral circulation, pre-existing infarctions, etc. Further, the repeated episodes of angina may also result in ischemic preconditioning, and antianginal medications in use may alter the clinical variables.

• It is often diffi cult to measure infarct size despite progress in cardiac imaging. The magnetic resonance imaging (MRI) techniques can distinguish a transmural from a subendocardial infarction but may miss small infarcts or overestimate the size of nontransmural infarcts.

• In patients with ACS/AMI, pre-treatment is usually not possible because of the unpredictable onset. Secondly, by the time treatment is instituted, a signifi cant damage may have already occurred. Thus, many promising therapies proved useful in preclinical experimental

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studies before ischemia occurs, lose applicability and effi cacy.

• Lack of appropriate biomarkers for ACS/AMI: The ability to monitor, in real time, during active ischemia is limited because of the lack of monitors and markers for guiding therapies during ACS/AMI. It is not possible to know about the adequacy of coronary blood fl ow.

Recent lack of interest in preconditioning:

In recent years, encouragement is given to the emergency PTCA following ACS/MI, the interest in cardioprotective research and interventions, namely pre-, per- and post-conditioning has been diluted. There is a school of thought which incriminate this to the rise in cost for ACS/MI therapeutic intervention as compared to revascularization procedures. This appears to have delayed the development of other cardioprotective modalities as well.

Opportunities for Applying ResearchInterventions to TherapeuticsDespite the numerous limitations, the fi eld of cardioprotection is promising, and some modalities have been proved clinically useful. The appropriate therapies can reduce the incidence of ACS/MI. In case of MI, it can modify favorably the resultant size of a myocardial infarct as well as the ensuing decompensated pump function and heart failure.

Preconditioning as a cardioprotective intervention can limit the infarct size in a clinical setting and protect the myocardium in general from ischemic injury. Many of the molecular and biochemical pathways involved in ischemic damage as well as associated with preconditioning have been identifi ed and provide potential routes/targets for the development of novel cardioprotective strategies. The preconditioning especially the delayed phase of preconditioning off ers an opportunity for cardioprotective interventions. Various classes of drugs, for example, NO-donors like nicorandil, adenosine receptor agonists, δ1-opioid receptor agonists, etc., suitably modify

the myocardial milieu in the late phase of ischemic preconditioning. For various reasons, the effi cacy of preconditioning has not been harnessed for therapeutic purpose in ACS/MI.

The most practical strategy for limiting infarct size and improving clinical outcome is by inducing a protected cardiac phenotype by triggering a sustained preconditioning with suitable pharmacologic agents (prophylactic cardio-protection). In a study in rabbits, the intermittent administration of adenosine A1 receptor agonists can maintain the heart in a chronically protected state for at least 12 days.25 Similarly, the heat shock protein HSP70 was shown to confer protection against ischemia/reperfusion injury.26

The feasibility of inducing a sustained state of cardioprotection can be an added effi ciently to AMI therapeutics and can limit both the ischemia-induced and the reperfusion-induced components of myocardial injury. Therefore, there is a high level of interest in cardioprotection in the scientifi c community and within the pharmaceutical industry. The investment in cardioprotection made by the pharmaceutical industry should be developed into clinically useful therapies. The Government should proactively intervene, and a body like ICMR should catalyze the translation of cardioprotection interventions into clinical reality. All studies should be randomized and blinded and all data analyzed by a centralized core facility using uniform statistical methods.

Benefi ts of Cardioprotective Interventions and Drugs extend Beyond Preventing ACS/MIThe studies indicate that medications prescribed to prevent heart attacks such as statins and aspirin are associated with reduced ACS/MI severity. Also, the prior use of preventive medications (antiplatelet agents such as aspirin, angiotensin converting enzyme inhibitors /angiotensin receptor blockers, statins, and beta-blockers) have been linked with favorable in-hospital outcomes in patients with ACS.27 Similarly, an eff ective treatment following hospitalization for

ACS has a signifi cant impact on reducing a patient’s risk for a future ACS/MI, stroke, complications like HF, or death.

The Clinical Pathways in Acute Coronary Syndromes in China Study (CPACS) is a three-part study that focused on management of ACS/MI in hospitals in China. Over 1, 2 and 3 phases, CPACS has progressed from identifying areas where improvement is needed in health services to manage and treat patients for ACS/MI.28 The fi rst phase, CPACS-1 identifi ed areas where improvement was needed. In the CPACS-2: Development, implementation, and evaluation of clinical pathways for ACS management based upon data collected in Phase 1 were worked-out. The vision of CPACS also includes a third phase, CPACS-3 which has been launched. The fi ndings from CPACS3 will be able to inform health policy-makers about the extent to which quality improvement initiatives can reduce the disability and mortality among the ACS patients.29

NOVEL CARDIOPROTECTIVE DRUGS

Development of novel Cardioprotective drugsThe aim is to develop new classes of drugs which –1. Activate specifi c cardioprotective

proteins and reduce damage to the heart muscle cells,

2. Have the potential to preserve the pumping ability of the heart and delay the onset of HF, and

3. Improve QOL and reducing mortality.

A. Cardioprotective Herbal Derivatives:

The current research holds promise about herbs and herbal-extracts supplements. There are two groups of constituents found in herbs employed for CVD and cardioprotection. These are fl avonoids and triterpenes, which appear to be safe for long-term administration and are present in various plants and herbs. The herb therapies have certain pitfalls, also. The herbal ingredients may interact with the drugs, might do little, or might even worsen specifi c outcomes.


• Flavonoids Studies indicate that the fl avonoids

inhibit platelet aggregation, thrombus formation, and coagulation. They reduce oxidative stress, atherosclerosis, and arterial blood pressure, favorably modify vascular infl ammatory and endothelial and capillary function. They also alter blood lipid levels and regulate carbohydrate metabolism.

The research supports that a regular dietary intake of polyphenols - particularly of fl avonoids and the specifi c class of fl avonoids named fl avanols, condensed fl avonoids, exert benefi cial vascular eff ects and reduce the risk for CV morbidity and mortality. The fl avonoids, particularly in cocoa and tea fl avanols, are helpful in protecting CV diseases.30 Apart from these, fl avonoids are the active components of Gingko leaf, Crataegus (hawthorn fruit) and Pueraria Mirifi ca.

The improvement in endothelial function has been observed in CAD patients on daily consumption of fl avonoids from purple grape juice (which includes fl avan-3-ols, fl avonols, proanthocyanidin, and anthocyanins), black tea and fl avonol-rich cocoa. The fl avonoids in red wine (e.g., fl avan-3-ols, fl avonols, proanthocyanidin, and anthocyanins) improve endothelial function by up-regulating endothelial nitric oxide synthase (eNOS) expression and increasing production of endothelial cell NO;31 and thus, enhance endothelium-mediated vasodilation.32 The European Food Safety Authority has approved the claim that consumption of 200 mg fl avanols from cocoa daily can improve blood fl ow. There is growing evidence that regular ingestion of fl avonoids can reduce the incidence of cardiovascular disease by lowering blood pressure, blood coagulation, and blood fats.

• Phytosterols The phytosterols also promote

general health and well-being and reduce CV risk. The potential

action mechanisms of polysulfi des in cardioprotection is through (a) hydrogen sulfi de-releasing activity; (b) radical scavenging activity; and (c) activity in enzyme inhibition and intervention of gene regulation pathways.33

Cruciferous vegetables and the Allium family include garlic (Allium sativum) and onion (Allium cepa) and are rich in organopolysulfi de as a natural donor of hydrogen-sulfi de (H2S). The organosulfi des in Alliums are well known for their broad spectrum of health-promoting benefi ts. However, human clinical trials in garlic found that allicin does not aff ect cholesterol level.

• Triterpenes Triterpenes are the main active

components of ginseng and other herbs like gynostemma, rhodiola, and ganoderma. The saponins in ginseng (triterpene glycosides) are believed to be used for recovery from ACS/MI. The triterpenes lower blood lipids and enhance oxygen utilization and reduce ROS. They have been shown to have cardiac protective eff ects.

• Other Herbs: Salvia divinorum (active constituent: a diterpenoid called Salvinorin A) can effi ciently improve myocardial ischemia and abnormal parameters in patients with coronary heart disease. Astragalus (active constituent: cycloastragenol a possible telomerase activator) has an ionotropic eff ect and enhance systolic function in patients with HF. It also has protective eff ects against myocardial ischemia and reperfusion injury, free radical injury and on platelet aggregation.34 Astragalus and salvia exhibit a synergistic eff ect for improvement of cardiac function. Aconite (Aconitum) having the alkaloid psuedaconitine, can effi ciently improve sinus-node function and cardiac performance in patients with sick sinus syndrome.

B. Novel cardioprotective drugsThe recent research is focussed on identifying novel strategies to recover the damaged and the dysfunctional

yet viable myocardium, improve symptomatology and quality-of-life (QOL), and prolong survival. There are needed a new class of drugs which can activate specifi c protective biomolecules and reduce ongoing damage to the heart and vasculature.35 These drugs will potentially preserve the myocardium and its functional ability of the heart, and delay the onset of heart failure, and reduce CV mortality.1. Carnitine and L-carnitine: In

experiments, administration of carnitine increases glucose oxidation in the isolated perfused rat heart by increasing the acetyl-carnitine concentration and decreasing the acetyl-CoA concentration, and thus relieving acetyl-CoA inhibition on pyruvate dehydrogenase (PDH).36 A randomized trial in 472 myocardial infarction patients showed that oral carnitine therapy (6 g/day) initiated within 24 h after the onset of chest pain failed to aff ect clinical outcome or LV injection fraction over the course of 1 year of treatment; however, it did signifi cantly reduce the rate of increase in the LV end-diastolic volume.

Some small studies suggest that people who take L-carnitine supplements soon after a myocardial infarction may be less likely to have another episode, die of heart disease, or develop heart failure.37 However, few other studies show no benefi t. Controlled trials in CAD patients relating to carnitine are needed.

2. Coenzyme Q10 (CoQ10): The CoQ10, endogenously synthesized and diet-supplied lipid-soluble cofactor, is a key component in the mitochondrial electron transport chain for ATP generation, and exists in abundance in the normal myocardium. It functions in the mitochondrial inner membrane to transfer electrons from complexes I and II to complex III. By its redox activity, also acts as a membrane antioxidant. The myocardial CoQ10 content tends to decline with age and myocardial dysfunction.

Some controlled trials with supplemental

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CoQ10 have shown improvements in functional parameters such as ejection fraction, stroke volume, and cardiac output. Recently, long-term therapy with CoQ10 has been shown to reduce major adverse cardiovascular events (MACE) and improve HF symptoms and found CoQ10 safe and well tolerated38. Subsequent meta-analyses have also confi rmed these fi ndings.39

Additionally, CoQ10, through its antioxidant eff ects, may reduce oxidative stress, which is known to aff ect left ventricular ejection fraction and alter disease outcomes adversely.40 Lastly, CoQ10 may stabilize calcium-dependent channels in the myocardium, enhancing effi cient ATP synthesis.

There is a potential role CoQ10 plays in the protection of heart, prevention of CVD and HF. CoQ10 supplementation improves heart and vascular function, reduces atherosclerosis, improves endothelial function, and protects against myocardial damage. For HF patients with either preserved (HfpEF) or decreased (HfrEF) ejection fraction CoQ10 presents as a safe therapeutic option. The recent Q-SYMBIO randomized controlled trial has demonstrated a reduction in major adverse cardiovascular events with CoQ10 supplementation in HF patients.41 A recent randomized controlled trial has suggested that there may be a mortality benefi t in patients with HFrEF with CoQ10 supplementation.42

CoQ10 formulations are available as either ubiquinol (reduced form) or ubiquinone (oxidized form). Regardless of whether the formulation contains ubiquinol or ubiquinone after ingestion

CoQ10 appears in the plasma circulation as ubiquinol. Nausea is the most common symptom, followed by an allergic maculopapular rash. Caution should be taken in the patients who are on oral anticoagulant therapy, given the similarities of CoQ10 with vitamin K. There may occur a reduction in blood pressure and heart rate, without any signifi cant ECG changes. Theophylline is also aff ected by cytochrome p450 enzymes, and animal studies have demonstrated altered pharmacokinetics of theophylline with co-administration of CoQ1043 Statin therapy appears to deplete CoQ10 levels.44 Here, CoQ10 supplementation will help.3. Resveratrol: Resveratrol (3,5,4,-trihydroxy-

stilbene), is a polyphenol, found predominantly in grapes and berries, and a signifi cant component of red wine. Resveratrol has multiple benefi cial cardiovascular eff ects, and its use as a nutraceutical for CVD and HF has been highlighted.

Current research has suggested its potential in preventing or regressing defects in cardiac structure and function in experimental models of heart disease. There are strong indications about its potential in preventing or retarding the development of HF,45 and it has an effi cacy of in humans with CVD and HF.46 The administration of resveratrol has been shown to improve outcomes of in animal models of HF induced by myocardial infarction, pressure overload, myocarditis, and chemotherapy-induced cardiotoxicity in animal studies.47 Also, experiments in animal have shown that resveratrol improves cardiac function and survival when co-administered with the treatment for established HF.

Resveratrol acts on the peripheral tissues to improve skeletal muscle and endothelial/vascular function. With resveratrol treatment in mice, there is lessening of cardiac fi brosis and improvement in the molecular and structural remodeling of the heart, diastolic function, vascular function, and energy metabolism.48

4. HSP20: The myocardium makes specifi c peptides including various heat-shock proteins (HSPs) to counteract apoptosis following physical and oxidative stress. In the heart, transient ischemia followed by reperfusion (ischemia/reperfusion, I/R) induces necrosis and apoptosis, leading to myocardial dysfunction. Preservation of myocardial function after I/R depends on critical adaptive responses, some of which are believed to involve the heat-shock proteins (HSPs). The HSPs synthesis arises transiently as a tool to protect cellular homeostasis after exposure to stressful and potentially deleterious stimuli. Thus, HSPs are mediators of myocardial protection, particularly in ischemia and reperfusion injury49.

The heart makes specifi c proteins to counteract heart cell apoptosis. One such protein, HSP20 is known to protect heart muscle cells following physical stress. It also improves the pumping ability of the heart. As the protective functions of HSP20 are required during stress, HSP20 lies dormant in heart cells until when needed. It is then switched on by a process called phosphorylation. The HSP20 regulates activities of vasodilation and platelet aggregation. The increased expression of HSP20 in cardiomyocytes is associated with improved contraction and protection against β-agonist-induced apoptosis.

The cardioprotective eff ects of HSP70 have been shown in isolated animal hearts after global or regional ischemia. Recently, protection against myocardial ischemia has also been shown for the small heat-shock proteins HSP27 and αB-crystallin. The HSP20 shares considerable homology with HSP27 and αB-crystallin, which appear signifi cant in cardioprotection against ischemic injury.49 In studies, the increased HSP20 expression in the heart protects against IR injury, resulting in functional recovery and reduced infarcted area. Thus, outlining the signifi cance of HSP20 in contractile function of heart

Physiological and clinical benefits of CoQ10 Improves NO availability Improves NO availability

Improves endothelial functionImproves endothelial function

Improves LV FunctionImproves LV Function

Decreases ROS & Inflammation Decreases ROS & Inflammation

May Reduce AtherosclerosisMay Reduce Atherosclerosis

Prevents LV HypertrophyPrevents LV Hypertrophy

Decreases LV FibrosisDecreases LV Fibrosis

Improve Overall Functional StatusImprove Overall Functional Status

Improves CVS related QOLImproves CVS related QOL

Reduce Hospitalization and MortalityReduce Hospitalization and Mortality


and cardioprotection.50 The idea is to develop innovative medicines that would ‘switch on’ HSP20 in individuals having a high risk of developing coronary heart disease (CHD) and prevent the disease progression. Certain peptides do the cardio-protective ‘switch on’ and effi ciently boost HSP20. Experimentally, these peptides protect against some of the features of high pressure and improve cardiac function. The data from animal studies, support the hypothesis that this new class of drugs can protect against CHD, cardiac hypertrophy, and heart failure.51

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prevention guidelines in daily practice: a comparison of EUROASPIRE I, II, and III surveys in eight European countries; Lancet 2009; 373: 929–40. Also, see Editorial page 867 and Comment page 873.

2. Kosteva K, David Wood D, Backer GD, et al. For the Euroaspire Group. EUROASPIRE III: a survey on the lifestyle, risk factors and use of cardioprotective drug therapies in coronary patients from 22 European countries. Eur J Cardiovasc Prev Rehabil, 2009 March 12 Epub.

3. Kurth T, Glynn RJ, Walker AM, et al. Myocardial Infarction with Nonsteroidal Anti-inflammatory Drugs; circ.ahajournals.org/ content/108/10/1191.pdf. Circulation 2004.

4. Maroko PR, Kjekshus JK, Sobel BE, Watanabe T, Covell JW, Ross J Jr, Braunwald E. Factors influencing infarct size following experimental coronary artery occlusions. Circulation. 1971; 43: 67–82.

5. Braunwald E, Maroko PR. The reduction of infarct size - an idea whose time (for testing) has come. Circulation. 1974; 50: 206–209.

6. Heusch G, Schulz R, Rahimtoola SH. Myocardial hibernation: a delicate balance. Am J Physiol Heart Circ Physiol. 2005; 288: H984–H999.

7. Shen Y-T, Depre C, Yan L, et al. Repetitive ischemia by coronary stenosis induces a novel window of ischemic preconditioning. Circulation. 2008; 118: 1961–1969.

8. Skyschally A, Schulz R, Heusch G. Pathophysiology of myocardial infarction: protection by ischemic pre- and postconditioning. Herz. 2008; 33: 88–100.

9. Schulz R, Gres P, Skyschally A, et al. Ischemic preconditioning preserves connexin 43 phosphorylation during sustained ischemia in pig hearts in vivo. FASEB J. 2003; 17: 1355–1357.

10. Bolli R, Li QH, Xian-Liang Tang XL, et al. The late phase of preconditioning and its natural clinical application—gene therapy. Heart Failure Reviews; Dec 2007, Volume 12, Issue 3–4, pp 189–199.

11. West MB, Rokosh G, Obal D, et al. Cardiac myocyte-specific expression of inducible nitric oxide synthase protects against ischemia/reperfusion injury by preventing mitochondrial permeability transition. Circulation. 2008; 118: 1970–1978.

12. Rassaf T, Poll LW, Brouzos P, Lauer T, Totzeck M, Kleinbongard P, Gharini P, Andersen K, Schulz R, Heusch G, Mödder U, Kelm M. Positive effects of nitric oxide on left ventricular function in humans. Eur Heart J. 2006; 27: 1699–1705.

13. Heusch G, Post H, Michel MC, Kelm M, Schulz R.

Endogenous nitric oxide and myocardial adaptation to ischemia. Circ Res. 2000; 87: 146–152). But, NO at high concentration triggers inflammation and suppresses contractile function (Schulz R, Kelm M, Heusch G. Nitric oxide in myocardial ischemia/reperfusion injury. Cardiovasc Res. 2004; 61: 402–413.

14. Murphy E, Steenbergen C. Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol Rev. 2008; 88: 581–609.

15. Boengler K, Hilfiker-Kleiner D, Drexler H, et al. The myocardial JAK/STAT pathway: from protection to failure. Pharmacol Ther. 2008; 120: 172–185.

16. Bassi R, Heads R, Marber MS, Clark JE. Targeting p38-MAPK in the ischaemic heart: kill or cure? Curr Opin Pharmacol. 2008; 8: 141–146.

17. Heusch G, Schulz R, Rahimtoola SH. Myocardial hibernation: a delicate balance. Am J Physiol Heart Circ Physiol. 2005; 288: H984–H999.

18. Bolli R, Becker L, Gross G, et al. Myocardial Protection at a Crossroads: The Need for Translation into Clinical Therapy; Circulation Research. 2004; 95:125-134.

19. Mizutani S, Prasad SM, Sellitto AD, et al. Myocyte volume and function in response to osmotic stress: observations in the presence of an adenosine triphosphate-sensitive potassium channel opener. Circulation August 2005; 112 (9 Suppl): I219–23.

20. Gomma AH1, Purcell HJ, Fox KM. Potassium channel openers in myocardial ischaemia: therapeutic potential of nicorandil. Drugs. 2001;61(12):1705-10.

21. Yoshitaka H, Yoshiki S, Shigeaki O, et al. Controlled Nicorandil Administration for Myocardial Protection During Coronary Artery Bypass Grafting Under Cardiopulmonary Bypass. Journal of Cardiovascular Pharmacology: July 2001 - Volume 38 - Issue 1 - p 21–28.

22. Theroux P, Chaitman BR, Danchin N, et al. Inhibition of the sodium-hydrogen exchanger with cariporide to prevent myocardial infarction in high-risk ischemic situations. Main results of the GUARDIAN trial. Guard during ischemia against necrosis (GUARDIAN) Investigators. Circulation. 2000;102:3032–3038.

23. Mentzer, RM Jr, the EXPEDITION Study Investigators. Effects of Na+/H+ exchange inhibition by cariporide on death and nonfatal myocardial infarction in patients undergoing coronary artery bypass graft surgery: The EXPEDITION study. Circulation. 2003;108: 3M.

24. Avkiran M, Marber MS. Na+/H+ exchange inhibitors for cardioprotective therapy: progress, problems, and prospects. J Am Coll Cardiol. 2002;39:747–753.

25. Dana A, Baxter GF, Walker JM, Yellon DM. Prolonging the delayed phase of myocardial protection: repetitive adenosine A1 receptor activation maintains rabbit myocardium in a preconditioned state. J Am Coll Cardiol. 1998;31:1142–1149.

26. Okubo S, Wildner O, Shah MR, Chelliah JC, Hess ML, Kukreja RC. Gene transfer of heat-shock protein 70 reduces infarct size in vivo after ischemia/reperfusion in the rabbit heart. Circulation. 2001;103:877–881.

27. Du X, Patel A, Li X, et al. Treatment and outcomes of acute coronary syndromes in women: An analysis of a multicenter quality improvement Chinese study. International Journal of Cardiology 2017 March 24.

28. Du X, Gao R, Turnbull F, et al. Hospital Quality Improvement Initiative for Patients with Acute Coronary Syndromes in China A Cluster Randomized, Controlled Trial; Circulation Cardiovascular Quality and Outcomes 7(2) March 2014.

29. Gao R, A Patel A, Gao W, et al. Prospective observational study of acute coronary syndromes in China: practice patterns and outcomes. Heart 2008;94:554-560. Assessed on http://heart.bmj.com/ on July 25, 2017.

30. Grassi, D.; Desideri, G.; Croce, G.; Tiberti, S.; Aggio, A.; Ferri, C. Current Pharmaceutical Design 2009 Vol.15 No.10 pp.1072-1084.

31. Erdman Jr.JW, Balentine D, L, et al. Flavonoids and Heart Health: Proceedings of the ILSI North America Flavonoids

Workshop, May 31–June 1, 2005, Washington, DC. 32. Davison K, Coates AM, Buckley JD, Howe PRC. Effect

of cocoa flavanols and exercise on cardiometabolic risk factors in overweight and obese subjects. Int J Obes (2008) 32:1289–96.

33. Tocmo R, Liang D, Yi Lin and Huang D. Chemical and biochemical mechanisms underlying the cardioprotective roles of dietary organopolysulfides; Front. Nutr., 02 February 2015.

34. Han Ling and Chen Keji, Advances in experimental pharmacological studies of effects of astragalus on the cardiovascular system, Chinese Journal of Integrated Traditional and Western Medicine 2001; 7(2): 146-151.

35. Vaduganathan M, Butler J, Pitt B, Gheorghiade M. Contemporary drug development in heart failure: call for hemodynamically neutral therapies. Circ Heart Fail. 2015; 8:826–831.

36. Kobayashi A, Masumura Y, Yamazaki N. L-carnitine treatment of congestive heart failure-experimental and clinical study. Jpn Circ J, 1992 Jan, 56(1) 86-94.

37. Ioannis K, Rizos, Aristoteles N, et al. Haemodynamical effects of L-carnitine on patients with congestive heart failure due to dilated cardiomyopathy. JACC Abstract 339a, 1996.

38. Mortensen SA, Rosenfeldt F, Kumar A, et al. The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: results from Q-SYMBIO: a randomized, double-blind trial. JACC Heart Fail 2014;2:641–9.

39. James J, DiNicolantonio, Jaikrit Bhutani, et al. Review: Coenzyme Q10 for the treatment of heart failure: a review of the literature. Open Heart. 2015; 2(1): e000326. Published online 2015 Oct 19.

40. Belch JJ, Bridges AB, Scott N et al. Oxygen free radicals, and congestive heart failure. Br Heart J 1991;65: 245–8.

41. Mortensen SA, Rosenfeldt F, Kumar A, et al. Q-SYMBIO Study Investigators. The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: results from Q-SYMBIO: a randomized, double-blind trial. JACC Heart Fail. 2014 Dec; 2(6):641-9.

42. Abhinav Sharma, Gregg C. Fonarow, Javed Butler, Justin A. Ezekowitz and G. Michael Felker Circulation: Heart Failure. 2016; 9: e002639, originally published March 24, 2016. July 2017, Volume 10, Issue 7.

43. Baskaran R, Shanmugam S, Nagayya-Sriraman S, et al. The effect of coenzyme Q10 on the pharmacokinetic parameters of theophylline. Arch Pharm Res. 2008; 31:938–944.

44. Berthold HK, Naini A, Di Mauro S, et al. Effect of ezetimibe and simvastatin on coenzyme Q10 levels in plasma: a randomised trial. Drug Saf. 2006; 29:703–712.

45. Wojciechowski P, Louis XL, Thandapilly SJ, et al. Potential of Resveratrol in Preventing the Development of Heart Failure; Current Chemical Biology; VOLUME: 4 ISSUE: 1 Year: 2010 Page: 84 – 88.

46. P Raj, XL Louis, SJ Thandapilly, et al. Potential of resveratrol in the treatment of heart failure. Life Sciences; Volume 95, Issue 2, 30 January 2014, Pages 63-71.

47. Sung MM, Dyck JR. Therapeutic potential of resveratrol in heart failure. Ann N Y Acad Sci. 2015; 1348(1):32-45.

48. Sung MM, Das SK, Levasseur J, et al. Resveratrol Treatment of Mice With Pressure-Overload–Induced Heart Failure Improves Diastolic Function and Cardiac Energy Metabolism. Circulation: Heart Failure. 2015; 8:128-137.

49. Fan GC, Ren X, Qian J, et al. Heart Failure: Novel Cardioprotective Role of a Small Heat-Shock Protein, Hsp20, Against Ischemia/Reperfusion Injury; Circulation. 2005; 111:1792-1799.

50. Fan GC, Kranias EG. Review Article: Small heat shock protein 20 (HspB6) in cardiac hypertrophy and failure; Journal of Molecular and Cellular Cardiology Volume 51, Issue 4, Oct 2011; 574-577.

51. Simpson PC. Where are the new drugs to treat heart failure? Introduction to the special issue of ‘key signaling molecules in hypertrophy and heart failure.’ J Mol Cell Cardiol. 2011; 51(4):435-7.

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Prehypertension: What to Do?

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A. K. PANCHOLIA

Keywords prehypertension cardiovascular risk lifestyle chronic kidney disease JNC-7

Dr. A. K. Pancholia, HOD-Medicine & Preventive Cardiology, Arihant Hospital & RC, Gumashta Nagar, Indore

AbstractPrehypertension (PHTN) is a global health problem that carries the risk of developing hypertension in future along with the risk of cardiovascular disease (CVD) which could be almost double. Its prevalence is 25-50% based on data from different countries, and it varies with age, sex, birth weight and BMI. Regarding its pathophysiology, several mechanisms have been proposed but most validated are RAS activation, oxidative stress, infl ammatory cytokines, sympathetic over drive and central nervous system activation. Therapeutic lifestyle changes are the foundation for all therapies in pre-hypertensive patients, which are recommended by all guidelines. Drug therapy has also been tried in a couple of trials and is recommended in high-risk patients.

HISTORY AND INTRODUCTIONIn 1939 Robinson and Brucer suggested the value of clinically overt hypertension when the levels are 120-139 mmHg (systolic) and 80-89 mmHg (diastolic).1 Three decades later it was termed as “borderline hypertension”,2 then in 1997 it was changed to “high-normal blood pressure”.3 The term “prehypertension” was coined in 2003 by the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7).1 This is to identify those individuals in whom early intervention by healthy lifestyles could reduce BP and reduce the rate of converting from PHTN to hypertension. Prehypertension precedes clinical hypertension and is associated with increased incidence of cardiovascular disease.2-4

DEFINITIONPrehypertension is defined as a systolic

blood pressure of 120–139 mmHg and a diastolic blood pressure of 80–89 mmHg. Later on, European Society of Cardiology (ESC) and European Society of Hypertension (ESH) bifurcated it to normal (120-129 mmHg systolic and 80-84 mmHg diastolic) and high normal (30-139 mmHg systolic and 85- 89 mmHg diastolic). The ESH-ESC committee decided against using the term “prehypertension” for several reasons--.1. There is no reason to combine the two

diff erent groups because the risk of developing hypertension was higher in those with high-normal BP than in patients with normal BP

2. The term “prehypertension” can create anxiety in many subjects along with unnecessary medical visits and tests

3. Although lifestyle changes have been recommended by JNC VII for all PHT, this category is a highly diff erentiated one, with the extremes


Overweight/Obese

PREVALENCE IN INDIAIn a study from northern India, the reported prevalence of prehypertension is 44%8 whereas a study in urban Chennai indicated a 47% prevalence of prehypertension in adults >18 years.9 In another study, the reported prevalence is 40% in males and 30 % in females.10 The state-wise prevalence in India is shown in Figure 1. RISK FACTORS

Overweight or obese Age: ...More in young Sex: M>F Black race Family history Lack of exercise Diet high in salt (sodium) or low in

potassium Tobacco use Alcohol

WHY CARE FOR PREHYPERTENSIONPatients with PHTN are at twice the risk of developing hypertension.11 Prehypertension is associated with increased cardiovascular risk. According to Framingham study, there is increased the risk of MI by 3.5 fold, increased risk of CAD by 1.7 fold.11 (Figure 2)

Results from Strong Heart Study showed increased risk of CV events when prehypertension is associated with diabetes compared to diabetes or prehypertension alone.12 (Figure 3)

The study also showed that 37% of prehypertensives would progress to

consisting of subjects with no need of any intervention

PREVALENCE The National Health and Nutrition Examination Survey (NHANES) 1999-2000 reported that the overall incidence of prehypertension was 31% all over the world, which was higher in men than in women.5 A statistical analysis of disease-free adult NHANES participants which was conducted from 1999 to 2006 found that the overall prevalence of PHTN in disease-free adults was 36.3%.6

Prevalence increases in people with7 Diabetes Microalbuminuria

Chronic kidney disease Heavy alcohol consumption

Figure 1. State-wise prevalence of PHTN in India

Figure 3. Strong Heart Study Source: Ruilope Dia Care (2009)

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Figure 2. PHTN and CV risk Source: JAMA (2002)

PHT is associated with increase in CV risk


reduction in weight Consume more fruits and vegetables

in diet; this is supposed to reduce

SBP by 8 to 14 mmHg Restrict sodium to no more than 6 g

of table salt per day; this is expected

hypertension over the next four years. There is two-fold increased the risk of diabetes in PHTN. Compared with a normal blood pressure, prehypertension is associated with a 27% increase in all-cause death and a 66% increase in cardiovascular deaths.13

Analysis from CARDIA study suggests that prehypertension in early adulthood leads to increased coronary calcium later in life.14 PHTN is also associated with increased carotid intima thickness.15 There is increase in left ventricular mass index also with PHTN16 (Figure 4).

It is associated with increased risk of chronic kidney disease (CKD).17 The study showed worsening of renal function by 11 to 91% in prehypertensive individuals. Pre-existing diabetes showed a strong relationship between PHT and CKD risk. The underlying pathophysiology for development of CKD is the greater degree of renal arteriosclerosis and mesangial proliferation in prehypertensives.17 High normal BP is associated with poor cognitive performance. The relationship between blood pressure and cognitive performance is linear, even in normotensive and prehypertensive ranges.18 PHTN also predict pregnancy-induced hypertension (PIH) and its postpartum progression.19 PHTN is linked with metabolic syndrome and CVD (Figure 5).

PATHOPHYSIOLOGYMany hypotheses are proposed to explain the underlying pathophysiology of PHT.

RAAS activation Oxidative stress Infl ammation SNS activation Central Mechanism

PREHYPERTENSION: WHAT TO DO?Therapeutic Lifestyle ChangesPractically all the guidelines, previous,20 and recent guidelines21 recommend specifi c lifestyle modifi cations for PHTN. The most recent recommendations (JNC7 report)22 are as follows:

Maintain BMI between 18.5 and 24.9 kg/m2; this is expected to reduce SBP by 5 to 20 mmHg for each 10 kg

Figure 4. PHTN and LV Mass Index

Figure 5. Cardio metabolic syndrome and link with CVD

Source: Expert Rev Cardiovasc Ther (2013)

Source: International Journal of Hypertension (2015).

Table 1: JNC RecommendationPrehypertension Lifestyle ChangesPrehypertension Lifestyle Changes

Items Modifications Effects on PressureItems Modifications Effects on Pressure

Sodium intake Allowable maximum is 2.4g of sodium 5.1/2.7 mmHg for 1800Sodium intake Allowable maximum is 2.4g of sodium 5.1/2.7 mmHg for 1800

Or 6 grams of sodium chloride mg/day sodium reduction Or 6 grams of sodium chloride mg/day sodium reduction

Weight loss Maintain normal body weight (Body 1.1/0.9 mmHg for 1kgWeight loss Maintain normal body weight (Body 1.1/0.9 mmHg for 1kg

Mass index 18.5 to 24.9), per kg lost. Weight loss Mass index 18.5 to 24.9), per kg lost. Weight loss

Alcohol Limit to 2 drinks/day men (1 drink/day 2 to 4 mmHgAlcohol Limit to 2 drinks/day men (1 drink/day 2 to 4 mmHg

Women & lightweight persons). Women & lightweight persons).

Exercise Do 30 minutesof aerobic exercise for 4 4.9/3.7 mmHg for 120 to 150Exercise Do 30 minutesof aerobic exercise for 4 4.9/3.7 mmHg for 120 to 150

to 7 days a week. Minutes/week of exercise to 7 days a week. Minutes/week of exercise

Healthy diet Take diet rich in fruits, vegetables 11.4/5.5 mmHgHealthy diet Take diet rich in fruits, vegetables 11.4/5.5 mmHg

Abdominal obesity

Insulin resistance

Prediabetes TriglyceridesHDL-C

Inflammation

HypertensionPrehypertension

Cardiovascular disease


to reduce SBP by 2 to 8 mmHg Brisk walk at least 30 min per day or

regular aerobic physical activity; this is expected to reduce SBP by 4 to 9 mmHg

Reduce alcohol consumption; this reduces SBP by 2 to 4 mmHg (Table 1).

Dietary Approaches to stop hypertension (DASH) diet plan23 (Table 2) which uses a diet rich in fruits, vegetables, legumes, nuts, and low-fat dietary products and low in saturated fats, have a signifi cant lowering of BP.

DASH diet can reduce BP by 8-14 mmHg, an eff ect that was augmented even further when dietary sodium was restricted. The Omni Heart Collaborative Research Group study24 in which the DASH diet was modifi ed to provide more protein and unsaturated fat and less carbohydrate showed impressive reductions of BP.

The TOHP I and TOHP II trials,25 (Figure 6) showed that dietary sodium reduction for 18 months (TOHP 1) or 36-48 months (TOHP 2) reduce the primary endpoints (myocardial infarction, stroke, coronary revascularization, or cardiovascular-related death) in middle-aged individuals with prehypertension

by 25% lower compared to placebo group.

PREMIER trial26 demonstrated that multicomponent behavioral interventions with and without the DASH diet produced signifi cant reductions in the 10-year risk of coronary heart disease in subjects with PHTN.

PHARMACOTHERAPYThe primary approach to treat PHTN is therapeutic lifestyle changes, which has been recommended by several guidelines. Pharmacotherapy is recommended

mainly in high-risk group with CVD and CKD. But still, there is no consensus. Few trials have been done with diff erent pharmacological agents with mixed results. TROPHY study evaluated the effect of the angiotensin II receptor antagonist candesartan cilexetil on the prevention of prehypertension to stage 1 hypertension.27 (Figure 7)

After four years, stage 1 hypertension developed in two-thirds of patients in placebo group while in intervention group there was 66% reduction in the risk of development of incident hypertension.

PHARAO study is the prevention of hypertension with the angiotensin-converting enzyme inhibitor Ramipril in patients with high-normal blood pressure - a prospective, randomized, controlled prevention trial of the German Hypertension League.28 The study showed signifi cantly reduced the risk of progression to manifest hypertension by 34.4 %.

PREVER prevention trial is the combination of chlorthalidone and Amiloride in prehypertensive patients that eff ectively reduces the risk of incident hypertension and benefi cially aff ects left ventricular mass. After 18 months the incidence of hypertension was 11.7% in the diuretic arm versus 19.5% in the placebo arm.29

Follow-up of Prehypertensive PatientsSubjects with PHTN be treated and

Figure 6. Cumulative incidence of CVD by sodium intervention group in TOHP I and II trials

Sodium Intervention

Control

TOHPI

Cu

mla

tive

inci

den

ce o

f C

VD

Cu

mla

tive

inci

den

ce o

f C

VD TOHP II

0.20

0.16

0.12

0.08

0.04

0

0.10

0.08

0.06

0.04

0.02

0 0 2 4 6 8 10 12 14 16

Follow-up (Years)Source: BMJ (2007)

Figure 7. Trophy: Reduction in new onset hypertension

Source: N Engl J Med. (2006)

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evaluated every month or two until the blood pressure goal is reached and then every 3-6 months after that. Subjects with complications/end organ damage such as heart or kidney disease may need to be evaluated more frequently at regular intervals.

CONCLUSION Prehypertension is a common

problem in the community. Prevalence is on the rise. It is associated with increased risk of

hypertension, target organ damage, and CVD.

Healthy lifestyle is the foundation for all therapies in persons with prehypertension.

Drug therapies are several, but there is no convincing evidence that antihypertensive treatment changes the course of prehypertension.

REFERENCES1. Robinson SC, Brucer M. Range of normal blood pressure:

a statistical and clinical study of 11,383 persons. Arch Int Med 1939; 64: 409.

2. Julius S, Schork MA. Borderline hypertension--a critical review. J Chronic Dis 1971; 23: 723-754.

3. The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med 1997; 157: 2413-2446.

4. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, Jones DW, Materson BJ, Oparil S, Wright JT,

Roccella EJ. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003; 289: 2560-2572.

5. Y. Wang and Q. J. Wang, “The prevalence of prehypertension and hypertension among US Adults According to the New Joint National Committee Guidelines: new challenges of the old problem,” Archives of Internal Medicine.2004;164(19):2126–2134.

6. A. K. Gupta, M. McGlone, F. L. Greenway, and W. D. Johnson, “Prehypertension in disease-free adults: a marker for an adverse cardiometabolic risk prole,” Hypertension Research. 2010;33 (9):905–910.

7. Glasser SP, Judd S, Basile J, et al. REGARDS Study. Am J Hypertens. 2010;24(2):194-9.

8. Prabhakaran D, Shah P, Chaturvedi V, Ramakrishnan L, Manhapra A, Reddy KS. Cardiovascular risk factor prevalence among men in a large industry of northern India. Natl Med J India. 2005;18:59-65.

9. Yadav S, Boddula R, Genitta G, Bhatia V, Bansal B, Kongara S, et al. Prevalence & risk factors of pre-hypertension & hypertension in an affluent north Indian population. Indian J Med Res. 2008;128:712-20.

10. Gupta R, et al. Normotension, prehypertension, and hypertension in urban middle-class subjects in India: prevalence, awareness, treatment, and control. American Journal of Hypertension. 2013;26(1):83-94.

11. Vasan RS, et al. The Framingham Study. JAMA. 2002;287:1003-1010.

12. Julian Segura, and Luis M. Ruilope. The Strong Heart Study. Dia Care. 2009;32:S284-S289.

13. Urbina EM, Khoury PR, McCoy C, et al. Cardiac and vascular consequences of pre-hypertension in youth.The Journal of Clinical Hypertension.2011;13(5):332-342.

14. Pletcher MJ, Bibbins-Domingo K, Lewis CE, et al. Prehypertension during young adulthood and coronary calcium later in life. Ann Intern Med. 2008;149:91-99.

15. Bidhan Ch. Mandal, Md. et al. IOSR Journal Of Pharmacy (e)-ISSN: 2250-3013, (p)-ISSN: 2319-4219

16. Terek M Mousa et al. Correlation of Prehypertension with Left Ventricular Mass Assessed by Cardiac

Magnetic Resonance Imaging. International Journal of Hypertension.2015;2015:742658. doi: 10.1155/2015/742658.

17. Kidney Int 2010 International Society of Nephrology18. Stefan Knecht et al. High-normal blood pressure

is associated with poor cognitive performance. Hypertension. 2008;51:663-668.

19. Shintaro Makino et al. Hypertension Research in Pregnancy Vol. 1 (201) No. 2 p. 71-74

20. The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med. 1997;157: 2413-2446.

21. Egan BM, Nesbitt SD, Julius S. Prehypertension: should we be treated with pharmacologic therapy? Ther Adv Cardiovasc Dis. 2008;2: 305-314.

22. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, Jones DW, Materson BJ, Oparil S, Wright JT, Roccella EJ. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560-2572.

23. Sacks FM, Svetkey LP, Vollmer WM, Appel LJ, Bray GA, Harsha D, Obarzanek E, Conlin PR, Miller ER, Simons Morton DG, Karanja N, Lin PH. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. N Engl J Med 2001;344:3-10.

24. Appel LJ, Sacks FM, Carey VJ, Obarzanek E, Swain JF, Miller ER, Conlin PR, Erlinger TP, Rosner BA, Laranjo NM, Charleston J, McCarron P, Bishop LM. Effects of protein, monounsaturated fat, and carbohydrate intake on blood pressure and serum lipids: results of the OmniHeart randomized trial. JAMA 2005;294:2455-2464.

25. Stevens VJ, Corrigan SA, Obarzanek E, Bernauer E, Cook NR, Hebert P, Mattfeldt-Beman M, Oberman A, Sugars C, Dalcin AT. Weight loss intervention in phase 1 of the Trials of Hypertension Prevention. The TOHP Collaborative Research Group. Arch Intern Med 1993;153:849-858.

26. Appel LJ, Champagne CM, Harsha DW et al, Effects of comprehensive lifestyle modification on blood pressure control: main results of the PREMIER clinical trial. JAMA 2003; 289: 2083-2093

27. S.Julius,S.D.Nesbitt,B.M.Eganetal. Feasibility of treating prehypertension with an angiotensin-receptor blocker. New England Journal of Medicine. 2006;354(16):1685–1697.

28. Lüders S, Schrader J, Berger J et al ; PHARAO Study Group. J Hypertens. 2008;26(7):1487-96.

29. Sandra Costa Fuchs et al. Effectiveness of Chlorthalidone Plus Amiloride for the Prevention of Hypertension: The PREVER Prevention Randomized Clinical Trial. J Am Heart Assoc. 2016;5:e004248.

Table 2. DASH Diet planHigh in Low inHigh in Low in

Fruits and vegetables (4/5 servings each/day) Saturated fatFruits and vegetables (4/5 servings each/day) Saturated fat

Fiber (7/8 servings /day) CholesterolFiber (7/8 servings /day) Cholesterol

Low-fat dairy products (2-3 servings/day) Fat Low-fat dairy products (2-3 servings/day) Fat

Lean meat (2 servings/day) Lean meat (2 servings/day)

Calcium, magnesium, potassium Calcium, magnesium, potassium


Algorithm of Management of Type-2 Diabetes –India Specifi c

REVIEW ARTICLE

RAJEEV CHAWLA, SHALINI JAGGI

Keywords type 2 diabetes cardiovascular risk euglycemia hyperglycemia lifestyle management HbA1c microvascular macrovascular complication individualized therapy

Dr. Rajeev Chawla is Senior Consultant Diabetologist, Director, North Delhi Diabetes Centre and Dr. Shalini Jaggi is Consultant Diabetologist and Head Dr.Mohans' Diabetes, Specialities Centre, New Delhi

AbstractSeveral countries and International bodies have proposed several algorithms; however, no recent updated management algorithm is available for Asian Indians. Specifi cally, algorithms developed and validated in developed nations may not be relevant or applicable to patients in India because of several factors: early age of onset of diabetes, the occurrence of diabetes in nonobese and sometimes lean people, differences in the relative contributions of insulin resistance and -cell dysfunction, marked postprandial glycemia, frequent infections including tuberculosis, low access to healthcare and medications in people of the low socioeconomic stratum, ethnic dietary practices (e.g., ingestion of high-carbohydrate diets), and inadequate education regarding hypoglycemia. All these factors should be considered to choose the appropriate therapeutic option in this population. The proposed algorithm is simple, suggests less expensive drugs, and tries to provide an effi cient and comprehensive framework for delivery of diabetes therapy in primary care in India.

INTRODUCTIONIndia today has the dubious distinction of being the ‘diabetic capital of the world’ with 69.2 million known diabetics in 2015 and a projected number of more than 123.5 million by 2040 as per the IDF estimates (IDF Diabetes Atlas, 7th edition, 2015. Diabetes has globally assumed epidemic proportions with its monumental load of microvascular as well as macrovascular complications and comorbidities resulting in a huge social as well as economic burden of the disease.

This load can be minimized by early screening as well as optimal management of diabetes and even prediabetes, and most of the life-changing complications can be prevented with an early and aggressive intervention to control hyperglycemia.

An ideal diabetes management strategy aims at not only treating the acute symptoms of hyperglycemia but also maintaining euglycemia with minimal glycemic excursions to prevent/delay the development of various diabetic complications and restoring the quality of


life of patients. Treatment should also work to preserve beta cell function and stop or slow the rate of apoptosis to delay the natural progression of the disease characterized by an inevitable decline in insulin secretion. Lifestyle management, weight loss in overweight/obese patients, regular exercise with an increase in physical activity and a healthy diet through medical nutrition therapy form the backbone of any diabetes treatment strategy. Pharmacotherapy using oral or injectable agents may be used in addition to lifestyle modifi cation therapies to achieve a target glycosylated hemoglobin target of less than 7% for all diabetic patients as far as possible to prevent complications.

A better understanding of the multiple pathophysiologies of type 2 diabetes along with the introduction of new drugs with evolving times has led to an era of pathophysiology-based pharmacotherapeutic approach to the management of hyperglycemia. Several guidelines all across the world provide diff erent treatment algorithms on ways in which these glucose-lowering agents can be used either alone or in combination. This review is based on consensus developed by the Research Society for the Study of Diabetes in India adapted from the IDF Guidelines 2014 that was subsequently published in October 2015 in IJJDC October 2015.1

PHARMACOTHERAPEUTIC APPROACH IN THE MANAGEMENT OF HYPERGLYCEMIAGlucose lowering medications may be started when lifestyle interventions alone are unable to maintain blood glucose control at target levels. It is necessary to continue lifestyle measures all along the management algorithm along with medical nutrition therapy alongside pharmacotherapy. The choice of medication should be based on individual needs of the patient with adequate consideration is given to the cost-benefi t ratio of each agent along with its effi cacy and pharmacological action. Each initiation or dose increment may be monitored for response in 2-3 months and ineff ective therapies may be discontinued

if needed. Therapy decision should also take into consideration hypoglycemia, the eff ect on weight as well as the adverse event profi le of the agent besides the pathophysiology it addresses.

First-line oral therapy– Begin therapy with metformin unless

there is evidence of renal impairment or any other contraindication

– Titrate the dose over early weeks to minimize discontinuation due to gastrointestinal intolerance

– Monitor renal function and use metformin with caution if estimated glomerular fi ltration rate (eGFR) < 45 ml/min/1.73 m2

– Other options include initiating with a sulfonylurea (or glinide) for rapid response where glucose levels are high, or a DPP-4 inhibitor or alpha-glucosidase inhibitor- these agents can also be used initially in place of metformin where it is not tolerated or is contraindicated.

– In some circumstances dual therapy may be indicated right for initiation where a single agent alone is unlikely to achieve glucose targets, underlining the need for an early aggressive approach to intensify glycemic control to prevent the ‘legacy eff ect’ and ensuing complications of prolonged hyperglycemia.

Second-line therapy– When glucose control targets are not

being achieved, add a sulfonylurea– Other options include adding

metformin if not used fi rst-line, α-glucosidase inhibitor, a dipeptidyl peptidase 4 (DPP-4) inhibitor or a thiazolidinedione based on the individual profi le of the patient.

– A Nonsulfonylurea insulin secret-agogue (glinides) is an alternative option to sulfonylurea especially if there is predominantly postprandial hyperglycemia.

– SGLT2 inhibitors can also be considered as second-line agents when weight and hypoglycemia are major concerns as well as their proven cardiovascular safety in type 2 diabetic patients with cardiovascular disease.

– GLP1 analogues are the good choice due to their effi cacy as well as multiple pleiotropic benefi ts of weight loss properties, less hypoglycemia, reduced appetite and cardioprotection, but due to their high cost, GI intolerance and mode of administration (injectable), they are prescribed as second-line agents to a very niche set of patients in India.

Third-line therapy– When glucose control targets are

no longer being achieved with two agents, it is recommended to either start insulin or add a third agent

– If starting insulin, add basal insulin or use premix insulin

– If adding third oral agent options include a α-glucosidase inhibitor, a DPP-4 inhibitor, an SGLT2 inhibitor or a thiazolidinedione

– Another option is to add a GLP-1 analog

– Since 2014 DCGI has approved Hydroxy Chloroquine as an adjuvant to diet and exercise to aid in glycemic control in type-2 Diabetes patients in addition to Metformin and Sulfonylurea dual therapy.

Fourth-line therapy– Begin insulin therapy in combination

with a sensitizing agent (metformin or glitazone) when optimized oral blood glucose lowering medications (and GLP-1 analogs) and lifestyle interventions are unable to maintain target glucose control

– Intensify insulin therapy in patients already using insulin

CONSIDERATIONSThe decision on the choice of OAD therapy in T2DM patients should be based on the cost and effi cacy factors in Indian context besides their effi cacy and other actions.

RATIONALE AND EVIDENCEAnti-Diabetic agents

Biguanide: Metformin remains the fi rst-line type 2 diabetes drug due to its effi cacy as well as properties such as weight neutrality and low


cost and no major adverse eff ects such as hypoglycemia etc. It works by reducing hepatic glucose output thus working as an excellent insulin sensitizer.2-3 Metformin is associated with initial gastrointestinal side eff ects, and caution also needs to be taken to avoid its use in patients at an increased risk for lactic acidosis (e.g., those with advanced renal insuffi ciency, alcoholism, hypoxemic states, etc). Anti-proliferative as well as cardiovascular benefi ts of this drug have also been reported although robust clinical trial data is still awaited.

Sulfonylurea: It is the oldest oral hypoglycemic agent class available and is characterized as insulin secretagogues. Sulfonylurea agents cause closure of ATP-sensitive potassium channels in beta cells thus stimulating insulin release.4 Although, they are useful in controlling glucose levels, their use is associated with modest weight gain and increased risk of hypoglycemia. The modern sulfonylureas particularly Gliclazide MR and glimepiride have a lower risk of hypoglycemia than the older generation agents such as glibenclamide and are recommended as preferred sulfonylureas to be used. Glibenclamide should be used only in case of non-availability of these agents. Studies have demonstrated increased chances of secondary failure with these agents probably due to an exacerbation of islet dysfunction over time.5 Shorter-acting secretagogues, the meglitinides (commonly called glinides), also stimulate insulin release through similar mechanisms (acting at a diff erent site away from the sulfonylurea site) but are associated with comparatively less hypoglycemia, though they require more frequent dosing.6

Thiazolidinediones (TZDs): TZDs or glitazones are peroxisome proliferator-activated receptor γ activators6 that improve insulin sensitivity in skeletal muscle and reduce hepatic glucose production.2-3 The risk of hypoglycemia is negligible with these agents,

and they are more durable than sulfonylureas and metformin in their eff ects.5 Pioglitazone demonstrated pleiotropic eff ects on cardiovascular events as a secondary outcome in one large trial involving patients with overt macrovascular disease.7-8 Recently pioglitazone was controversially linked with a possible increased risk of bladder cancer9 though it was not substantiated. Data from a retrospective study in India involving 2222 T2DM patients including patients with age >60 years, duration of diabetes> 10 years and uncontrolled diabetes (1111 pioglitazone users and 1111 pioglitazone non-users) found no evidence of bladder cancer in any group.10 The commonly recognized side eff ects of TZDs include weight gain, increased risk of bone fractures, fl uid retention leading to edema and increased incidence of heart failure in predisposed individuals.5-8

Incretin-based therapies: The injectable GLP-1 receptor agonists (incretin mimetics) mimic the eff ects of endogenous GLP-1, thereby stimulating pancreatic insulin secretion in a glucose-dependent fashion. They also suppress pancreatic glucagon output, slow gastric emptying and reduce appetite. Their main advantage is weight loss, which ranges from modest to signifi cant in most patients. A limiting side eff ect is a nausea and vomiting, particularly early in the course of treatment. There have been concerns regarding an increased risk of pancreatitis, but recently published ELIXA study & LEADER study did not show any increased risk of pancreatitis, pancreatic cancer or thyroid cancer with lixisenatide11 or Liraglutide12

The dipeptidyl peptidase IV (DPP-4) inhibitors or Incretin enhancer therapies enhance circulating concentrations of active GLP-1 and gastric inhibitory polypeptide (GIP) by preventing their immediate degradation by the DPP-4 enzyme.13,14 Their primary eff ect appears to be in

the regulation of insulin and glucagon secretion; besides being oral agents, they are weight neutral. Recent cardiovascular studies with DPP-4 inhibitors have shown that these agents do not increase CV risk.15-17 Typically, none of the incretin-based classes cause hypoglycemia by themselves.

Sodium-glucose cotransporter 2 (SGLT2) Inhibitors: SGLT2 inhibitors provide insulin-independent glucose lowering by blocking SGLT2 receptors thus inhibiting increased glucose reabsorption in the proximal renal tubule. These agents also produce modest weight loss and blood pressure reduction. Although there are three FDA approved agents for use in patients with type 2 diabetes, there is insuffi cient data to recommend clinical use in type 1 diabetes at this time.18 SGLT2 inhibitors have the potential to reduce CV risk in patients with T2DM not only through optimization of glycemic control, but also via benefi cial eff ects on body weight, BP, lipids, and serum uric acid.19-20

Other Agents: Two agents that are infrequently used in the management of type 2 diabetes are α-glucosidase inhibitors (AGIs), which retard gut carbohydrate absorption,21 and colesevelam, a bile acid sequestrant whose mechanism of glucose-lowering action remains poorly understood with its signifi cant additional benefi t of LDL-cholesterol reduction.22 Both have gastrointestinal eff ects, main fl atulence with AGIs and constipation with colesevelam. The dopamine agonist bromocriptine (quick release formulation) is also available as an anti-hyperglycemic agent that supposedly acts by mimicking the morning surge of Dopamine.23 Its mechanism of action and precise role are unclear. Another agent, the amylin agonist, pramlintide (not available in India), is typically reserved for patients treated with intensive insulin therapy, usually in type 1 diabetes mellitus; it decreases postprandial glucose excursions by

REVIEW ARTICLE


inhibiting glucagon secretion and slowing gastric emptying.24

The glucose-lowering eff ect of non-insulin pharmacological agents is said to be high with metformin, sulfonylureas, TZDs and GLP-1 agonists (expected HbA1c reduction ~1.0–1.5%),25-27 and comparatively lower for meglitinides, DPP-4 inhibitors, SGLT2 Inhibitors, AGIs, colesevelam and bromocriptine (~0.5–1.0%). However, older drugs have typically been tested in clinical trial participants with higher baseline HbA1c, which is associated with greater treatment-emergent glycemic reductions, irrespective of therapy type. In head-to-head trials, any diff erential eff ects on glucose control are small. So agent- and patient-specifi c properties, such as ease of administration, dosing frequency, side-eff ect profi les, cost and other benefi ts often help in their selection.

INDIVIDUALIZING THERAPYABCD (EFGH) approach for diabetes management as proposed in “RSSDI Therapeutic Wheel”1

Choice of any anti-diabetic agent should

take into account the patient’s general health status and associated medical disorders. This patient-centric approach may be referred to as the ABCD (EFGH) approach for diabetes management. As shown in the Figure 1, for any T2DM patient fi rst line of therapy should be Metformin unless not tolerated or contraindicated.

INDIVIDUALIZED TREATMENT For an individual who has been

diagnosed with diabetes, consider a combination of metformin and one of these treatment options based on the following parameters- age, BMI, CKD, duration of diabetes, established CVD, fi nancial condition, glycemic status and Hypoglycemia concern.

Drug choice should be based on patient preferences as well as the presence of various comorbidities, complications, and drug characteristics, with the goal of reducing blood glucose levels and minimizing side eff ects, especially hypoglycemia and weight gain.

A comparative eff ectiveness meta-analysis1 suggests that overall each new class of noninsulin agents added

to initial therapy lowers HbA1c around 0.9–1.1%.27

AGE• Estimated Glomerular Filtration Rate

(eGFR) adjusted doses of gliptins may be a suitable addition to metformin for elderly patients in whom one will like to avoid hypoglycemia and weight gain.28

• Agents belonging to AGI could also be important choice in elderly patient. These agents have moderate effi cacy but minimal side eff ects.

• In elderly males, glitazones may be a safer alternative in patients with preserved cardiac function. However, post-menopausal females must be spared for its use because of high predisposition to osteoporosis.

• While SU’s, glucagon-like peptide-1 receptor agonists (GLP-1 RA), SGLT2 inhibitors or Glinides should emerge as the last choice since there are adverse eff ects as well as premium price associated with these agents. Risk benefi ts ratio must be properly evaluated before using them.

BMI• GLP-1 RA seems to be the best add-

on therapy for those having high BMI. This group of medications has the highest weight reducing property in addition to the excellent effi cacy

• SGLT 2 inhibitors also have a weight reduction property albeit less than that of GLP-1 RA. The medicines in this group have an additional advantage of excellent tolerance and can be given orally as compared to GLP-1 RA. However, their glycemic effi cacy seems to be less than that of GLP-1 RA. The experience with this group of agents is less than that with GLP-1 RA.29

• AGIs and Gliptins are weight neutral and so can be used as the third line of agents.

• The last option for such kind of patients should be SUs, insulin or glitazones since they have weight gain properties.

Su – Sulfonyl UreaSu* - Preferably Glimiperide or GliclazideSuS – Short acting Sulfonyl ureasI – InsulinIc – Conventional Insulins Ia – Insulin AnaloguesIaS– Short Acting Insulin analoguesD – DPP4 inhibitorsD-L – LinagliptinP – PioglitazoneP* - Pioglitazone if EF > 40% Sg – SGLT2 InhibitorsA –Alphaglucosidase InhibitorsG – GLP AnaloguesGl – Glinides

From Innermost to Outermost : A Age = Advancing Age; B BMI = Increasing BMI; C CKD = Advancing CKD; D Duration of Diabetes = Increasing Duration; E Established CVD = Low CVD risk to Established CVD Risk; F Finance = Adequate to Limited; G Glycemic Status = Worsening glycemic control; H Hypoglycemia = Hypoglycemia concern

Lesser Options available

Wider Options available

Figure 1. RSSDI Diabetes Therapeutic Wheel


CHRONIC KIDNEY DISEASE (CKD)• In the same manner, if we focus on

complications (renal impairment) preference of therapy would be Gliptins as add-on therapy with metformin.30

• Few of the gliptins need dose adjustment as per eGFR while Vildagliptin needs a dose adjustment in hepatic insuffi ciency. Linagliptin does not require any dose adjustment in renal disease.

• Repaglinide is another agent which may be used across all stages of renal insuffi ciency. Similarly, glitazones may be used in CKD. However, one has to be careful about fl uid retention.

• Short-acting sulfonylurea and AGI’s may also be used across renal insuffi ciency; however, hypoglycemia is a huge limiting factor.

• Insulin may be used in any stages of renal insuffi ciency and is the best agent for this purpose.

DURATION OF DIABETES• As results of recent trials have

suggested utilizing an aggressive approach in cases where the duration of diabetes is less than fi ve years, SU or glinide, as an add-on therapy to metformin, will be the best choices, being very potent agents. Addition of glitazones may be useful at this stage.31

• GLP-1 RA may score over gliptins for this indication as they are more effi cacious than gliptins.

• SGLT-2 inhibitors may be used as the second add-on agent due to their independent insulin action which is pathophysiologically diff erent.

• Gliptins and AGIs are last choices due to their moderate effi cacy. However, they may be used as add-on agents at any stage after triple-drug fails.

ESTABLISHED CVD• In patients with established CVD,

DPP4 inhibitors may be preferred agents after Pioglitazone, SGLT inhibitors and AGIs because of low risk of hypoglycemia. GLP1 analogs may be a suitable alternative for patients who are overweight or obese.

AGIs may be preferred in patients with postprandial hyperglycemia.

• Pioglitazone has also been shown in diff erent studies to reduce CVD risk.

• Recent data from Empaglifl ozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes study has shown that SGLT inhibitors reduce CV risk and CV mortality, and may be preferred.

FINANCIAL CONDITION• Cost of therapy also plays an essential

role considering the treatment remains continued lifelong.

• SUs should be the fi rst choice with metformin by considering its cost, then after AGI’s or Glitazone should be used at next therapy level,32 in the next level the therapeutic option should be Glinides or Insulin.

• High cost will prevent the use of insulin analogs, Gliptins, SGLT2 inhibitors and GLP-1 RA in most of the patients.33

GLYCEMIC STATUS• Good Glycemic control of patients is

directly correlated with the effi cacy of any anti-diabetic agent.

• Insulin followed by GLP-1RA, SUs and glitazones have the highest effi cacy regarding reducing HbA1c.34

• Gliptins, SGLT2i or AGIs should be considered as add-on therapy if these agents are not able to achieve glycemic targets.

• It is always to be understood that suitable effi cacy, in most cases, comes with a price written on it in the form of increased incidence of hypoglycemia or prohibitive cost.

HYPOGLYCEMIA CONCERN• Hypoglycemia is the most signifi cant

hurdle that any medical fraternity is facing during treatment course of diabetes.

• In patients with history of hypoglycemia or for those at high risk of hypoglycemia, GLP-1RA or gliptins should be considered as the fi rst choice with other options include SGLT2 inhibitors, glitazones, and AGIs.35

• Last option for such patients should be either glinides, SU’s or Insulin since there are high chances of hypoglycemia with these agents.

• Group of patients where one will require avoiding hypoglycemia include:• those with established CV disease• elderly patients• hose suff ering from retinopathy

and cannot perform SMBG without the help of others

• those who stay alone, especially in remote areas

• those who are having poor longevity

• those who are having documented hypoglycemia unawareness

• those who met with severe symptomatic hypoglycemia requiring hospitalization

How to use the RSSDI Diabetic Therapeutic Wheel?• RSSDI therapeutic wheel is designed

to be a simple, user-friendly approach to decide the appropriate antidiabetic agent to be used in Type 2 Diabetes Mellitus

When you see a patient in your clinic • Prescribe lifestyle intervention to all

and metformin to most patients as mentioned in the inner core of the wheel (white and light blue rings)

• Then identify the 2/3 most important concerns/factors (from ABCDEFGH) that you feel should infl uence your choice of antidiabetic agent, eg. Age / CKD / Finance etc.

• Identify the best choices available to you from the outer rings of the wheel (Orange and red)

• Further, fi ne-tune your choices if more concerns exist in a given patient and reach a rational fi nal choice in an ‘individualized approach.’

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3. Lamanna C, Monami M, Marchionni N, Mannucci E. Effect of metformin on cardiovascular events and mortality: a meta analysis of randomized clinical trials. Diabetes ObesMetab. 2011;13(3):221-8.

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treatment of type 2 diabetes: a comparative review. Diabetes ObesMetab 2011;13(1):7-18.

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15. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317-26.

16. White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327-35.

17. TECOS: Sitagliptin Cardiovascular Outcome Study. ClinicalTrials.gov identifier: NCT00790205.

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20. Baker WL, Smyth LR, Riche DM, Bourret EM, Chamberlin KW, White WB. Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: a systematic review and meta-analysis. J Am SocHypertens. 2014;8(4):262-75.e9.

21. Van de Laar FA, Lucassen PL, Akkermans RP, van de Lisdonk EH, de Grauw WJ. Alpha-glucosidase inhibitors for people with impaired glucose tolerance or impaired fasting blood glucose. Cochrane Database Syst Rev. 2006;(4):CD005061.

22. Fonseca VA, Handelsman Y, Staels B. Colesevelam lowers glucose and lipid levels in type 2 diabetes: the clinical evidence.DiabetesObesMetab 2010;12(5):384–92.

23. Defronzo RA. Bromocriptine: a sympatholytic, D2-

dopamine agonist for the treatment of type 2 diabetes. Diabetes Care 2011;34(4):789–94.

24. Singh-Franco D, Robles G, Gazze D. Pramlintide acetate injection for the treatment of type 1 and type 2 diabetes mellitus. ClinTher 2007;29(4):535–62.

25. Bolen S, Feldman L, Vassy J Wilson L, Yeh HC, Marinopoulos S et al. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med 2007;147(6):386–99.

26. Peters A. Incretin-based therapies: review of current clinical trial data. Am J Med 2010;123:S28–37.

27. Bennett WL, Maruthur NM, Singh S, Segal JB, Wilson LM, Chatterjee R et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med 2011;154(9):602–13.

28. Type 2 diabetes - newer agents (partial update); NICE Clinical Guideline. 2009 Available at: patient.info/doctor/antihyperglycaemic-agents-used-for-type-2-diabetes (Last accessed on 27 Aug 2015).

29. Cauthon K, Yendapally R. A Review of GLP-1 Receptor Agonists and SGLT2 inhibitors for Type 2 Diabetes.

30. BMJ Blogs: Gliptins – where are we now? 31. Hanefeld M. Pioglitazone and sulfonylureas: effectively

treating type 2 diabetes. Int J ClinPract Suppl. 2007;(153):20-7.

32. Kalra S, Chadha M, Sharma SK, Unnikrishnan AG. Untapped diamonds for untamed diabetes: The -glucosidase inhibitors. Indian J EndocrinolMetab. 2014;18(2):138-41.

33. Second- and Third-Line Pharmacotherapy for Type 2 Diabetes: Update. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2013.

34. GallwitzB. The Future of Combination Therapies of Insulin with a Glucagon-like Peptide-1 Receptor Agonists in Type 2 Diabetes – Is it Advantageous ?European Endocrinology, 2014;10(2):98–9.

35. McCulloch DK, Nathan DM, Mulder JE. Management of persistent hyperglycemia in type 2 diabetes mellitus. 2015.


Iatrogenic Hypertension: How to Approach?

REVIEW ARTICLE

VITULL K. GUPTA, MEGHNA GUPTA, VARUN GUPTAKeywords hypertension secondary hypertension blood pressure primary hypertension

Dr. Vitull K. Gupta is Consultant Physician & Dr. Meghna Gupta is Resident, Kishori Ram Hospital and Diabetes Care Centre, Bathinda. Dr. Varun Gupta is International Fellow, Thoracic and Cardiovascular Surgery, Bundang Hospital, Seoul, South Korea.

AbstractThis review summarizes the current state of knowledge about drugs, other chemical substances, and toxins on blood pressure. Many classes of drugs, such as steroids, sympathomimetic amines, immunosuppressive agents, nonsteroidal anti-infl ammatory agents, antidepressants, erythropoietin, substances of abuse and other agents can induce transient or sustained hypertension, exacerbate well-controlled hypertension, antagonize the effects of antihypertensive therapy, or precipitate hypertensive emergencies. Increased awareness on the part of the physician is essential to avoid unnecessary tests in search of other etiologies and to reduce antihypertensive medication prescriptions by eliminating contributing agents whenever possible. These agents represent an important modifi able cause of secondary or resistant hypertension.

INTRODUCTIONHypertension (HTN) is one of the most common disease worldwide aff ecting millions of people and is a signifi cant risk factor for stroke, myocardial infarction (MI), vascular disease and chronic kidney disease (CKD). Due to the associated morbidity and mortality and cost to society, preventing and treating HTN is a signifi cant public health challenge.

Approximately 970 million people worldwide have high BP, and it is estimated that by 2025, 1.56 billion adults will be living with HTN.1 The lifetime risk of developing HTN among those

55 years of age and older who currently have normal BP is 90%.2-3 There is a proportional relationship between the level of blood pressure (BP) and the risk of complications and cardiovascular disease (CVD) risk doubles with each increment of 20/10 mmHg throughout the BP range starting at 115/75 mmHg.4-5

CLASSIFICATION ACCORDING TO BPIndian guidelines defi ne HTN as: “HTN in adults age 18 years, and older is defi ned as systolic blood pressure (SBP) of 140 mmHg or greater and/ diastolic blood pressure (DBP) of 90 mmHg or higher


Classification of blood pressure for adults age 18 and older*7,8

Category Systolic (mmHg) Diastolic (mmHg)Category Systolic (mmHg) Diastolic (mmHg)

Optimal** < 120 and < 80 Optimal** < 120 and < 80

Normal < 130 and < 85 Normal < 130 and < 85

High-normal 130–139 or 85–89 High-normal 130–139 or 85–89

Hypertension*** Hypertension***

Stage 1 140–159 or 90–99Stage 1 140–159 or 90–99

Stage 2 160–179 or 100–109Stage 2 160–179 or 100–109

Stage 3 Stage 3 180 or 180 or 110 110

Isolated systolic hypertensionIsolated systolic hypertension

Grade 1 140–159 and < 90Grade 1 140–159 and < 90

Grade 2 Grade 2 160 and < 90 160 and < 90*Not taking antihypertensive drugs and not acutely ill. In addition to classifying stages of hypertension on the basis of average blood *Not taking antihypertensive drugs and not acutely ill. In addition to classifying stages of hypertension on the basis of average blood

pressure levels, clinicians should specify presence or absence of target organ disease and additional risk factors.pressure levels, clinicians should specify presence or absence of target organ disease and additional risk factors.

**Optimal blood pressure concerning cardiovascular risk is below 120/80 mmHg. However, unusually low readings should be **Optimal blood pressure concerning cardiovascular risk is below 120/80 mmHg. However, unusually low readings should be

evaluated for clinical signifi cance.evaluated for clinical signifi cance.

***Based on the average of two or more blood pressure, readings taken at least on two visits after an initial screening. ***Based on the average of two or more blood pressure, readings taken at least on two visits after an initial screening.

Source: From second Indian guidelines for hypertension by Association of Physicians of India (API) Source: From second Indian guidelines for hypertension by Association of Physicians of India (API)

or any level of BP in patients taking antihypertensive medication.6

ETIOLOGY OF HYPERTENSION2,3,9

Primary or essential HTN: Primary HTN is diagnosed in the absence of an identifi able cause or when the cause is unknown. About 90–95% of adults have primary HTN. Primary HTN can be controlled not cured. Genetic factors may play an important role, and it tends to develop gradually over many years. Secondary HTN: It is caused by an identifi able underlying disease or medication which is potentially correctable and less than 10% of patients have secondary HTN. Controlling medical condition or removing the causative medication (s) will result in resolving secondary HTN, so detection of a secondary cause is of utmost importance because it provides a better opportunity for a cure, prevents target organ damage, reduces socioeconomic burden and health expenditure.

What is Iatrogenic Hypertension?10

Iatrogenic HTN is secondary HTN which is caused by various medications or toxic or chemical agents particularly over-the-counter drugs, nutritional supplements, diets and health foods. Over-the-counter medicines, nutritional supplements, diets and health foods, are often not considered to be drugs and therefore, are frequently omitted from the history of the patients.

Approach to a patient of Iatrogenic HTN involves

Focused medical history and physical examination.

Accurate measurement of patient’s BP, which is based on the average of two or more properly measured BP readings from two or more clinical visits. Home/ambulatory BP monitoring may be of great help.

Routine laboratory studies and 12-lead electrocardiogram help to risk stratify and diagnose target organ damage.

Once the patient is confi rmed to be hypertensive, history, physical examination and investigations are focused to determine:

Classifi cation according to BP. Identify the etiology or the causative

agent for HTN. Detection of target organ disease. Identifi cation of risk factors for

cardiovascular disorders. Baseline values for judging

biochemical eff ects of therapy. HTN is known as the “silent killer” because it typically has no warning signs or symptoms, and many people do not realize they have it. Even when BP is dangerously high, most people do not have any signs or symptoms. Some may experience dull headaches, vomiting, dizzy spells and more frequent nosebleeds. Only way for detection of HTN is to measure blood pressure.3-11

Careful history helps in identifi cation of

Duration and level of elevated BP, if known.

Symptoms of CAD, heart failure, cerebrovascular disease, peripheral vascular disease, retinopathy, and CKD.

Diabetes mellitus, dyslipidemia, obesity, gout, sexual dysfunction & other co-morbid conditions.

Family history of high BP, obesity, premature CAD and stroke, dyslipidemia and diabetes.

Symptoms suggesting secondary causes of HTN.

History of smoking or tobacco use, physical activity, dietary assessment including intake of sodium, alcohol, saturated fat and caff eine.

Socioeconomic status, professional and educational levels.History of use or intake of any

prescribed and over-the-counter medica-tions, herbal remedies is the only way to diagnose or detect iatrogenic HTN, and it is essential to verify the agents reviled in history physically.

Common agents causing Iatrogenic HTN:10,12,13Glucocorticoids, Mineralocorticoids: HTN occurs in about 20% treated with high dose steroids and increase in BP is apparent within 24 hours. Mechanism of cause of HTN remains uncertain and rise in BP may be because of increasing circulatory volume, cardiac output, and peripheral resistance. Certain exogenous compounds such as liquorice, phenylbutazone, carbenoxolone, 9-α fl uoro prednisolone and 9-α fl uorocortisol have mineralocorticoid activity and may cause HTN. Prolonged use of high-dose ketoconazole may alter enzymatic degradation of steroids, leading to mineralocorticoid-related HTN. Skin ointments, antihemorrhoidal preparations, ophthalmic drops and nasal sprays may contain substances with mineralocorticoid activity (9-α fl uoroprednisolone) and sympathetic amines so their excessive use may even cause severe HTN. Discontinuation of steroids is recommended to treat steroid-


induced HTN, but when steroid treatment is mandatory, diuretics are preferred.

Sex Hormones: Oral contraceptives (OCs) can cause increase in BP in about 5% of people using high dose OCs and small increase in BP has been reported with low dose OCs also. Risk of HTN decreased quickly with cessation of OCs and increase in BP is usually minimal. However, severe HTN including malignant HTN, have been reported. Postmenopausal estrogen replacement therapy (ERT) decreases BP slightly, and rare cases of HTN represent an idiosyncratic reaction. Cessation of ERT is recommended when HTN develops, and if ERT should be continued, a diuretic is most appropriate choice to treat HTN. BP may increase in men taking estrogen for prostatic cancer. Danazol, a semi-synthetic androgen to treat endometriosis and hereditary angioedema can induce HTN by fl uid retention.

Anesthetics and Narcotics Ketamine hydrochloride has been

reported to increase BP severely, and initial therapy with clonidine or α-blockers is suggested to control BP.

Desfl urane may increase BP by stimulating the sympathetic system and treatment with α-blockers, or α+ β-blockers may be benefi cial as compared to other antihypertensive agents.

Naloxone has also been reported to increase the BP. Naloxone seems to reverse the antihypertensive eff ects of clonidine acutely and can cause an acute hypertensive emergency when given in patients on clonidine. α-blockers may be benefi cial to lower BP.

Sevofl urane may increase BP and treatment with clonidine, or combination of diltiazem and nicardipine is suggested.

Ophthalmic solutions containing phenylephrine, a sympathomimetic agent with a potent vasoconstrictor activity, has been reported to increase BP severely. Another agent dipivalyl adrenaline, an adrenaline prodrug used topically in management of simple chronic glaucoma, can also increase BP in treated

hypertensive patients. It is suggested that concomitant use of sympathomimetic agents and -blockers can severely increase BP because of unopposed a-adrenergic vasoconstriction. The substitution with -blockers or both - and -adrenergic receptors blockers like labetalol or carvedilol, should prevent this detrimental reaction and b-blockers should be avoided.

Antiemetic agents like metoclopramide, alizapride, and prochlorperazine are reported to cause transient increase in BP in patients treated with cisplatin. This transient increase may not require any treatment but needs to be observed.

Yohimbine hydrochloride is an α2-adrenoceptor antagonist approved (questionable effi cacy) for treatment of impotence. It may signifi cantly increase BP in hypertensive patients and patients on tricyclic antidepressants so it should be avoided or used intermittently in HTN and patients on tricyclic antidepressants. Cocaine intoxication is often associated with increased BP because of α-adrenergic overactivity and may be related to acute increase in BP, and chronic HTN is seldom reported. Severe HTN has been published in subjects on propranolol. Most cocaine-related HTN do not require therapy but require β-Blockers, which can be useful in cardiac dysrhythmias, but in uncomplicated HTN may increase BP due to unopposed α-receptor activity. α-blockers, nitroglycerin, verapamil are suggested as initial therapy.

Sibutramine is anti-obesity drug with novel serotonin and noradrenaline reuptake inhibitor activity. It may increases heart rate and BP by activating sympathetic system so obese people on sibutramine should be monitored periodically for changes in BP and if BP becomes elevated, sibutramine should be discontinued or antihypertensive therapy should be modifi ed.

Clozapine is an antipsychotic agent and reported to increase BP possibly by sympathetic activation. Management includes discontinuation of clozapine, and if discontinuation is not possible, then α-blockers or nifedipine are suggested antihypertensive treatment modalities.

Anorexics: Most nonprescription anorexic agents contain antihistamine and an adrenergic agonist (usually phenylpropanolamine [PPA], ephedrine, pseudoephedrine, or caff eine) act by potentiating presynaptic norepinephrine release and by directly activating adrenergic receptors to increase BP. If there is increase in BP, the drugs should be discontinued.

Nasal decongestant & Cough medications: α-Adrenergic intoxication is induced by nasal decongestant and cough medications containing oxymetazoline, phenylephrine, and ephedrine have been reported to cause severe HTN. Initial therapy with α+β-blockers (Labetalol) is benefi cial but if possible discontinuation of drug is suggested.

Caff eine can acutely and transiently increase BP by increasing peripheral resistance. Concomitant medications, such as MAOIs, OCs, NSAIDs & antihypertensive drugs, seem to increase risk of HTN because of caff eine intake. Best treatment is to avoid caff eine.

ANTIDEPRESSANT AGENTSMAOIs can induce HTH if patient is taking foods containing tyramine or even without use of concomitant medications. Increase in BP is because of delay in metabolism of sympathomimetic amines and 5-hydroxytryptophan and by increasing the store of norepinephrine in postganglionic sympathetic neurons. Management by α-blockers is suggested.

Tricyclic antidepressants are reported to cause increase BP, mainly in patients with panic disorders because they may block the reuptake of the neurotransmitters in the synapse in the central nervous system and initial therapy with α-blockers is suggested to be benefi cial.

Serotonin agonists are reported to cause small but sustained and dose-dependent increase in BP. Venlafaxine has a dose-dependent eff ect on BP and episodes of severe HTN were described with fl uoxetine, fl uoxetine plus selegiline, and thioridazine. Initial therapy with α-blockers seems to be useful in such cases of HTN.

Antineoplastic Agents: Several

REVIEW ARTICLE


alkylating agents can increase BP. In one series, 15 of 18 patients treated with multiple alkylating agents following autologous bone marrow transplantation developed HTN. HTN is reported with paclitaxel treatment.

Cyclosporine has been reported to cause HTN. It has been suggested to discontinue, or switch to tacrolimus, if not possible to treat HTN with calcium antagonists. Other antihypertensive drugs are also useful. Calcium antagonists may increase cyclosporine blood levels. Multidrug therapy may be necessary.

Recombinant human erythropoietin (r-HuEPO) can lead to a dose-related increase in BP. Risk factors include pre-existing HTN, rapid increase or low hematocrit, high doses, IV dose & native kidneys. Potential mechanisms include blood viscosity; loss of hypoxic vasodilation; activation of catecholamines, RAS; and direct vascular eff ect. Management of HTN include decreasing the dose of EPO, start calcium antagonists or α-blockers. Diuretics and ACE inhibitors may be less eff ective. Dialysis with antihypertensive treatment may be eff ective. Phlebotomy may rapidly lower BP in refractory HTN.

Disulfi ram 500 mg/day or even low dose of 125 mg/day for 2 to 3 weeks may increase BP. Changes in peripheral or central noradrenergic activity may be responsible for the increase in BP.

Alcohol: Dose-dependent excessive chronic alcohol intake increases BP and decreases the eff ect of antihypertensive therapy. Pathogenesis is multifactorial involving direct vasculotoxicity, sympathetic activity, saltwater retention and activation of RAS. BP eff ects of alcohol are independent from obesity, salt intake, cigarette smoking and potassium intake. Initial therapy includes abstinence or moderation of alcohol to no more than ~1–2 ounces of alcohol.

NSAIDs can increase the BP and interfere with antihypertensive treatment, nullifying its eff ect. Indomethacin, piroxicam, and naproxen were associated

with the most signifi cant increases in BP and COX-2 inhibitors; celecoxib aff ects less than rofecoxib. The mechanisms are not fully understood. NSAIDs may interact with diuretics, beta blockers, and ACE inhibitors but do not interact with calcium antagonists so calcium antagonists are suggested as initial therapy for NSAID induced HTN.

Heavy Metals: Several studies show that cumulative exposure to lead, even at low levels, sustained intake by the general population, may increase the risk of HTN. Some reports suggest that arsenic or cadmium exposure also may induce HTN.

Herbal supplements14 may cause HTN or aff ect antihypertensive therapy. Herbal supplements include: Arnica (Arnica montana), Bitter orange (Citrus aurantium), Ephedra (ma-huang), Ginkgo (Ginkgo Biloba), Ginseng (Panax quinquefolius and Panax ginseng), Guarana (Paullinia cupana), Licorice (Glycyrrhiza glabra), Senna (Cassia senna), St. John’s wort (Hypericum perforatum), Blue cohosh, dong quai, pennyroyal oil, Scotch broom,southern bayberry and yohimbine. Herbal supplements are not safe so patients with HTN should be careful and may need to avoid herbal supplements.

CONCLUSIONIatrogenic HTN is secondary HTN which is caused by various medications or chemical agents particularly over-the-counter drugs, nutritional supplements, diets and health foods. Numerous therapeutic agents or chemical substances can induce either transient or sustained HTN, exacerbate well-controlled HTN, or antagonize the eff ects of antihypertensive therapy. Most crucial modality to identify iatrogenic HTN is careful evaluation including history and physical verifi cation of a patient’s drug regimen, may identify drug-induced HTN and prevent or minimize the need for lifelong antihypertensive therapy. Whenever chemically induced HTN is detected, the

causative agent should be discontinued. However, when discontinuation is not possible, institution of appropriate and targeted antihypertensive therapy is indicated. In the absence of specifi c treatment guidelines for iatrogenic or drug-induced HTN, the recommended initial treatment should be directed towards the specifi c mechanism by which the chemical agent causes HTN.

REFERENCES1. WHO: Raised blood pressure [Internet]. World Health

Organization; c2015. [updated 2014, cited 2015 Jan 26]; Available from: http:// www.who.int/gho/ncd/risk_factors/blood_pressure_prevalence_text/en/

2. Saseen JJ, MacLaughlin. Hypetension. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors. Pharmacotherapy: A pathophysiologic approach. 9th ed. New York: McGraw-Hill Medical; c2014. Chapter 3.

3. CDC: high blood pressure [Internet]. Centers for Disease Control and Prevention; c2015. [updated 2014 Oct 29, cited 2015 Jan 26]. Available from: http://www.cdc.gov/bloodpressure/index.htm

4. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality: A meta-analysis of individual data for one million adults in 61 prospective studies. Prospective Studies Collaboration. Lancet 2002;360:1903-1913.

5. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, et al. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Hypertension 2003; 42:1206-52.

6. Indian guidelines on hypertension (I.G.H.)-III, SPECIAL ISSUE, JAPI , FEBRUARY 2013 , VOL. 61

7. Indian Guidelines Management of Hypertension 2001. Hypertension India 2001; 15:1-34.

8. Williams B, Poulter NR, Brown MJ, Davis M, McInnes GT, Potter JF, et. al Guidelines for management of hypertension: report of the fourth working party of the British Hypertension Society, 2004-BHS IV. J Hum Hyperten 2004;18:139-185.

9. Saseen J. Essential hypertension. In: Alldredge BK, Corelli RL, Ernst ME, Guglielmo BJ, Jacobson PA, Kradjan WA, Williams BR, editors. Koda-Kimble and Young’s Applied Therapeutics: The Clinical Use of Drugs. 10th ed. Philadelphia: Lippincott Williams & Wilkins; c2013. Chapter 14.

10. Ehud Grossman, Franz H. Messerli. Iatrogenic and Drug-Induced Hypertension. Secondary Hypertension: Clinical Presentation, Diagnosis, and Treatment. Edited by: G. A. Mansoor. Humana Press Inc., Totowa, NJ

11. Mayo clinic: high blood pressure (HTN) [Internet]. Mayo Foundation for Medical Education and Research; c2001-2015. http://www.mayoclinic.org/diseases-conditions/high-bloodpressure/basics/definition/con-20019580

12. Serveaux M, Burnier M, Pruijm M. Drugs: an underestimated cause of arterial hypertension. Rev Med Suisse. 2014 Sep 10; 10(441):1661-2,1664-5.

13. Mounier-Vehier C, Boudghène F, Claisse G, Delsart P. Iatrogenic and drug-induced hypertension. Rev Prat. 2015 Jun; 65(6):809-16.

14. Jalili J, Askeroglu U, Alleyne B, Guyuron B. Herbal products that may contribute to hypertension. Plast Reconstr Surg. 2013 Jan;131(1):168-73.


Hypertensive Crisis: Clinical Recognition and Treatment Approaches

REVIEW ARTICLE

T GOVINDAN UNNIKeywords

calcium channel blockers fenoldopam hypertension hypertensive crises hypertensive encephalopathy labetalol nicardipine nitroprusside pregnancy

Dr. T Govindan Unni is Professor & Medical Director, Jubilee Hrudayalaya, Jubilee Mission Medical College & Research Institute, Thrissur, Kerala

AbstractHypertension is an extremely common clinical problem, affecting approximately 50 million people in the USA and nearly 1 billion individuals worldwide. Around 1% of these patients will develop acute elevations in blood pressure at some point in their lifetime. Some terms have been applied to severe hypertension, including hypertensive crises, emergencies, and urgencies. By defi nition, acute elevations in blood pressure that are associated with end-organ damage is called hypertensive crisis. Immediate reduction in blood pressure is required only in patients with acute end-organ damage. This article reviews current concepts and common misconceptions and pitfalls in the diagnosis and management of patients with acutely elevated blood pressure.

INTRODUCTIONHypertensive crisis can be classifi ed into hypertensive emergency and hypertensive urgency. This is dependent on the presence or absence of acute end-organ damage. In hypertensive emergency, there is impending or progressive acute end-organ damage.1 It is the percentage increase in blood pressure (BP) that is more relevant than the actual BP level.

HYPERTENSIVE URGENCY Emergency department referrals or rapid BP-lowering strategies in patients with hypertensive urgencies do not lead to improved outcomes. In fact, most patients with signifi cantly elevated blood pressure (≥180 /≥120 mmHg) have no acute, end-organ injury. These patients are also referred to as “severe asymptomatic

hypertension.” There may be evidence of preexisting target organ damage in these patients. But there will be no acute progressive target organ dysfunction. Majority of these patients can be safely managed in the outpatient setting. Hence the term “urgency” is a misnomer. A less ominous term such as “uncontrolled BP” may be better.HYPERTENSIVE EMERGENCYPatients with hypertensive emergency have acute or progressively worsening hypertensive target organ damage and require hospitalization, prompt treatment, and close monitoring. Among all patients with hypertensive crisis in the emergency department, 75% have hypertensive urgency, and only 25% have hypertensive emergency.2 Patients with hypertensive emergency have signs or symptoms of


acute, ongoing target organ damage. It can develop in patients with or without preexisting chronic hypertension. Newly detected hypertension constitutes 23% of the emergencies.3 Patients with history of chronic hypertension are more tolerant to the abrupt increases in Blood Pressure. Vascular smooth muscle hypertrophy in chronic hypertension provides some degree of tissue protection at the capillary level. Patients who are normotensive at baseline lack this protection from the smooth muscle hypertrophy.4 Why some patients with severe hypertension develop end-organ damage and why others with the same elevation in blood pressure does not develop progressive end-organ damage is an unanswered question. Children and pregnant women are more likely to develop hypertensive emergency than chronic hypertensives.

PROGNOSISThe term "malignant hypertension" was used fi rst in 1928 because prognosis of this condition was similar to many cancers. However, now we have antihypertensive therapy that quickly and safely lower BP and the outcomes have improved.5 Five-year survival rate, which was 37% in 1960s, has increased to 91% in 2000s.6 But the prognosis continues to be grave, and there is a signifi cant risk of cardiovascular morbidity and mortality. Hypertensive urgency is associated with more than 50% increased risk of cardiovascular events.7 In-hospital mortality rate is 2.6% with hypertensive crisis in general.8 30-day mortality is 4% in patients who require parenteral antihypertensives.9 Ninety-day readmission rate is 29% for patients who need hospitalization.10

RISK FACTORS PROMOTING HYPERTENSIVE CRISISNon-adherence to antihypertensive medications are the most important factor. Excessive salt intake increased alcohol consumption, and illicit drug use are other important factors. Readmission with the same diagnosis is not uncommon.

PATHOPHYSIOLOGYPathophysiology remains unclear. Two

diff erent, but interrelated mechanisms are often cited as the most important factors.

Failure in autoregulatory mechanism is considered to be the most important. Autoregulation is defi ned as the ability of the organs (brain, heart, and kidneys) to maintain a stable blood fl ow irrespective of alterations of perfusion pressure. When blood pressure shoots up, lack of autoregulation in vascular bed leads to transmission of high pressure to tissues leading to increased mechanical stress and endothelial injury. There is also over perfusion or luxury perfusion of tissues. Thus as long as the blood pressure remains in the autoregulatory range, there is no progressive end-organ damage, and it is hypertensive urgency. But when the blood pressure crosses this range, progressive end-organ damage ensues and patient lands up in hypertensive emergency. Since the autoregulatory range depends on several factors including age, the state of vascular bed and the rate of riseing BP, it is not surprising that for a similar blood pressure elevation, some people develop hypertensive emergency and some others develop urgency. In chronic hypertension, there are functional and structural changes in the arterial walls. The autoregulatory curve is shifted to the right. Hence organ perfusion is maintained at higher mean arterial pressure levels.11

The physiological response to high blood pressure is to maintain relatively constant tissue perfusion and prevent high BP from being transmitted to small distal vessels. This leads to intense vasoconstriction and thickening of the arteriolar walls. As the blood pressure goes further up, the already severely constricted vessels get exhausted, and the intense vasoconstriction gives way to vasodilatation. Dysregulation of the pressure-dependent blood fl ow deteriorates into frank vasculitis and ischemia. Vessels take on a “sausage string” appearance. The response is not uniform throughout the tissues, and so we can have areas of intense vasoconstriction alternating with areas of vascular exhaustion and dilation.

The second mechanism is the activation of renin-angiotensin system.12 This leads to further vasoconstriction.

There is the vicious cycle of continuous injury and subsequent ischemia. There is also a prothrombotic state. The possible association of a polymorphism of the ACE and the DD genotype can explain the genetic facet to hypertensive emergency.13 Survivors of a hypertensive emergency, when compared to healthy controls and hypertensives who never had hypertensive emergency, were found to have poorer endothelial function and stiff er vessels.

COMMON CLINICAL PRESENTATIONSCNS manifestations, cardiac mani-festations, renal manifestations and pregnancy related problems constitute the major presentations.

TREATMENT OF HYPERTENSIVE EMERGENCIESTreatment of hypertensive emergency depends on the target organ that is being damaged (e.g., brain, heart). It is the organ that is damaged that determines the target blood pressure that is to be attained, the rapidity with which the target blood pressure is to be achieved, optimal therapy, the choice of agent and the blood pressure goal.14 In general, it is unwise to lower the BP too quickly or too much. All patients will require continuous cardiac monitoring, frequent neurologic examinations and precise measurement of urine output. Parenteral, short-acting and titratable agents are preferred. Sublingual and intramuscular routes should be avoided because of unpredictable pharmacodynamics of the medications. Ideally, all patients should be admitted to ICU for close monitoring of BP. Mean arterial pressure should be reduced gradually by about 10 to 20 percent in the fi rst hour. A further 5 to 15 percent reduction of mean arterial pressure should be attained over the next 23 hours.15 After a suitable period (often 8 to 24 hours) of BP control in the ICU, IV therapy should be tapered and discontinued, and oral medications started.

There are two signifi cant exceptions to this gradual BP lowering recommendations. In the acute phase


of an ischemic stroke blood pressure should not be lowered at all, unless it is above 185/110 mmHg in patients who are candidates for reperfusion therapy and above 220/120 mmHg in patients who are not candidates for reperfusion therapy. The second exception is acute aortic dissection where the SBP should be rapidly lowered to 100 to 120 mmHg (in 20 minutes).16

Volume status has to be assessed before starting treatment. Pressure natriuresis response refers to the increased natriuresis that occurs following a rise in blood pressure. Thus in hypertensive crisis, there is increased urinary sodium excretion in response to acute elevations in BP. The abrupt rise in BP may lead to volume depletion. So careful evaluation of the volume status is essential. In many patients, when antihypertensive treatment is initiated, IV volume replacement may be needed to prevent an exaggerated decline in BP and an impairment of tissue perfusion. In the majority of patients, subtle or overt volume depletion is present, and hence diuretics are not the fi rst drug of choice. Vasodilators in the setting of volume depletion may lead to precipitous drop in BP. Thus, the initial management should include IV isotonic sodium chloride solution.17 Moreover, volume depletion leads to activation of RAAS and restoration of intravascular volume helps in down-regulation of the RAAS and breaking the hypertensive cycle.

Sublingual Nifedipine, once considered as a fi rst line drug, should not be used. There is negligible oral absorption, and hypotensive eff ects are unpredictable.

There is also increased risk of arrhythmias, stroke, or worsening cardiac ischemia or infarction.

NEUROLOGIC EMERGENCIES: In ischemic stroke, most often antihypertensive drugs are not given. However, if the patient is a candidate for tissue plasminogen activator (rtPA) and initial BP is more than 185/110 mmHg, they have to be treated.

If the patient is not a candidate for

reperfusion therapy, treatment has to be started only if initial BP is more than 220/120 mm Hg. Commonly used drugs are Labetalol and Nicardipine. Other agents like Hydralazine and Enalaprilat can also be tried.

If the BP is not maintained at or below 185/110 mmHg, do not administer rtPA. Maintain BP at or below 180/105 mmHg during and after acute reperfusion therapy. Monitor BP every 15 minutes for 2 hours from the start of rtPA therapy, then every 30 minutes for 6 hours, and then every hour for 16 hours. If blood pressure is not controlled or diastolic blood pressure is above 140 mmHg, consider intravenous sodium nitroprusside.

The important point to be remembered is that among patients who present with acute stroke, 80% have increased BP at the time of hospitalization. By day 10, two thirds already become normotensive, even without treatment. We have to distinguish between hypertension produced by stroke and hypertension producing a stroke. Identify patients who are in need of antihypertensive therapy so that treatment provides benefi t rather than harm.

Hemorrhagic stroke includes spontaneous intracerebral hemorrhage and subarachnoid hemorrhage. There are competing risks by treatment. While reducing blood pressure will reduce cerebral perfusion, it also benefi ts by lowering further bleeding. Lowering BP (within one hour) to less than 140 mmHg is safe and found to have nonsignifi cant benefi ts on death and major disability.18 US guidelines indicate that BP lowering therapy should be given if there are no contraindications.19 When there is elevated intracranial pressure (ICP), cerebral perfusion pressure is the diff erence between blood pressure and ICP. It is advisable to keep cerebral perfusion pressure in the range of 61 to 80 mmHg by intermittent or continuous IV medication.

In head trauma, it is the increased intracranial pressure that produces severe elevations in blood pressure. Blood pressure is treated only if the cerebral perfusion pressure (mean arterial pressure minus intracranial pressure) is above 120 mmHg and the intracranial pressure is

less than 20 mmHg.Hypertensive encephalopathy is most

often a diagnosis of exclusion. BP is to be lowered by approximately 10 to 20% during the fi rst hour. Additional lowering should be gradual. BP is to be reduced by no more than 25 percent at the end of the fi rst day.

CARDIAC EMERGENCIESAcute heart failure is one situation where loop diuretics form the fi rst line drug. Amelioration of heart failure is the primary aim of this condition. A 10 to 15% reduction in BP is advisable in the fi rst hour. IV Nitroglycerine (NTG) reduces preload and afterload and hence considered one of the fi rst line drugs. IV morphine, which reduces preload, sympathetic drive and air hunger, is also advised. Supplemental O2 and noninvasive or invasive mechanical ventilation will help in more serious patients.

Acute coronary syndrome is diffi cult to diagnose in the setting of hypertensive crisis because Troponin elevation can be seen in patients with hypertensive crisis. In fact, one-third of patients with hypertensive crisis have elevated troponin-I. Elevated troponins may not suggest acute coronary syndrome, but it is a strong predictor of future adverse CV events.20 IV nitroglycerine (NTG), clevidipine, nicardipine, or esmolol can be used as fi rst-line drugs. They not only reduce blood pressure but also reduce coronary ischemia and reduce the increased myocardial oxygen consumption. Beta-blockers or nondihydropyridine CCBs such as diltiazem or verapamil are also useful in the long-term.

Vascular emergenciesAcute aortic dissection is the most severe vascular emergency. Estimated mortality is about 40%. Recommendation is to rapidly reduce systolic blood pressure (SBP) to 100 to 120 mmHg within about 20 minutes of diagnosis. Intravenous beta-blockers are the fi rst line drugs because they reduce blood pressure and also reduce the shear stress on the aortic wall. Heart rate should be reduced to

REVIEW ARTICLE


below 60 beats per minute. Intravenous nitroprusside reduces blood pressure rapidly and is a useful drug to reduce BP to below 120 mmHg. It should be given preferably on top of beta-blockers. Involvement of ascending aorta is considered as a surgical emergency. Mortality risk increases by 1–2% every hour after the onset of symptoms unless surgically repaired. Severe hypertension in patients with recent vascular surgery can threaten suture lines and is treated with rapidly acting intravenous antihypertensive agents.

Renal emergenciesSevere hypertension and chronic kidney disease often coexist. Severe hypertension can also produce acute injury to the kidneys. Hematuria, usually microscopic, is found in approximately 75% with hypertensive emergencies. Elevated serum creatinine is quite common, but may be preexisting. The most important fi nding is red blood cells (RBCs), and RBC casts typical of acute glomerular and tubular injury. It is important to determine whether these fi ndings are recent, because it may predate the severe BP elevation. The common pathologic fi ndings include fi brinoid necrosis of small arterioles and "onion skinning" of small renal arteries. Antihypertensive therapy often leads to worsening kidney function, because of acute reduction in fi ltration pressure. Sometimes they may even require dialysis. Long-term BP control usually reverses these complications.21 Fenoldopam is associated with a temporary improvement in renal function. It is considered as a useful antihypertensive agent in renal hypertensive emergencies.

Sympathetic overactivity resulting in hypertensive emergenciesMajor causes of sympathetic overactivity resulting in hypertensive emergencies are withdrawal of short-acting antihypertensive agents, ingestion of sympathomimetic agents, pheochromocytoma and severe autonomic dysfunction (e.g., Guillain Barré and Shy Drager syndromes or acute spinal cord injury). Unless a beta-blocker was recently withdrawn, administration

of a beta-blocker alone is contraindicated since the unopposed alpha action produces vasoconstriction and further rise in blood pressure.

Hypertensive emergencies during pregnancyPregnancy-related issues include preeclampsia and eclampsia. Preeclampsia is characterised by hypertension, peripheral edema and proteinuria in women after the twentieth week of gestation. Eclampsia is a more severe form with onset of seizures. The mainstays of treatment include bed rest, fl uid management, particularly when oliguria is present, serial monitoring and delivery of the fetus when appropriate. Intravenous magnesium sulfate, methyldopa, hydralazine, and labetalol are commonly used drugs. Fenoldopam and nicardipine have also been used. However, delivery of the fetus is the defi nitive treatment in severe eclampsia. Esmolol or clevidipine have also been used.

Pediatric hypertensive emergencies:Most frequent cause of pediatric hypertensive emergencies is post-streptococcal glomerulonephritis. Traumatic brain injury leading to a hypertensive crisis is also common. The focus should be on acute renal injury because the kidney is the most common organ to be aff ected in younger children. Labetalol, hydralazine, and nicardipine has been tried. Follow-up in hypertensive crisisFollow-up of these patients is important because a signifi cant proportion of patients without follow-up will return with a repeated hypertensive emergency. Adherence to long-term treatment and high-quality outpatient follow-up are essential. Secondary causes of hypertension are common, and so all patients should be evaluated for common forms of secondary hypertension.

PARENTERAL AGENTS FOR HYPERTENSIVE EMERGENCIESSodium nitroprusside is a very predictable

and potent vasodilator. It has extremely rapid onset of action within seconds of initiating an infusion and rapid off set of eff ect within 1 to 2 minutes. Hence a patient on nitroprusside requires constant monitoring and supervision of BP. It reduces preload and afterload. It does not cause sedation or somnolence. It is rapidly degraded by light, requiring periodic exchange of solution. It can cause signifi cant renal impairment.

Accumulation of thiocyanate is another serious problem especially in the presence of poor tissue perfusion and depressed hepatic function. Cyanide accumulates and can lead to cyanide poisoning.22

Nicardipine is an IV form of dihydropyridine calcium channel blocker. It is eff ective in a high percentage of emergencies. It reduces both cerebral and coronary ischemia. It can cause tachycardia, headache, nausea, and vomiting.

Nitroglycerine is the preferred drug in coronary artery disease or myocardial ischemia. It dilates collateral coronary vessels. It has rapid onset and off set of eff ect.23 Hence requires close nursing supervision. While lower infusion rates have eff ect on capacitance vessels, higher infusion rates aff ect arteriolar vasodilation.

Fenoldopam is a peripheral dopamine one receptor agonist. It produces systemic vasodilation, especially in renal circulation.24 It has eff ects on renal proximal and distal tubules. It increases urine fl ow, natriuresis, and diuresis and improves creatinine clearance. Its onset of eff ect is rapid (within 5 minutes), and eff ects dissipate within 30 minutes of discontinuation. Side eff ects include headache, fl ushing, tachycardia, and dizziness and a dose-related increase in intraocular pressure.

Enalaprilat is the active form of enalapril. It is given IV 1.25 mg at 6-hour intervals. Its onset of action is within the fi rst 30 minutes. It is particularly useful in heart failure or other conditions with high plasma angiotensin II concentrations. The response is unpredictable, in part due to variable degrees of plasma volume expansion.


CONCLUSIONHypertensive emergency is a severe disease. More than 45% will fi nally have new evidence of end-organ damage. In-hospital death rate is 6.9%. Readmission rate within 90 days is 37.2%. Hypertensive urgency, on the other hand, is a less severe disease. Rapid reduction of BP may produce more harm than good. Most of them can be managed as outpatient with oral drugs but they also require strict close and regular follow-up.

REFERENCES1. ESH/ESC Task Force for the Management of Arterial

Hypertension. 2013 Practice guidelines for the management of arterial hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC): ESH/ESC Task Force for the Management of Arterial Hypertension. J Hypertens 2013;31:1925.

2. Pinna G, Pascale C, Fornengo P, et al. Hospital admissions for hypertensive crisis in the emergency departments: a large multicenter Italian study. PLoS One 2014; 9:1–6

3. Pinna G, Pascale C, Fornengo P, Arras S, Piras C, Panzarasa P, et al. Hospital admissions for hypertensive crisis in the emergency departments: a large multicenter Italian study. PLoS One (2014) 9(4):e93542. doi:10.1371/journal. pone.0093542

4. Aggarwal M, Khan IA. Hypertensive crisis: hypertensive emergencies and urgencies. Cardiol Clin 2006; 24:135–146.

5. Katz JN, Gore JM, Amin A, et al. Practice patterns, outcomes, and end organ dysfunction for patients with acute severe hypertension: the Studying the Treatment of Acute hyperTension (STAT) registry. Am Heart J 2009158:599.

6. Lane DA, Lip GYH, Beevers DG. Improving survival of malignant hypertension patients over 40 years. Am J Hypertens 2009; 22:1199–1204.

7. Vlcek M, Bur A, Woisetschla¨ger C, et al. Association between hypertensive urgencies and subsequent cardiovascular events in patients with hypertension. J Hypertens 2008; 26:657–662.

8. Deshmukh A, Kumar G, Kumar N, et al. Effect of joint national committee VII report on hospitalizations for hypertensive emergencies in the United States. Am J Cardiol 2011; 108:1277–1282.

9. Vuylsteke A, Vincent J-L, de La Garanderie DP, et al. Characteristics, practice patterns, and outcomes in patients with acute hypertension: European registry for Studying the Treatment of Acute hyperTension (Euro-STAT). Crit Care 2011; 15:R271.

10. Gore JM, Peterson E, Amin A, et al. Predictors of 90-day readmission among patients with acute severe hypertension. The cross-sectional observational Studying the Treatment of Acute hyperTension (STAT) study. Am Heart J 2010; 160:521–527.

11. Taylor DA. Hypertensive crisis: a review of pathophysiology and treatment. Crit Care Nurs Clin North Am (2015) 27(4):439–47. doi:10.1016/j. cnc.2015.08.003

12. Papadopoulos DP, Mourouzis I, Thomopoulos C, Makris T, Papademetriou V. Hypertension crisis. Blood Press (2010) 19(6):328–36. doi:10.3109/08037 051.2010.488052

13. Sunder-Plassmann G, Kittler H, Eberle C, et al. Angiotensin converting enzyme DD genotype is associated with hypertensive crisis. Crit Care Med 2002; 30:2236–2241.

14. Kaplan NM, Victor RG. Chapter 8: Hypertensive Crises.

In: Kaplan's Clinical Hypertension, 10th Ed, Lippincott, Williams & Wilkins, Philadelphia 2010. p.274

15. Elliott WJ. Clinical features in the management of selected hypertensive emergencies. Prog Cardiovasc Dis 2006;48:316.

16. Khan IA, Nair CK. Clinical, diagnostic, and management perspectives of aortic dissection. Chest (2002) 122:311–28. doi:10.1378/chest.122. 1.311

17. Marik PE, Rivera R. Hypertensive emergencies. Curr Opin Crit Care 2011;17:569–580.

18. Anderson CS, Heeley E, Huang Y, et al. Rapid blood pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med 2013;368:2355.

19. Hemphill JC 3rd, Greenberg SM, Anderson CS, et al. Guidelines for the Management of Spontaneous Intracerebral Hemorrhage: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2015;46:2032.

20. Pattanshetty DJ, Bhat PK, Aneja A, Pillai DP. Elevated troponin predicts long- term adverse cardiovascular outcomes in hypertensive crisis: a retrospective study. J Hypertens 2012) 30(12):2410–5. doi:10.1097/HJH.0b013e3283599b4f

21. González R, Morales E, Segura J, et al. Longterm renal survival in malignant hypertension. Nephrol Dial Transplant 2010;25:3266.

22. Hall VA, Guest JM. Sodium nitroprusside-induced cyanide intoxication and prevention with sodium thiosulfate prophylaxis. Am J Crit Care (1992)1(2):19–25; quiz 26–7.

23. Murphy C. Hypertensive emergencies. Emerg Med Clin North Am (1995) 13(4):973–1007

24. White WB, Radford MJ, Gonzalez FM, Weed SG, McCabe EJ, Katz AM. Selective dopamine-1 agonist therapy in severe hypertension: effects of intra-venous fenoldopam. J Am Coll Cardiol (1988).

REVIEW ARTICLE


ST-Segment Depression

ECG OF THE MONTH

SR MITTAL

AbstractCommonest cardiac cause for ST-segment depression is subendocardial injury. In context of coronary artery disease, greater the depression, greater is the impairment of fl ow. Transmural infarctions can also produce signifi cant reciprocal ST-segment depression in opposite leads. Intraventricular conduction defects, ventricular hypertrophy and mitral valve prolapse are other common causes for ST depression. Digitalis, hypokalemia and tachyarrhythmias also frequently produce ST-segment depression. Sympathetic overdrive, neurocirculatory asthenia and hyperventilation can produce ST-segment depression in absence of underlying cardiac disease.

Keywords coronary artery disease digitalis electrocardiography hypokalemia

ST-SEGMENT DEPRESSIONST-segment starts with J point and merges smoothly into T wave. Level of ST-segment is considered in relation to T-P segment. ST-segment depression of >0.5mm in consecutive leads is considered signifi cant.

CAUSES OF ST-SEGMENT DEPRESSION

(A) Subendocardial ischemia or injuryLeads V5 and V6 are most commonly in-volved.1 Depending on severity of impair-ment of coronary fl ow ST-segment can take following shapes (Figure 1).

(a) Horizontal ST-segmentST-segment is horizontal with sharp angle at the point of junction of T wave with ST-segment.

Dr. SR Mittal is Head, Department of Cardiology at Mittal Hospital and Research Centre, Ajmer, Rajasthan

Figure 1. Diagrammatic representation of various shapes of ST-segment in myocardial ischemia (a) Normal ST-segment (b) Horizontal ST segment (c) Rapid up sloping ST depression (d) slow up sloping ST depression (e) Horizontal ST-segment depression (f) down sloping ST depression.


(b) Upward sloping Horizontal ST-segmentJ point is depressed relative to T-P segment. Upsloping ST depression can be-i. Rapid upsloping- Aft er a depressed J

point, ST-segment rises rapidly with the result that within 0.08 second af-

ter J point, it touches the isoelectric line (Figure 2). Such a depression can also be present in normal persons due to eff ect of atrial repolarization wave. Atrial repolarization wave (Ta) is op-posite in direction to the P wave. Nor-mally it falls within the QRS complex and does not deform ST-segment. If P wave amplitude is increased, Ta wave also becomes prominent, it can depress early part of QRS and J point. In such cases, the line joining the distal limb of P wave, P-R segment, J point, ST-segment and proximal limb of T wave forms a smooth parabola (Figure 3a). In pathological condi-tions, this line is broken and step like (Figure 3 b).

ii. Slow upsloping In this situation ST-segment remains

0.2 mv below the isoelectric line aft er 0.8 second of J point. Th is is usually pathological.

(c) Flat or horizontal ST depression (Figure 4)Aft er a depressed J point, ST-segment is horizontal with sharp ST-T angle. It is pathological.

(d) Downsloping (Figure 5)Aft er a depressed J point, ST-segment is further depressed with a sharp ST-T an-gle. It is pathological.

In context of coronary artery disease, greater the depression, greater is the impairment of coronary fl ow.

ST-segment depression of 0.5 mm or more that appears during chest discom-fort and disappears aft er relief strongly suggests transient myocardial ischemia. However if such a change is constantly present with or without chest pain, it is a nonspecifi c fi nding. LOCALIZATION OF ISCHEMIA(i) Leads V1 to V4 – It suggests antero-

septal subendocardial infarction.2 It could be reciprocal changes

of infero-lateral (formerly called posterior) STEM-I (Figure 6). In the setting of transmural inferior MI, such changes may also be due to infero-septal MI.3

Right ventricular subendocardial

ischemia can also produce similar change.

(ii) ST depression in leads V4 to V6 It suggests subendocardial ischemia.

However such pattern may also be seen in patients with LVH, cardiomy-opathy etc. It can also be a reciprocal change in patients with inferior myo-cardial infarction or posterolateral myocardial infarction (Figure 7,8,9)

(iii) ST depression in seven or more leads with ST elevation in lead aVR greater

ECG OF THE MONTH

Figure 2. Electrocardiogram showing upsloping ST depression.

Figure 3. Diagrammatic representation of difference between physiological (a) and pathological (b) up sloping ST depression.

Figure 4. Electrocardiogram showing horizontal ST depression.

Figure 5. Electrocardiogram showing downsloping ST depression.

Figure 6. Electrocardiogram showing ST depression in leads V1 to V4 in setting of acute inferior infarction.


Figure 7. Electrocardiograms from a case of acute inferior infarction (a) showing ST depression in leads I, aVL and V2 to V6 (b) electrocardiogram recorded on 2nd day showing sequential T inversion in leads II, III, aVF with reduction in ST depressions.

Figure 8. Electrocardiograms from a case of acute inferior infarction (a) showing ST depression in leads I, aVL, V1 to V9 (b) Electrocardiogram recorded on 2nd day showing sequential changes of inferior infarction with normalization of ST depressions.

Figure 9. Electrocardiogram from a case of posterolateral infarction showing ST de-pression in leads V1 to V3 and V3R to V6R.

Figure 10. Electrocardiogram showing ST elevation in lead aVR with ST depression in leads I, II, aVL and V4-V9.

Figure 11. Electrocardiogram showing ST elevation in leads aVR and V1 with ST depression in leads II, III, aVF, V4 to V9.

than in lead V1 suggests occlusion of left main coronary artery or its equiv-alent (2 or 3 proximal vessel disease)4 (Figure 10,11).

(iv) Upsloping ST depression with tall positive T waves in the anterolat-eral leads should suggest regional ischemia due to subtotal occlusion of the LAD or left circumfl ex artery specially if seen in patients with typi-cal symptoms and at a relatively slow heart rate.5

(v) ST depression in leads I and aVL Such ST depression may be reciprocal

of ST elevation in inferior leads6 (Fig-ure 12). ST elevation in inferior leads may not be diagnostic in early stage especially in patients with low voltage QRS complexes in inferior leads.

(vi) ST depression in leads III and aVF. It suggests inferior subendocardial

infarction. It can also be a reciprocal change of infarction involving leads I and aVL (Figure 13 & 14).

(B) Causes other than ischemic heart disease(a) Normal variants4

Figure 12. Electrocardiogram from a case of acute inferior infarction showing (a) ST depression in leads I and aVL (b) Electrocardiogram recorded on 2nd day showing sequential changes in inferior leads with normalization of ST in leads I and aVL.

Figure 13. Electrocardiogram from a case of acute high lateral myocardial infarction involving leads I and aVL (a) showing ST depression in leads II, III and aVF (b) electrocardiogram recorded on second day showing sequential changes in leads I and aVL with normalization of ST depression in inferior leads.

Figure 14. Electrocardiogram from a case of acute high lateral myocardial infarction involving leads I and aVL with reciprocal ST depression in leads II, III and aVF.


ECG OF THE MONTH

Figure 15. Electrocardiogram from a case of left bundle branch block showing ST depression in leads I, aVL, V5 and V6.

Figure 16. Electrocardiogram from a case of right bundle branch block showing ST depression in leads V1 and V2

Figure 17. Electrocardiogram from a case of pre-excitation showing ST depression in leads I, aVL, V1 and V6.

Figure 18. Electrocardiogram from a case of left ventricular hypertrophy showing ST depression in leads I, II, III, aVL, aVF, V5 & V6.

(iii) Preexciation syndromes ST-segment is opposite to delta

wave (Figure 17). (c) Secondary to ventricular hypertrophy (i) Left ventricular hypertrophy ST depression is seen in leads I,

aVL, V5 to V9 (Figure 18). (ii) Right ventricular hypertrophy

(Figure 19) ST depression is seen in leads V1

to V3 and V3R to V6R. (d) Digitalis7 (Figure 20). J point is not depressed. ST-segment

takes a straight downward course from J point with a sharp ST-T junc-tion. T wave amplitude is diminished and there is shortening of QT inter-val. Classically it takes the shape of mirror image of correction mark. Changes are most prominent in leads with dominantly upright QRS. Such change suggest adequate dose of digitalis but do not suggest digitalis toxicity. First degree A-V block, ven-tricular ectopics, multifocal or bidi-rectional ventricular tachycardia or junctional tachycardia appearing for the fi rst time aft er adequate dose of digitalis, suggest digitalis overdose.

(e) Hypokalemia Low amplitude or invisible T wave,

prominent U wave and QT prolonga-tion suggest hypokalemia (Figure 21).

(f) Mitral valve prolapse ST-segment depression and or T wave

inversion are seen in leads II, III, aVF, V5, V6.

(g) During tachyarrhythmia (Figure 22).(h) Post tachycardia (Figure 23)(i) Myocarditis(j) Cardiomyopathy (Figure 24)

Figure 19. Electrocardiogram from a case of corpulmonale showing ST depression in leads II, III, aVF.

(i) Sympathetic overdrive (ii) Neurocirculatory asthenia (iii) Hyperventilation(b) Secondary to intraventricular con-

duction defects (i) Left bundle branch block ST depression is seen in leads I,

aVL, V5 to V9 (Figure 15). (ii) Right bundle branch block ST depression is seen in leads

V1 to V3 and V3R to V6R (Figure 16).


Figure 20. Electrocardiogram from a case of digitalis overdose showing atrial fibrillation with slow ventricular rate, ST depression in leads II, III, aVF, V6 and ventricular bigeminy.

Figure 22. Electrocardiogram from a case of AV nodal re-entrant tachycardia showing ST depression in leads I, II, aVF, V5 and V6.

Figure 24. Electrocardiogram from a case of cardiomyopathy showing increased left ventricular voltages and ST depression in leads V5 and V6.

REFERENCES1. Schamroth C. Coronary insufficiency. In Schamroth C

(ed). An introduction to Electrocardiography. Wiley India, New Delhi;1982:157-185.

2. Bimbaum Y, Nikus K, Kligfield P, et al. The role of the ECG in diagnosis, risk estimation and catheterization laboratory activation in patients with acute coronary syn-dromes: A consensus document. Annals of Non-invasive Electrocardiology 2014;19: 412-25.

3. Boden WE, bough EW, Korr KS, Russo J, Gandsman EJ, Shulman RS. Inferoseptal myocardial infarction : Another cause of precordial ST segment depression in transmural inferior wall myocardial infarction ? AM J Cardiol 1984; 54:1216-23.

4. De luna AB, Goldwasser D, Fiol M, Bayes Genis A. Surface electrocardiography. In Fuster V, Walsh RA, Harrington RA(eds) Hurst’s The Heart. Mc Graw Hill, New York ; 2011:307-370.

5. Bimbaum Y, Wilson JM, Fiol M, de Luna AB, Eskola M, Nikus K. ECG diagnosis and classification of acute coronary syndromes. Ann Noninvasive Electrocardiol 2014;19:4-14.

6. Hassen GW, Talebi S, Fernaine G, Kalantari H. Lead aVL on electrocardiogram: emerging as important lead in early diagnosis of myocardial infarction ? Am J Emerg Med 2014;32:785-8.

7. Schamroth C. Drugs and electrolytes. In Schamroth C (ed). An introduction to Electrocardiography. Wiley India, New Delhi;1982:241-53.

Figure 21. Electrocardiogram from a patient of hypokalemia showing ST depression, invisible T wave, prominent U wave and prolonged QT-U.

Figure 23. Electrocardiogram from a case of recovery after tachyarrhythmia showing ST depression in leads I, II, aVL, aVF, V4 and V6.


Q1. During angina, ST-segment de-pression is considered signifi -cant if it is

(A) > 0.5 mm(B) > 1.0 mm(C) > 2.0 mm(D) > 2.5 mm

Q2. Subendocardial injury mostly produces ST-segment depression in leads

(A) V1 to V3(B) V5 and V6(C) V7 to V9(D) V3R to V6R

Q3. Severity of impairment of coronary fl ow is maximum when ST depression is

(A) Horizontal (B) Rapid up sloping(C) Slow up sloping(D) Down sloping

Q4. In normal persons, upsloping ST-segment depression touches baseline in

(A) 0.08 second(B) 0.10 second(C) 0.14 second(D) 0.16 second

Q5. Normally Ta wave falls in (A) P wave(B) QRS(C) ST-segment (D) T wave

Q6. ST depression in leads V1 to V4 can be seen in

(A) Anteroseptal subendocardial infarction

Q12. ST depression in leads III and aVF can occur in

(A) Inferior subendocardial infarction (B) High lateral transmural myocar-

dial infarction (C) Right ventricular infarction (D) All

Q13. Up sloping ST depression can be seen in

(A) Sympathetic overdrive (B) Neurocirculatory asthenia (C) Hyperventilation (D) All

Q14. ST depression alone in a patient receiving digitalis suggests

(A) Inadequate dose of digitalis (B) Digitalis eff ect (C) Digitalis toxicity (D) Hyperkalemia

Q15. Which of the following should suggest digitalis overdose

(A) New onset of otherwise unex-plained ventricular ectopics

(B) Atrial fi brillation with otherwise unexplained slow ventricular rate

(C) Bidirectional ventricular tachycar-dia

(D) None

Q16. Which of the following does not cause ST depression

(A) Hyperkalemia (B) Viral myocarditis (C) AV nodal re-entrant tachycardia(D) Hyperventilation

(B) Posterior infarction (C) Right ventricular subendocardial

ischemia(D) All

Q7. ST-segment depression in leads V4 to V6 is seen in

(A) Subendocardial ischemia(B) Left ventricular hypertrophy (C) Left bundle branch block(D) All

Q8. ST-segment depression in leads V4 to V6 is seen in

(A) Cardiomyopathy (B) Myocarditis(C) Inferior infarction (D) All

Q9. ST-segment depression in seven or more leads with ST elevation in lead aVR more than V1 sug-gests

(A) Left main stem disease(B) Proximal LCX occlusion (C) Proximal RCA occlusion (D) All

Q10. Upsloping ST depression with tall positive T waves in antero-lateral leads can occur in

(A) Subtotal occlusion of LAD(B) Subtotal occlusion of LCX(C) Occlusion of mid RCA(D) All

Q11. ST depression in leads I and aVL can occur in

(A) High lateral transmural myocardial infarction

(B) Inferior infarction (C) Posterior infarction (D) None

MCQsST Segment Depression

Answers: 1) A, (2) B, (3) D, (4) A, (5) B, (6) D, (7) D, (8) D, (9) A, (10) A, B, (11) B, (12) A, B, (13) D, (14) B, (15)A, B, C, (16) A.

ECG OF THE MONTH


PICTORIAL CME

MONIKA MAHESHWARI

Dr. Monika Maheshwari is Professor at Jawahar Lal Nehru Medical College, Ajmer, Rajasthan

Giant Thrombus in Inferior Vena Cava

Primary mechanisms in the pathophysiology of inferior vena cava (IVC) thrombosis is hypercoagulability secondary to haematological or neoplastic abnormalities, venous stasis due to extraluminal pressure from tumours or infl ammatory process and vessel injury due to trauma . We report here a case of severe Mitral Stenosis presenting with a giant thrombus in inferior vena cava on trans thoracic echocardiogram (Figure-1). Treatment options in the case of IVC thrombus without anatomical variance include life long anticoagulation, mechanical thrombectomy, systemic thrombolytic therapy, transcatheter regional thrombolysis, pulse-spray pharmacomechanical thrombolysis and angioplasty.

Figure 1. Trans Thoracic Echocardiogram showing Giant Thrombus in Inferior Vena Cava (IVC)


Volume IndexTable of ContentsVolume XXI, 2017

EDITORIALChrono-Nutrition – A Resurrection OP YADAVA Jan-Feb 3

Budgeting the Doctors- Aren't we one too many? OP YADAVA Mar-Apr 51

Taxing the Vice = Good Health? OP YADAVA May-Jun 95

Rational Prescription - Don't shoot (....hic) -prescribe off the hips ! OP YADAVA Jul-Aug 129

Generic Medicines – A Cause for Concern ? OP YADAVA Sep-Oct 172

Learning Medicine – Does Pedagogy need a Paradigm Shift ? OP Yadava Nov-Dec 215

REVIEW ARTICLESLeft Atrial Appendage Occlusion Devices –Hype or Hope? MOHAMMED SADIQ AZAM, DAYASAGAR RAO V Jan-Feb 5

PCSK9 inhibitors: Are we Heading for a New Revolution after Statin Therapy BHUPINDER SINGH, RAVINA SHARMA, GURPREET S WANDER Jan-Feb 18

Aortic Valve Surgery Present, Future Beyond 2016 YUGAL K MISHRA, PRITAM PAL Jan-Feb 25

Door to Balloon Time for STEMI in Indians: Challenges and Solutions H.K. CHOPRA Mar-Apr 53

Drug Therapy for Treating Chronic Heart Failure ABHISHEKH SINGH, UPENDRA KAUL Mar-Apr 57

Managing Persistent Hyperglycemia is a Challenge for Patient and Physician MOHIT MINAL, SABOO BANSHI, SANJEEV MAHESHWARI, MOHIT VOHRA Mar-Apr 68

OSA and Heart Failure SN ROUTRAY, SASMITA SWAIN May-Jun 97

Asymptomatic Severe Mitral Regurgitation ROHIT TANDON, SATISH K PARASHAR May-Jun 105

Take Home Messages from a Meeting on "Innovations in Thrombosis Management" Held on January 7-8, 2017 at Mumbai organized by Academy of Cardiology (AOC 2017), www.acadcard.com SATYAVAN SHARMA, NIKHIL RAUT May-Jun 112

Medical Therapy of Heart Failure: Harnessing the Recent Research and Concepts VINOD NIKHRA Jul-Aug 133

Pathogenesis, Classification and Primary Prevention of Atrial Fibrillation PRANAB JYOTI BHATTACHARYYA Jul-Aug 145

Best Practices in Hypertension-2017 P C MANORIA, PANKAJ MANORIA, S K PARASHAR, R K JHA Jul-Aug 148

Endothelial Cell Dysfunction (ECD) Modulation by Diet, Exercise and Drugs GS SAINANI, RAJESH SAINANI Sep-Oct 174

From Irregular Pulse to Slurring of the Speech: Echocardiographic AF Evaluation: Relevant at all Stages SHRADDHA RANJAN, MANISH BANSAL, RAVI R KASLIWAL,H K CHOPRA Sep-Oct 180

Arrhythmias in Acute Coronary Syndrome: Etiopathogenesis and Management CHANDRA BHAN MEENA, DAULAT SINGH MEENA Sep-Oct 189

The Cardioprotection: Recent Research and Concepts Vinod Nikhra Nov-Dec 217Prehypertension: What to Do? A K. PANCHOLIA Nov-Dec 225Algorithm of Management of Type-2 Diabetes — India Specific RAJEEV CHAWLA, SHALINI JAGGI Nov-Dec 230Iatrogenic Hypertension: How to Approach? VITULL K. GUPTA, MEGHNA GUPTA, VARUN GUPTA Nov-Dec 236Hypertensive Crisis: Clinical Recognition and Treatment Approaches T GOVINDAN UNNI Nov-Dec 240

FEATURED ARTICLEComprehensive Management of Modifiable Cardiovascular Risk Factors: Potential for the Polypill A. GEORGE KOSHY Jan-Feb 30

IMAGEVegetations SR MITTAL Jan-Feb 37

Echocardiographic evaluation of complications of infective endocarditis SR MITTAL Mar-Apr 82

Biventricular Hypertrophic Obstructive Cardiomyopathy in a Neonate SR MITTAL May-Jun 117

Tissue Doppler Imaging in Evaluation of Diastolic Dysfunction SR MITTAL Jul-Aug 157

Echocardiography of Hypertrophic Cardiomyopathy SR MITTAL Sep-Oct 197

ECG OF THE MONTHAcute Right Ventricular Pressure Overload – Acute Pulmonary Embolism SR MITTAL Jan-Feb 41

Biventricular Enlargement/ Hypertrophy SR MITTAL Mar-Apr 85

‘J’ Point SR MITTAL May-Jun 121

Low Voltage Electrocardiogram SR MITTAL Jul-Aug 160

ST Segment Elevation SR MITTAL Sep-Oct 203

ST-Segment Depression SR MITTAL Nov-Dec 245

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1CT Nov-Dec 2017 Content Today Nov-Dec.pdf · lecture-based medical education to a problem-based...

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