ROLE OF IMAGING INLV HYPERTROPHY

FOCUS ON HYPERTENSION AND

OTHER NON SPECIFIC CAUSES

Alban REDHEUIL Professor of Radiology, Cardiovascular Imaging Department

Institute of Cardiologie, La Pitié Salpêtrière, Paris

Laboratoire d’Imagerie Biomédicale LIB-INSERM-CNRS

ICAN Imaging Core Lab

SFICV journées scientifiquesVichy, juin 2019

Hypertension

• #1 cardiovascular disease in the world (prevalence) and increasing / age• Main risk factor for mortality and cardiovascular events (MI, stroke, PAD) in a real-life setting

Myocardial Hypertrophy

• Cardiomyocytes are terminally differentiated after birth

• AGING : physiological LVH maintaning cardiac efficiency over time

• PATHOLOGICAL LVH: adverse CV events, HF, arrhythmia, death

Normal Hypertrophie

Etiologies of LVH

Hypertension (BP)

Aortic StiffnessArterial Stiffness

Aortic valve stenosis

Pressure overload

X

Myocardial DiseaseFINITE CARDIOMYOCYTE

CAPITAL

ADAPTIVE RESPONSE TO WORKLOAD

PATHOLOGICAL

HYPERTROPHY

HEART FAILURE

Cardiomyocyte hypertrophy-Inherited: HCM-Myocardial hypoxia

- Obesity- Diabetes- Aging- MI- Obs. Pulmonary Dis.- Anemia

Extracellular matrix storage-Fibrosis-Amyloid-Fabry-EdemaLV WALL STRESS WS

Volume overload

Valvular regurgitationCKD

Tissue Characterization

PerfusionMicrovesselsCoronary arteries

Adipose tissueSteatosis

Extra Cellular MatrixCollagen fibers

Myocardium

CardiomyocyteContractile Cell

LV Geometry and Events

MESA n=5000FU= 4 years

Definition of thresholds of risk

Bluemke et al. JACC 2008

LV massCumulative events

LV massCumulative events

CHDCHD

StrokeStroke

M/VM/V

Which heart is hypertrophic ?

Maximal thickness = 15 mmMass index = 80 g/m2

EDV index = 67 ml/m2

M/V=1.2

Maximal thickness = 6 mmMass index = 105 g/m2

EDV index = 210 ml/m2

M/V=0.5

Diastole SystoleIRMIRM

VentriculographieVentriculographie

d’après Netter

EchocardiographieEchocardiographie

Etude de la contraction myocardique en IRM:

CMR vs. Echo

Armstrong et al. iJACC 2012

No study directly compared the methods for the ability to predict events, agreement in hypertrophy classification, or performance in cardiovascular risk reclassification

ECHOCMR

Reproducibility –Availability ++Data on events ++

Reproducibility ++Availability +/-Data on events +

Cardiac Remodelingimportance of precision imaging and reproducibility

Grothues F. et al. Am J Cardiol

Altérations géométriques : remodelage ventriculaire

Atteinte du VG

Remodelage excentrique•Dilatation VG

•Amincissement parois VG

•Hypertrophie (masse)

Dilatation OG

Atteinte VD•Dilatation VD

•Dilatation OD/VCI/VSH

Volumes, masse, épaisseurs 4 cavités

Volumes, masse, épaisseurs 4 cavités

Ventricular Remodeling in VHD

Normal Pressure overload Volume overload

ConcentricHypertrophy

EccentricHypertrophy

Etude de la contraction myocardique en IRM:•Approche multiphase-multicoupe synchronisée au cycle cardiaque => anatomie•Pondération T1/T2•Résolution temporelle: 1 image toutes les 30 à 60 ms

diastole systole

apex

médio-ventriculaire

base

coupe transverse

calcul de la fraction d’éjection globale et régionale

MRI Strain Imaging to predict Heart Failure in Asymptomatic Individuals

Osman N JHU

Choi EY et al. Eur Heart J 2013

MESA N=1768FU=10 years

Whole Heart Strain Imaging

Evin M. et al. JMRI 2015Lamy J. PhD LIB

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Doppler echocardiography

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Young male (35 years)

Transmitral

Aortic

DTIVRT

Ef

Af

Bollache & Kachenoura . JCMR, 2010Ashrafpoor & Kachenoura, ESC, 2012, revision in JACC CVi

Mitral annulus longitudinal velocity

Transmitral flow

Fonction diastolique

Diagnostics différentiels

• H43

• HTA

• 5xTt

CoA native

HTA sujet âgé

Parois:AS=12-13mmANT=10mmLAT=8mmINF=9mm

Diagnostic d’HVG

F34SportivePas ATCDAsympto

ETT:15mm

LV volumesEDV=107ml=68ml/m2

ESV=36ml=23ml/m2

LVEF=66%CO=4.7l/min

LV Mass90g=57g/m2

Wall Thickness AS=10mmANT=8mmLAT=6mmINF=8mm

BG, 36 y/o male

Wall thickness = 12-15 mmMass index = 80 g/m2

EDV index = 67 ml/m2

M/V=1.2LVEF=68%Normal RWM

BG, 36 y/o male

LGE

T1 pre

T1 post

T2

Diastolic Function

E’ A’

E ANon specific junctional LGE Normal T2=46ms

Ashrafpoor et al. Eur Radiol 2014

BG, 36 y/o male

• American football player• Headaches and fatigue, android obesity

(115kg/186cm=BMI: 33)• No personal or family history of HTN• Severe hypertension: SBP=200mmHg• ECG=LVH, incomplete LBBB• Therapy x4: Sartan+CaI+BB+diuretic followed R

• Renal function normal, Cortisol + Aldosterone normal• Renal arteries and absominal aorta normal in US +CT • Adrenal glands = normal CT• Femoral and carotid US normal• Normal exercise test and Holter (ECG)• TTE = septum=17mm => addressed for suspicion of

HCM

Role of cMRI in the case of BG

• Precise measurement of LV wall thickness, volumes and mass

– Increased thickness (15mm not 17mm in TTE), not LV mass

– Concentric remodeling

• Etiology

– Normal mitral apparatus, normal RV

– No fibrosis within hypertrophied myocardium

– No edema, signs of amyloid, iron or PAG deposits

– No aortic coarctation

• Complications

– No myocardial infarction

– Normal systolic and diastolic function

Subsequent results and evolution

– Genetics negative for HCM

– Control of BP with sartan

MRI PROTOCOL IN HTN•LV cine LA+SA•Native and Post-Gd T1 mapping•T2 mapping•LGE

•Aortic valve cine•Aortic valve and ascending aorta V-ENC imaging•3D aorta

•Renal arteries: 3D MRA•Adrenal imaging: T1w, T2w, Dixon (VIBE pre/post Gd)

Longitudinal changes in LV structure and EF in cMRI

N=2935 participants with baseline and follow-up cardiac MRI in the MESA

Eng et al. Radiology 2015

Issues with defining normal LV mass values

• Geographic / cultural / ethnic differences– In MESA (Eng et al.) BMI=27.7 vs. 24.4 in

UK biobank (Petersen et al. 2017)

• Methods– In Kawel et al. JCMR 2015 the 3 studies

included papillary muscles in LV mass vs. exclusion in UK biobank (Petersen et al. 2017)

• Other determinants: HTN, Diabetes, CKD

• MRI strengths– Reproducibility

– Precision: internal check = systole=diastolePetersen et al. JCMR 2017

Normal values for LV mass and geometry

Kawel Boehm N. et al. JCMR 2015 Petersen. et al. JCMR 2017

MEN

WOMEN

LV mass index upper limitMen: 85 vs. 72 g/m2

Women: 81 vs. 55 g/m2

Which heart is hypertrophic ?

Maximal thickness = 15 mm ABNORMAL US/UKMass index = 80 g/m2 NORMAL US/ ABNORMAL UKEDV index = 67 ml/m2 NORMAL US/UKM/V=1.2 ABNORMAL US/UK

Maximal thickness = 6 mmMass index = 105 g/m2 ABNORMAL US/UKEDV index = 210 ml/m2 ABNORMAL US/UKM/V=0.5 NORMAL UK (NA US)

Hypothesis & expected results in Hypertension

Control group Treatment normalized hypertension

Grade 1 or 2 hypertension

Grade 3 hypertension

Heart-LV shape-Fibrosis- Systolic and Diastolic Function

Aorta-Stiffness indexes-Thickness-Curvature

Retinal arteries- Wall to lumen ratio

? ?

Controlled HypertensionTesting the limits of cMRI

• Treibel et al. JCMR • N=40 HTN with N=26 no LVH and 14 with

LVH• T1 native and ECV increase in HTN only in

the presence of LVH. No significant change in ECV (p=0.06)

• Increment is small• Determinants = LV mass, LV thickness

• Non ischemic pattern LGE = 28% (junction, papillary, mid-patchy)

• Note: 13 % of patients had new diagnoses of hypertrophic cardiomyopathy or silent infarction

Discriminating HTN cardiomyopathy vs. HCM

• HCM, n=95; hypertension, n=69

• Native T1 = best predictor of HCM vs. HTN

• Association with increased LV mass, thickness, LGE presence and extension

• Major drawback = cutoff

Increased ECV and T1 associated with altered contraction in HTN only if LVH is present

Kuruvilla et al. JACC imaging 2015

Systolic Function

Systolic Function

Diastolic Function

Aortic distensibility concentric remodelingAltered Strain increased LV mass

Biomarkers of sequential effects of increased afterload?

Concentric remodeling and LVH in Hypertension are most associated with LV dysfunction and Aortic Stiffness

Rodrigues JCL, et al. Heart 2016

Cardiovascular effects of Aldosterone

AldosteroneAldosterone AortaAorta

MyocardiumMyocardium

HypertensionHypertension

Structure

Hypertrophy

Structure

Hypertrophy

CompositionFibrosis

Volume overload

CompositionFibrosis

Volume overload

Biology/Cell

Oxidative stressApoptosis

Inflammation

Biology/Cell

Oxidative stressApoptosis

Inflammation

Cardiovascular morbidity and mortalityHeart Failure

Arrhythmias, Sudden death

Cardiovascular morbidity and mortalityHeart Failure

Arrhythmias, Sudden death

FibrosisInflammationStiffness

Regulationof extra cellular matrix

= IMAGING TARGET

Regulationof extra cellular matrix

= IMAGING TARGET

Increased afterload is related to increased

cardiomyocyte volume

Increased aldosterone is independently related to

increased ECM

Spironolactone prevents fibrosis and cellular hypertrophy in mice

Coehlo-Filho et al. JAHA 2016

COEURALDO Study

• Hypothesis: the respective effects of aldosterone and hypertension on intra and extracellular myocardial mass beyond the degree of global hypertrophy be characterized and quantified by imaging in humans

• Design: double case-controlled study enrolling 80 asymptomatic participants in 4 groups of 20

– Healthy volunteers– Bartter-Gitelman syndrome– Essential hypertension – Primary hyperaldosteronism

• Exclusion criteria included: diabetes, any preexisting cardiomyopathy, treatment interfering with RAAS

• Main measures: clinical, ECG, Biology, Tonometry, MRI

Interaction between HTN and ALDO to promote myocardial fibrosis

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Redheuil A., Blanchard A. Kachenoura, N,Azizi M, Mousseaux E. et al. submitted

Cardiac Remodeling in Obesity

Aurigemma G P et al. Circ Cardiovasc Imaging. 2013

Obesity, Epicardial Fat and CAC

N=573 healthy post menopausal womenDe Vos et al. EHJ 2008

N=4093 healthy individualsMahabadi et al. JACC 2013

LV Geometry in obesity in MESA

Turkbey et al. JACC imaging 2010

N=5098 multiethnic multicenter general US population study

LV massLV mass LV volumeLV volume

M/VM/V

BMIBMI Fat massFat mass

LV massLV mass LV volumeLV volume

M/VM/V

Cardiac Remodeling in Obesity

Aurigemma G P et al. Circ Cardiovasc Imaging. 2013

Effect of Bariatric Surgery in CMR

Gaborit, Clément et al. JACC

LV MassLV Mass Cardiac outputCardiac output E/AE/A LA areaLA area

Epicardial fatEpicardial fat Visceral abdominal fatVisceral abdominal fat Myocardial TG (%)Myocardial TG (%)

Unrecognized MI detected by CMR

• N=936 ICELAND MI Study in older adults

• Diagnosis and prognosis CMR > ECG

• Metabolic rather than atherosclerotic profile

Schelbert et al. JAMA 2012

Detecting myocardial scar in Diabetes

• EDIC Study: type I DM

• N=749 with CMR

• Scar = 4.3%

• Correlates:

– Age, HTN, male

– LV mass, EDV

– HbA1c, macroalbuminuria

Turkbey E B et al. Circulation. 2011;124:1737-1746

Prognosis of unrecognized scar in diabetes

Kwong R Y et al. Circulation. 2008;118:1011-1020

N=187

T1 mapping in diabetes

• 50 diabetic patients with normal LV ejection fraction (EF) and no underlying coronary artery disease or regional macroscopic scar on MRI delayed enhancement

Ng. et al. Circulation cvi 2011

ECV in diabetes for prognosis ?

• N=1176• ECV increased in diabetes = ECM expansion• Independent of inducible ischemia or chronic MI• Reversible with RAAS inhibition

• Detectable and treatable phenotype?

Schelbert et al. EHJ 2013

Cortisol and cardiac remodeling and dysfunction

JCEM 2014

T1 mapping in Cushing’s DiseaseA Pilot Longitudinal Study

Native T1Native T1

LVEFLVEF

LV massLV mass M/VM/V

Roux C, Kachenoura N, Redheuil A. JMRI 2016

Unexplained LVH detected by MRI in the general population

Massera et al. JAHA 2019

Phenotypical Heterogeneity in HFpEF

LVHLVH

LA dilationLA dilation

Diastolic DysfunctionDiastolic Dysfunction

Lewis et al. JACC 2017

New Imaging Biomarkers for HFpEF

• N=112 (62 with HFpEF, 22 HTN, and 28 healthy controls)

• Echo GLS and MRI ECV were the only variables able to independently stratify among the 3 groups of patients.

• ECV was the best technique for differentiation between HTN and HFpEF (ECV AUC: 0.88; GLS AUC: 0.78; p <

0.001). • ECV cutoff of 31% gave 100% sensitivity

and 75% specificity. • ECV was significantly higher and GLS was

significantly reduced in subjects with reduced exercise capacity (lower peak oxygen consumption and higher minute ventilation–carbon dioxide production) (p < 0.001 for both ECV and GLS)

Ify R. Mord JACC cvi 2018

Myocardial Microstructural Dynamics by In Vivo Diffusion Tensor MRI

Challenge in LVH = Classify Disease and Stratify Risk

• Physiological or pathological?

• Imaging ?

• Proteomics ?

• Metabolomics ?

• Genetics ?

• New targets for therapy