Systemic Lupus and Cardiovascular Disease

A Brief Overview

Mark A. Menegus, MD, FACC, FSCAI

October 2010

Disclosures--none

ACR Criteria for Lupus*

• Malar Rash• Discoid Rash• Photosensitivity• Oral Ulcers• Arthritis• Serositis (pericard.-

pleura)• Renal Disorder: (eg

proteinuria)

• Neuro Disorder: (seizures/psychosis)

• Heme Disorder: (low platelets, etc)

• Immunologic Disorder (AntiDS DNA; Anti Sm; APL Ab)

• + Antinuclear Ab (ANA)

4 required to include in SLE cohort * These are NOT Diagnostic Criteria

Lupus

Lupus and Inflammation

• SLE is a chronic, inflammatory disease with circulating Autoantibodies (“anti-self”); activated T cells (tissue autoimmunity); immune complexes (Antigen-Antibody) and inflammatory Cytokines (cell messenger proteins)

• Lupus Therapy over the last 4 decades has converted a rapidly fatal disease into a chronic condition

Cardiac Involvement in Lupus

All “layers” of the heart can be involved:

1) Pericardium

2) Myocardium

3) Valves

4) Conducting System

5) Coronary Vessels

Pericardium

• The thin layer(s) covering the heart

• Inflammation (Pericarditis) occurs in 11-54% of Lupus patients

• Often occurs at Onset or with Relapses

• Pericarditis is the most characteristic feature and is one of the ACR/ARA Classification Criteria for Lupus

• Treated with NSAIDs or Steroids

A. Doria; Lupus; 14; 2005

Pericardium and Pleura

Myocardium

• The active muscle (“pump”) of the heart

• Inflammation (“Myocarditis”) occurs in 7-10% of cases (and is treated with Steroids)

• Myocardial Dysfunction, however, is more commonly due to early coronary artery disease, hypertension, renal failure, valvular disease

Doria; Lupus; 2005

Myocardium and Valves

Cardiac Valves

• Connective Tissues that control blood flow into and out of the heart

• Inflammatory lesions usually on Mitral or Aortic Valves (both active and healed)

• Some thickening seen in 40-50% of Echos• “Verrucous” or Libman-Sacks lesions

characteristic but not usual• Significant clinical valve pathology is

unusual (leaking or narrowing)

Doria; Lupus; 2005

Focal Mitral Valve Thickening (51 year-old Lupus patient)

Farzaneh-Far; ArthritisRheum; Dec 2006

Conducting System

• Carries the electrical impulses from the heart’s “pacemaker” (Sinus Node) in the atria (top chambers) thru the Atrioventricular Node to the ventricular (pump) muscles (lower chambers)

• Conduction “Block” rare in adults

• Seen in 2% of children born to mothers with Anti-Ro/SSA positive Lupus

Doria; Lupus; 2005

Coronary Arteries

• Larger (surface) and smaller (myocardial) vessels that supply the working muscle of the heart

• Coronary Artery Disease in 6-10%; Lupus patients have a 4-8 fold increased risk of developing CAD

• Smaller vessel inflammation (vasculitis)-usually in younger patients with active SLE

• Larger vessel inflammation (atherosclerosis)-usually in older patients with long-standing SLE

Doria; Lupus; 2005

Coronary Artery Stenoses (Atherosclerosis)

Acute Coronary Thrombosis

Definitions:

• ACS: Acute Coronary Syndrome, ie chest pain with/without blood enzyme elevation

• MI: Myocardial Infarction—”heart attack”

• PCI: Percutaneous Coronary Intervention, ie angioplasty/stent placement

• CABG: Coronary Artery Bypass Grafting, ie open heart bypass surgery

Vascular Disease in Lupus

Prevalence of M.I., Angina and Peripheral Vascular Disease in Lupus Cohorts:

1) Toronto Lupus Cohort = 10%

2) Baltimore Cohort = 8.3%

3) Pittsburgh Cohort = 6.7%

Mean Age at 1st “Event” was 48-49 years old

Frequently affected: Pre-menopausal Women

Bruce I; Rheum. Dis. Clinics North America 26; 2 May 2000

Cohort Commonality

The Toronto, Baltimore and Pittsburgh Lupus Cohorts each had clinical predictors for early Coronary Heart Disease.

The Three Cohorts all shared two common

features: a. Older Age at Diagnosis of SLE

b. Dyslipidemia (high cholesterol)

Bruce, I.; Rheum.Dis.Clinics North Amer.; 26; 2 May 2000

Vascular Disease and Lupus

Hahn,B; NEJM; Dec 18, 2003

Inflammation and Vascular Disease

• Atherosclerosis is also a chronic inflammatory disorder, with characteristic Cellular (monocyte-macrophage) and Circulating (C-reactive protein-”CRP”)

• 40% of Lupus patients ages 40-45 have established Carotid Artery Plaque

• Later mortality in SLE is more frequently due to Atherosclerosis—aggressive risk reduction is essential.

Salmon; Curr.Opin.Rheum; 13(5) Sept 2001

Carotid Plaque and Lupus

• 197 registry patients from H.S.S.-NYC

• Well matched to controls by age, sex, BP and race

• Carotid Ultrasound (focal protrusion > 50% of wall thickness= Plaque)

• Cardiac Echo to examine valve thickening

• Measured hs-CRP and routine serology

Roman, M: NEJM; 349: Dec 18, 2003

Carotid Ultrasound-I.M.T.

Carotid Plaque and Lupus

Roman; NEJM; 2003

Carotid Ultrasound-Plaque

Carotid Plaque and Lupus

Roman; NEJM; 2003

Coronary Calcium and Lupus

• 65 lupus patients (85% female; avg 40 yo)

• 69 age, sex, race-matched controls

• Excluded prior history vascular disease (stroke, MI, angina)

• Assessed SLEDAI and SLE Damage Scores

• Measured degree (score) of Coronary Calcium on EBCT scan

Asanuma,Y; NEJM; 349; Dec 18 2003

Coronary Calcium and Lupus

Asanuma; NEJM; Dec 18, 2003

*

*

*

Calcified and Non-Calcified Coronary Plaque

Kiani, A; J.Rheumatology;37: 579; 2010

Coronary Calcium and Lupus

Asanuma; NEJM; Dec 18, 2003

Summary-Vascular Disease and Lupus

• Odds ratio for Atherosclerosis in SLE patients= 4.8 in Roman’s study

9.8 in Asanuma’s study• Neither found significant correlation with

inflammatory markers (CRP, etc)• Both found less disease in patients with

greater use of steroids or chloroquine• Traditional risk factors are often under-

treated in the SLE population

Hahn, B; NEJM; Dec 18, 2003

Framingham Risk Assessment

• Ongoing study of Cardiovascular Risk in a US cohort; study inception in 1940’s

• Allows calculation of Expected 10 year risk of developing Coronary Disease

• Factors in:

Age/Sex Diabetes

Blood Pressure LV Hypertrophy

Smoking

Cholesterol

Lupus-Beyond Framingham

• 296 Canadian and Parisian Lupus patients• Excluded 33 with prior Vascular Event• Tabulated vascular outcomes (non-fatal MI, fatal

Coronary event or Stroke) over 8.6 years • Compared these to the “expected” outcome

rates by traditional Framingham risk assessment.

• Observed events far exceeded expected events in this lupus cohort (note: retrospective study)

Esdaile; Arthrit.Rheum.;44; Oct. 2001

Beyond Framingham

Esdaile; Arthritis.Rheumat; 44; Oct. 2001

Myocardial Perfusion (Blood Flow) Imaging

Perfusion Imaging in Asymptomatic Lupus Patients*

Nikpour, M; J. Rheumatology; 36: 2009* f/u for 8.7 years

© 2001 L ippincott Williams & Wilkins , Inc. P ublis hed by L ippincott Williams & Wilkins , Inc. 2

T able 1Accelerated atheros cleros is in s ys temic lupus erythematos us : implications for patient management.S almon, J ane; R oman, Mary

C urrent Opinion in R heumatology. 13(5):341-344, S eptember 2001.

T able 1 . S trategies to reduce atheros clerotic cardiovas cular dis eas e in patients with s ys temic lupus erythematos us AS C VD, atheros clerotic cardiovas cular dis eas e; B P , blood pres s ure; L DL , low-dens ity lipoprotein.

Statins and Vasodilation in SLE

• 64 women with SLE (avg age 31) rec’d Atovastatin 20mg x 8 weeks

• 24 women with SLE (avg age 34) rec’d Placebo x 8 weeks

• 16 healthy female controls

Baseline and 8 week analysis: Brachial Artery Ultrasound with BP cuff “reactive hyperemia” –artery diameter and flow

G.Ferreira; Rheumatology 46; 1560; 2007

Flow-Mediated Dilation (%) STATIN PLACEBO

Ferreira; Rheumatology 2007

Atorvastatin and Vasodilation

• At 8 weeks of active treatment, Total and LDL Cholesterol and TG all decreased*

• Resting Diameter and Flow-Mediated dilation of Brachial Artery increased*

• SLEDAI scores decreased (4.47 to 3.08)* but not in the Placebo group

• Short-term Statin Therapy improved Endothelial function in SLE patients

Ferreira; Rheumatology; 2007* Indicates statistical significance

Clinical Trials of Statins in Lupus

• 10 Trials registered with the NIH• 4 are recruiting• 4 are completed• 1 not recruiting; 1 is terminated• Trials using either Atorvastatin or Rosuvastatin• End-points: ↓Coronary Calcium; ↓Carotid

Disease; ↓ SLEDAI score, etc• To Date: no published results by my search

www.ClinicalTrials.gov

Vascular Health and Disease

Moreno, P; JACC; 53 Nov 25, 2009

Therapy: Post MI / Post ACS

• A—Aspirin and ACE Inhibitors (the “prils”)

• B—Beta Blockers and Blood Pressure

• C—Cholesterol / Cigarettes / Clopidogrel

• D—Diet (for Weight and Diabetes)

• E—Exercise and Education

Conti, CR Clin. Cardiology 2007

Aspirin

• “Class I” for all CAD, MI and PVD patients

• 325 mg/day initially; 81-162mg/d long term

• Post MI: 35 vascular events prevented per 1000 patients x 30d

• 1 life saved at cost of $13 per year!

• ASA allergic?—can use Clopidogrel (Plavix)

Angiotensin Converting Enzyme (ACE) Inhibitors (the “prils”)

• For post MI; overt CHF and Heart (LV) dysfunction even without symptoms

• HOPE trial: 25% women; had 22-25% decline in death rates in MI/CAD/Diabetic patients without CHF

• ex: Lisinopril 10-40 mg/d

• If ACE intolerant (allergy or dry cough) use and ARB (ex: Losartan)

Lipid Lowering

• 13-33 death/Mi prevented per 1000 patients x 5 yr

• Measure lipids on initial blood draw

• Start Rx acutely—statins are Anti-Inflammatory (ex: Atorvastatin 10-80/d)

• Muscle: usually Myalgias—check CPK; rechallenge or use different statin (pravastatin)

• Liver: about 1/1000 asymptomatic mild elevation in liver enzymes

NCEP-ATP III Guidelines

• Total Cholesterol

< 200 desirable

200-239 borderline high

> 240 high

NCEP-ATP III Guidelines

• LDL

<100 optimal

100-129 near-opt.

130-159 borderline high

160-189 high

>190 very high

Risk Factors (that modify LDL goal)

• Smoking• High BP• Low HDL (< 40)• Family history CAD• Central Obesity• Physical Inactivity• NOTE: Diabetes, PVD, Aortic Aneurysm and

Coronary Calcium are CHD “Equivalents”

LDL Goals

Risk Factor LDL Goal 10 year event rate

CHD or Equivalent

< 100 mg/dl > 20%

2 or more Risk Factors

< 130 mg/dl 10-20%

0-1 Risk Factors

<160 mg/dl < 10%

Framingham Risk: 10 vs 30 year(25 yo female)

Pencina, M; Circulation; 119; 2009

Framingham Risk: 10 vs 30 year (45 yo female)

Pencina, M; Circulation; 119; 2009

Therapy = “T.L.C.” (Therapeutic Lifestyle Change)

• Decrease Saturated Fat in diet

• Decrease Weight (ideal BMI = 18.5 to 24.9 kg/m2)

• Increase Physical Activity—even walking 30 min day

Incorporating Triglycerides into the Mix

• The typical “Lupus” Lipid profile often has low HDL (“good” cholesterol), elevated Triglycerides and elevated levels of Lp(a) (a lipoprotein that ties into the clotting cascade)

• This profile is similar to the average patient with Diabetes

• Calculation of “Non-HDL” Cholesterol allows us to set goals with TG as well

• Lp(a) may be modifiable with exercise and Niacin

Incorporating Triglycerides(Total Chol – HDL = “Non HDL” )

Risk LDL Goal Non-HDL Goal

CHD or equiv. <100 <130

2 or more risk factors

<130 <160

0-1 risk factors <160 <190

Lipid Lowering, cont’d

• High Total and LDL Cholest Statins

(zocor, lipitor,etc)

• High Trig and Low HDL Cholest Fibrates (lopid, tricor)

• High LDL and Trig and low HDL Cholest Niacin (niaspan)

• High Triglycerides prescript. Fish oil (Omega 3 FAs) (lovaza)

Diet Modification: Healthy Choices

• Fruits and Vegetables• Whole Grain and High Fiber• Oily (cold water) fish 2 x / week• Alcoholic drink not > 1/day• Sodium (Na+) < 2.3 gram/day• Saturated Fat < 10% of total calories• Limit Trans-Fat: Baked Goods and Fried

Foods

Hormone Therapy

• Estrogen Replacement with or w/o Progestin—of no benefit in preventing CHD

• Small but increased risk of Stoke

• Use short term for peri-menopausal Sx only

• Estrogen receptor modulators (raloxifene) of no benefit for CHD.

Cardiac (Exercise) Rehab

• Prevents 23 deaths per 1000 patients

• Safety: Mortality 1 / 784,000 pt-hours

• Cost: $1200 / QOL-year (comparable to Left main surgery!) By comparison, Dialysis costs $40,000 / QOL-yr

• Usually 3 x /week for 12-16 weeks

• YET-- < 20% of patients get referred??

Smoking Cessation

• Smokers have 3 x the risk of MI of non-smokers

• Cessation prevents 70 deaths per 1000 patients x 1 year

• YET: few are asked and few are counseled

• My motto: “Attack ‘em in the hospital and kick ‘em when they’re down”!!

Still Lacking Evidence

• Although it’s argued that Lupus and other disorders (RA) are “vascular risk equivalents” this is NOT proven or accepted

• No evidence (yet) for routine (imaging) screening in Lupus for asymptomatic vascular disease

• No evidence (yet) for empiric therapy with statins, etc in Lupus

• Major organizations (ACC, AHA, ACR) as yet, have no specific guidelines for Lupus and Vascular disease (“evidence-based medicine”)

Do…..

• See your MD regularly and report new signs or symptoms

• If you have routine vascular risk factors (or a prior “event”, take your medications (statins, aspirin, etc)

• Take the lowest dose of steroids and continue antimalarials

• Exercise 4-5 x week for 30-40 min (even a good walk)

• Stop Smoking!• Eat fresh and “colorful”

foods—avoid processed• If asked to participate in

clinical trials—consider it strongly--that’s how we develop evidence-based treatment