Pathophysiology of Heart Failure Shi Yin Foo MD PhD Cardiovascular Translational Medicine

1. Pathophysiology of Heart Failure Shi Yin Foo MD PhD Cardiovascular Translational Medicine Novartis Institute for Biomedical Research April 6th 2011

2. Heart Failure: Epidemiology • In the US alone/yr: 6 million patients • 600,000 incident cases • 1 million hospitalizations • Is deadly • In-hospital mortality 4-5% • Short-term mortality (30day) 9-11% • Long-term mortality (1year) 24-28% • (5 year) 45-59% • Repeat hospitalizations are a significant burden • 14% at 30 days • 40% at 6 months • CHF costs are ~$55 billion annually, with hospitalizations >60%, medications ~5% Both an opportunity and imperative for improvement 2 | Heart Failure | Shi Yin Foo | April 6th 2011 | ACoP 2011 | Business Use Only

3. Heart Failure: many causes to a final common outcome Hypertensive heart disease Right heart failure Atherosclerosis Cardiomyopathies Rheumatic heart diease Congential, inflammatory, and other causes Heart failure : when the output of the heart is insufficient for the needs of the body Organ hypoperfusion (most evidently renal) Hepatic and pedal edema Decreased exercise capacity Pulmonary congestion 3 | Heart Failure | Shi Yin Foo | April 6th 2011 | ACoP 2011 | Business Use Only

4. Heart Failure: Phenotypes and physiology Atherosclerosis Hypertension Pressure overload → myocardial hypertrophy Coronary occlusion → myocardial infarct Systolic dysfunction i.e. Heart Failure with impaired Ejection Fraction “Diastolic dysfunction” i.e. Heart Failure with Preserved Ejection Fraction 4 | Heart Failure | Shi Yin Foo | April 6th 2011 | ACoP 2011 | Business Use Only

5. Systolic dysfunction is better understood HCVD – hypertensive cardiovascular disease CHD – coronary heart disease Etiology of Heart Failure (McKee 1971) Heart failure as a result of hypertensive heart disease is ~60% of all heart failure Nevertheless, systolic dysfunction is better understood and better treated HFPEF is less tractable because it requires cellular-level approaches but has become increasingly important to understand and treat 5 | Heart Failure | Shi Yin Foo | April 6th 2011 | ACoP 2011 | Business Use Only

6. The Heart as a Pump -a focus on the left ventricle • Preload • Myocardial stretch determines contractility (Frank-Starling mechanism) • Afterload • Determines the energetics and efficiency of myocardial contractility • Affected by • total body volume • venous capacitance/return • pulmonary resistance • Affected by • systemic vascular resistance (blood pressure as surrogate) • discrete constrictions • intrathoracic pressure Cardiac output = stroke volume x heart rate (Litres/min) CO = SV x HR 6 | Heart Failure | Shi Yin Foo | April 6th 2011 | ACoP 2011 | Business Use Only

7. The Heart as a Pump PV loops as graphical representation of cardiac function Pressure-Volume loops are useful to study/predict the effect of drugs on cardiac function, but physiologic changes are seldom only in one parameter DDAH.org Cardiac output = stroke volume x heart rate (Litres/min) CO = SV x HR Does not take into account myocardial energetics – inferred from systolic contractility, but no capture of diastolic energy use 7 | Heart Failure | Shi Yin Foo | April 6th 2011 | ACoP 2011 | Business Use Only

8. The Heart as a Pump Pathophysiological changes e.g., after myocardial infarction Coronary occlusion ↑↑ myocardial workload and strain Myocardial cell death Blood pressure maintenance via vasoconstriction (↑↑ afterload) ↓↓ Cardiac contractility Fluid retention (↑↑ preload) ↓↓ Renal perfusion Secretion of neurohormones to maintain organ perfusion 8 | Heart Failure | Shi Yin Foo | April 6th 2011 | ACoP 2011 | Business Use Only

9. What does Acute Decompensated Heart Failure look like? - an example from the clinic A 75-year-old man states that for the past two months, he has had gradually progressive fatigue; occasional cough; dyspnea (shortness of breath) during exertion; orthopnea (shortness of breath while lying down); ankle edema; and a 10-lb (22-kg) weight gain. He denies chest discomfort, fever, or chills. He has hypertension treated with diltiazem, quit smoking 20 years ago, and rarely drinks alcohol. Physical examination :- Heart rate 105 bpm, blood pressure 145/85 mm Hg Respiratory rate 18/min, oxygen saturation 94% on room air. Distended jugular veins and mild hepatic fullness. Pulmonary examination shows expiratory wheezing and wet rales. The heart rate is regular without murmur, the apical impulse is displaced. 2+ ankle edema. Laboratory values show acute renal failure with creatinine of 2.1mg/dL Echocardiography shows moderate left ventricular dilation with segmental hypokinesis in the anterior wall, LVEF of 30%, left atrial enlargement, mild mitral and tricuspid valve regurgitation, and pulmonary artery systolic pressure ranging from 45 mm Hg to 50 mm Hg. Angiography in this patient shows a chronically occluded left anterior descending artery. Cardiac output = stroke volume x heart rate (Litres/min) CO = SV x HR 9 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

10. Freedom from the Congestion of Acute Heart Failure requires Preload Reduction, i.e. getting rid of body sodium and water New York Heart Association Class I – No symptoms or limitation of activity II – Mild symptoms and slight limitation of ordinary activity III – Marked limitations; shortness of breath with minimal exertion (20-100m walk) IV – Severe limitations to activity; shortness of breath at rest, unable to perform activities of daily living without symptoms Lucas C, et al. Amer Heart J 2000; 140: 840-7. 10 | Heart Failure | Shi Yin Foo | April 6th 2011 | ACoP 2011 | Business Use Only

11. How clinically relevant are cardiac hemodynamics per se? Fluid overload is the most proximal and common cause of acute heart failure NYHA I NYHA II NYHA III NYHA IV % of HF Patient s NYHA Classification 33% 6% 32% 29% Compensated • 5-Yr Mortality = 50–70%* • Five-year mortality rates are comparable to certain types of cancer and other chronic diseases Episode of acute decompensation Chronically Decompen- sated Clinical Status • 1-Yr Mortality = 10–20%* • One-year mortality rates increase dramatically with NYHA class progression Acutely Decompensated Disease Progression The underlying cause of HF hospitalizations has traditionally been viewed as a problem of fluid overload 11 | Heart Failure | Shi Yin Foo | April 6th 2011 | ACoP 2011 | Business Use Only

12. The Heart as a Pump Hemodynamic regulation and the Cardiorenal Axis ↑↑ myocardial workload and strain ↓↓ Cardiac contractility Blood pressure maintenance via vasoconstriction (↑↑ afterload) Hemodynamic? Neurohormonal? Fluid retention (↑↑ preload) ↓↓ Renal perfusion Secretion of neurohormones to maintain organ perfusion • Homeostatic mechanisms activated when cardiac output↓↓ via the CardioRenal Axis • Derangements of this axis are arguably the single biggest driver of morbidity and • mortality in HF • What is the ideal point of regulation of this axis? 12 | Heart Failure | Shi Yin Foo | April 6th 2011 | ACoP 2011 | Business Use Only

13. The Heart as a Pump Neurohormones as key regulators of the heart as a pump • Neurohormones implicated in heart failure: • Renin-Angiotensin-Aldosterone System (RAAS) • Catecholamines • Endothelin • Natriuretic Peptides • Others • Neurohormones are potent and pleiotropic • affect myocardium, vasculature, renal, cerebral beds • affect short term hemodynamics and natriuresis (renal sodium loss) • regulate longer term fibrosis, remodeling, apoptosis Modulations of the RAAS is best understood, validated and in clinical use 13 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

14. The RAAS system Heart failure is usually a inappropriately high angiotensin II, aldosterone state vasoconstriction and fibrosis fibrosis Aldosterone ↓perfusion Salt/water retention, fibrosis ACE Renin Angiotensin II Angiotensin I Angiotensinogen 14 | Heart Failure | Shi Yin Foo | April 6th 2011 | ACoP 2011 | Business Use Only

15. Neurohormonal modulation affects heart failure outcomes ~ no mortality benefit of hemodynamic optimization • Neurohormonal activation contributes to • increased oxygen consumption • accelerated myocardial remodeling/fibrosis • lowered threshold for arrhythmias • Neurohormonal antagonism leads to • decreased mortality • decreased hospitalizations • improved symptoms and quality of life • CONSENSUS: • Severe HF • 6 mth mortality placebo =44% • ESCAPE: • Severe HF, hemodynamically optimized • No difference in morbidity or mortality 15 | Heart Failure | Shi Yin Foo | April 6th 2011 | ACoP 2011 | Business Use Only

16. Implications of hemodynamics and neurohormones in HF Acute symptom relief vs mortality NYHA I NYHA II NYHA III NYHA IV % of HF Patient s NYHA Classification 33% 6% 32% 29% Compensated • 5-Yr Mortality = 50–70%* • Five-year mortality rates are comparable to certain types of cancer and other chronic diseases Episode of acute decompensation Chronically Decompen- sated Clinical Status • 1-Yr Mortality = 10–20%* • One-year mortality rates increase dramatically with NYHA class progression Acutely Decompensated Disease Progression DEATH Muntwyler J, Abetel G, Gruner C, et al. Eur Heart J. 2002; 23:1861-1866. Ahmed A., Aronow W., Fleg J. American Heart Journal, Volume 151, Issue 2, Pages 444-450. 16 | Heart Failure | Shi Yin Foo | April 6th 2011 | ACoP 2011 | Business Use Only

17. Heart Failure ~ summary and take-homes • Physiology of the heart can be likened to a pump • Cardiac hemodynamics can be predictable • Cardiac hemodynamics do not predict longer term cardiac outcomes • Neurohormones, especially the RAAS system, play a critical role in both the acute regulation of hemodynamics and the modulation of longer term morbidity and mortality • The lessons learned thus far apply only to systolic Heart Failure 17 | Presentation Title | Presenter Name | Date | Subject | Business Use Only