Pathophysiology of Heart Failure
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Pathophysiology of Heart Failure Shi Yin Foo MD PhD Cardiovascular Translational Medicine Novartis Institute for Biomedical Research April 6 th 2011. Heart Failure: Epidemiology. In the US alone/yr:6 million patients 600,000 incident cases 1 million hospitalizations Is deadly

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

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Pathophysiology of Heart Failure

Shi Yin Foo MD PhD

Cardiovascular Translational Medicine

Novartis Institute for Biomedical Research

April 6th 2011


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

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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

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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

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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


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


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


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


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

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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


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


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


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

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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


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


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


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

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