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

Pathophysiology of Heart Failure

Shi Yin Foo MD PhD

Cardiovascular Translational Medicine

Novartis Institute for Biomedical Research

April 6th 2011


Pathophysiology of heart failure shi yin foo md phd cardiovascular translational medicine

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


Heart failure many causes to a final common outcome

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


Heart failure phenotypes and physiology

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


Systolic dysfunction is better understood

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


Pathophysiology of heart failure shi yin foo md phd cardiovascular translational medicine

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


Pathophysiology of heart failure shi yin foo md phd cardiovascular translational medicine

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


Pathophysiology of heart failure shi yin foo md phd cardiovascular translational medicine

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


Pathophysiology of heart failure shi yin foo md phd cardiovascular translational medicine

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


Pathophysiology of heart failure shi yin foo md phd cardiovascular translational medicine

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


Pathophysiology of heart failure shi yin foo md phd cardiovascular translational medicine

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


Pathophysiology of heart failure shi yin foo md phd cardiovascular translational medicine

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


Pathophysiology of heart failure shi yin foo md phd cardiovascular translational medicine

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


Pathophysiology of heart failure shi yin foo md phd cardiovascular translational medicine

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


Pathophysiology of heart failure shi yin foo md phd cardiovascular translational medicine

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


Pathophysiology of heart failure shi yin foo md phd cardiovascular translational medicine

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


Pathophysiology of heart failure shi yin foo md phd cardiovascular translational medicine

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


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