Heart Failure, Shock and Hemodynamics Howard Sacher D.O. Long Island Cardiology

Learning Objectives To gain insight into the definition of, epidemiology of, pathophysiology of, changes in treatment recommendations for, clinical trials pertaining to, and prevention of ventricular dysfunction and heart failure. To understand the pathophysiology of heart failure with specific reference to the syndrome's molecular biodynamics, humoral, neurohumoral, and cytokine milieu.

Learning Objectives (cont.) To place in proper perspective the clinical trials that have shaped our contemporary heart failure therapeutic philosophies. To understand alternatives to pharmacologic therapies of heart failure.

Heart Failure Today’s perception of heart failure is quite different from that of only a few decades ago. Recent insight emphasizes the importance of neuro-endocrine, humoral, and inflammatory factors perpetuating heart failure originally precipitated by many disparate diseases.

Cont’d Heart failure should be not be considered a specific disease but rather a syndrome comprised of molecular genetic, organelle, contractile-protein and circulatory neurologic and humoral abnormalities that develop after a spectrum of diseases produce cardiac or circulatory injury. Heart failure patients can, in fact, be entirely asymptomatic Broadly the definitions allow earlier identification of at-risk populations so that intervention can begin earlier and attenuate the devestating morbidity and mortality of heart failure.

Cont’d Experimental and clinical trials now give clinicians guidance on the benefits and detriments of surgical and pharmaco-therapeutic strategies, allowing physicians to better diagnose and treat patients with heart failure. An integrated overview of the heart failure mileu shows that the molecular dynamics of the heart are critical to syndrome evolution Heart failure is a dynamic situation providing opportunity for both prevention and treatment.

Ventricular Dysfunction Is comprised of systolic and diastolic dysfunction The initial myocyte injury can be intrinsic as in cardiomyopathy of muscular dystrophy or extrinsic, as in anoxia (myocardial infarction), inflammation (lymphocytic myocarditis) or chemical toxins(anthracyclines).

Cont’d Resulting increase in interstitial matrix decomposition comprised of varying quantities of fibrin, collagen, and other ground substances effects diastolic cardiac properties making the heart much more stiff and therefore non- compliant. This plays a significant role in precipitating significant decline in global pump performance. It is not known if therapies currently used for heart failure have beneficial effects on this matrix or if they do to what degree.

Disease Processes Trigger the molecular genetic cellular physiologic and functional alterations that cause failure of systems, producing contractile dysfunction or impaired filling.

Hemodynamic Abnormalities Systolic and diastolic ventricular dysfunction then cause hemodynamic abnormalities that create flow volume and pressure derangements in the heart and systemic blood vessels

Compensatory Mechanisms A. Triggered by hemodynamic abnormalities are many and varied B. They include activation of the renin- angiotensin-aldosterone system (that ultimately induces salt and water retention and increased systemic vascular resistance) and sympathetic nervous system up-regulation (that augments cardiac contractility and increases heart rate, venous and arterial tone).

Hemodynamic Abnormalities of HF trigger many subsequent compensatory mechanisms designed to augment peripheral organ perfusion Increased sympathetic tone increases: –Contractility –HR –Venous and Arterial Tone –Pressure RAA system is upregulation Ventricular dilation and hypertrophy are compensatory mechanisms designed to augment SV and peripheral organ flow

Symptoms and Physical Findings As metabolic abnormalities and compensatory mechanisms intertwine, they create a variety of metabolic changes, symptoms, and physical findings. –Azotemia-prerenal due to hypoperfusion (decrease effective arterial volume) –Hyponatremia- decrease circulating volume leading to increased thirst and vasopressin, also diuretics without water restriction

Cont’d –Hypokalemia- diuretics –Hypomagnesemia- diuretics –Hyperuricemia- diuretics –Acidosis- hypoperfusion –Alkalosis- diuretics

Please see Essentials of Medicine, Cecil pg 49 Fig 5-6

Generally Pt’s dying from HF have either sudden cardiac death 2 nd to: –Fatal Arrhythmias Electrolyte Abnormalities Inc. serum catacholamines Ischemia –Developing significant systemic hypoperfusion Congestion Low Cardiac Output

Basic Elements of Heart Failure Syndrome Impaired contractility cause depressed cardiac output that leads to sympathetic nervous and inflammatory cytokine and system activity. Increased arteriolar vasoconstriction. Increased impedance to left ventricular ejection Decreased renal perfusion resulting in retention of salt and water with subsequent increase in cardiac filling pressures and congestion or edema.

Pathophysiology of Heart Failure Heart failure is difficult to simply define and is a wide spectrum of processes ranging from ischemia to myocardial toxins to volume or pressure overload and even genetic abnormalities that create the mileu of heart failure which is characterized by multiple neuro-endocrine, humoral and inflammatory feedback loops.

Cont’d As compensatory mechanisms themselves become problematic by exacerbating detrimental remodeling processes –Myocardial hypertrophy –Chamber enlargement Abnormalities characterizing heart failure should be considered physiologic, hormonal, cellular, subcellular, organelle, molecular biodynamic and genetic.

Cont’d Understanding the hallmark of cardiac response to injury, of myocyte growth and hypertrophy, interstitial fibrosis, apoptosis, sarcomere slippage and cardiac chamber enlargement is important when attempting to explain circulatory dysfunction. Heart failure should be described as –Acute or chronic –Right or left sided –Systolic or diastolic –Asymptomatic, minimally symptomatic or symptomatic

Blood Pressure Parameters BP=CO x TPR CO=HR x SV Carotid aortic baroreceptors and central nervous system and medullary vasomotor and cardiac centers modulate heart rate, PVR, cardiac contractility and venous tone which influences venous return and preload. Several factors are responsible for left ventricular diastolic dysfunction –Fibrosis and hypertrophy- increase diastolic chamber stiffness –Ischemia produces abnormalities of energy dependent relaxation Most cases of advanced symptomatic heart failure are a combination of significant systolic and diastolic dysfunction

Study shows that HF patients have lower oxygen carrying capabilities (VO2), decreasing exercise tolerance

HF patients are noted to have an inappropriate increase in PCWP and increased EDV

The flat stroke volume index curve is pathopneumonic of heart failure

HF Pt’s shows an increase in LVEDV consistently with a concomitant rise in PCWP with exercise

Myocyte Adaptation Protein turnover in normal myocyte is orderly and forms an adult myocyte and specific gene products Terminally differentiated post-natal myocytes are not capable of cell division Contractile proteins regenerate every days

Cell Membrane Receptors Activation of these receptors (GH, A2, NE, TNF- a, etc) precipitates second messengers such as cAMP, Inositol-Tri-Phosphate that then induces intracellular mediators such as phosphokinase C. The adult myocyte genetic program is induced by intramuscular mediators of gene activity such as C-fas, C-jun to produce adult and fetal muscle specific gene products. In heart failure this leads to unnatural growth of the cell that leads to hypertrophy and eventually apoptosis.

Cont’d The induction of fetal protein phenotype ultimately produces large myocytes that do not contract with normal vigor.

Necrosis and Apoptosis Both are important in the life and death cycle of the myocyte. Apoptosis- cell death by myocyte condensation without disruption of cell membrane. Eventually there is cell fragmentation with pinocytosis of cell content and phagocytosis of neighboring cells.

Cont’d Necrosis characterized by cell surface membrane disruption, inflammation and fibrotic replacement. In heart failure there may be acceleration of apoptosis (accelerated senescence).

Heart Failure Mileu A. Neurohumoral –With baroceptor dysfunction in heart failure there is excessive sympathetic activity with decreased parasympathetic activity. B. Kidney –Increased sympathetic activity is a potent stimulator of renin production C. B1 receptor density decreased –Alpha1 receptor density increased –AT1 receptor density decreased

Cont’d Nitric Oxide plays a role in sympathetic and parasympathetic autonomic responses. Inflammatory cytokines play a significant role in patients with heart failure (TNF-a. IL-1, IL-6, etc.).

Studies On LV Dysfunction (SOLVD) looks at vasoactive peptides norepi, renin, arginine vasopressin, and atrial natriuretic hormone

Importance of neuroendocrine receptors B1, B2, Alpha 1, and Angiotensin II specific receptors all play a key role in signal transductance at the myocyte surface generating specific proteins –Adenyl Cyclase (AC) –Ang II –Ang I –ATP –cAMP

The failing heart has fewer receptors