Heart Failure Pathophysiology, Pharmacotherapy, and Cardiovascular Pharmacogenetics

Comprehensive vocabulary flashcards covering the pathophysiology, clinical classifications, hemodynamics, guideline-directed pharmacotherapy, acute decompensated heart failure management, and cardiovascular pharmacogenetics of heart failure.

Heart Failure (Universal Definition)

A clinical syndrome characterized by current or prior symptoms and/or signs caused by a structural and/or functional cardiac abnormality, corroborated by at least one of the following: elevated natriuretic peptide levels (BNP or NT-proBNP) or objective evidence of cardiogenic pulmonary or systemic congestion.

Replacement Fibrosis

Post-myocardial infarction healing process wherein recruited monocytes become macrophages to clear necrotic debris, and inflammatory cytokines activate fibroblasts into myofibroblasts; these cells synthesize non-contractile collagen and extracellular matrix (ECM), replacing dead myocytes and diminishing functional myocardial contractile mass.

Preload

The degree of myocardial fiber stretch immediately preceding ventricular contraction, directly determined by the end-diastolic volume (EDV); an acute increase augments stroke volume via the Frank-Starling mechanism.

Contractility (Inotropy)

The intrinsic ability of the myocardium to generate contractile force and eject blood independently of loading conditions; an increase in contractility reduces end-systolic volume (ESV) and increases stroke volume.

Afterload

The resistance or impedance against which the ventricle must pump to eject blood into the systemic or pulmonary circulation; elevated afterload increases end-systolic volume (ESV) and reduces stroke volume.

End-Diastolic Volume (EDV)

The volume of blood remaining in the ventricle at the conclusion of diastolic filling, immediately prior to systolic contraction; represents the maximal ventricular filling volume.

End-Systolic Volume (ESV)

The volume of blood remaining inside the ventricle at the completion of systolic contraction and ejection.

Ejection Fraction (EF)

The fraction of blood pumped out of the ventricle with each heartbeat, calculated as $\text{Ejection Fraction (EF\%)} = \frac{\text{Stroke Volume}}{\text{End-Diastolic Volume}} \times 100$.

Frank-Starling Relationship

The intrinsic physiological principle stating that an increase in end-diastolic volume (preload) stretches ventricular myocytes, thereby increasing the force of contraction and augmenting stroke volume until excessive overstretching leads to decompensation.

Ventricular Wall Stress (Laplace's Law)

The mechanical tension experienced across the ventricular wall during the cardiac cycle, described by $\text{Wall Stress} = \frac{\text{Pressure} \times \text{Radius}}{2 \times \text{Wall Thickness}}$.

Concentric Left Ventricular Hypertrophy

A pattern of ventricular remodeling triggered by chronic pressure overload (e.g., hypertension or aortic stenosis) characterized by the parallel addition of new myofibrils, which thickens the ventricular wall and reduces chamber internal radius.

Eccentric Left Ventricular Hypertrophy

A pattern of ventricular remodeling driven by chronic volume overload, characterized by the series addition of new sarcomeres, causing progressive chamber enlargement and ventricular dilation.

Left Ventricular End-Diastolic Pressure (LVEDP)

The hydrostatic pressure measured within the left ventricle at the completion of diastole; in a stiff or non-compliant ventricle, elevated LVEDP is transmitted retrogradely into the left atrium and pulmonary venous vasculature.

Isovolumetric Contraction

The phase of ventricular systole (represented by point b on the left ventricular pressure-volume loop) in which both the atrioventricular (mitral) and semilunar (aortic) valves are closed, causing intraventricular pressure to rise sharply while ventricular volume remains unchanged.

Isovolumetric Relaxation

The early phase of ventricular diastole (represented by point d on the left ventricular pressure-volume loop) following aortic valve closure where both sets of valves are closed, causing intraventricular pressure to fall precipitously at a constant volume (ESV).

Forward Failure (Hypoperfusion)

A clinical consequence of decreased cardiac output wherein tissue perfusion becomes inadequate to meet metabolic demands, leading to exercise intolerance, profound fatigue, and reduced renal blood flow.

Backward Failure (Congestion)

A clinical consequence of elevated ventricular filling pressures transmitted retrogradely into upstream venous circuits, causing pulmonary congestion (dyspnea, orthopnea, crackles) or systemic venous congestion (peripheral edema, hepatomegaly, jugular venous distention).

Heart Failure with Reduced Ejection Fraction (HFrEF)

A clinical heart failure phenotype defined by a documented left ventricular ejection fraction of $\le 40\%$, associated with impaired contractile pump function and ventricular cavity dilation.

Heart Failure with Mildly Reduced Ejection Fraction (HFmrEF)

A clinical heart failure phenotype defined by a left ventricular ejection fraction between $41\%$ and $49\%$.

Heart Failure with Preserved Ejection Fraction (HFpEF)

A clinical heart failure syndrome characterized by symptoms and signs of heart failure accompanied by a documented left ventricular ejection fraction of $\ge 50\%$, characterized by abnormal diastolic filling, ventricular stiffness, and steep pressure-volume curves.

Heart Failure with Improved Ejection Fraction (HFimpEF)

Patients with a baseline LVEF of $< 40\%$ who achieve a $\ge 10$-point increase from baseline along with a subsequent measured LVEF of $> 40\%$.

Stage A Heart Failure (At Risk)

Patients at high risk for heart failure due to comorbidities (e.g., hypertension, diabetes, atherosclerotic CVD, cardiotoxin exposure), but who exhibit no current or prior symptoms/signs of HF and have no structural cardiac disease or elevated cardiac biomarkers.

Stage B Heart Failure (Pre-HF)

Patients without current or prior symptoms or signs of heart failure who have objective evidence of at least one of the following: structural heart disease, abnormal cardiac function, or elevated natriuretic peptide or troponin levels.

Stage C Heart Failure (Symptomatic HF)

Patients presenting with current or prior symptoms and/or signs of heart failure caused by an underlying structural and/or functional cardiac abnormality.

Stage D Heart Failure (Advanced HF)

Patients with severe heart failure symptoms and/or signs at rest, recurrent hospitalizations despite guideline-directed medical therapy (GDMT), and refractory or intolerant disease requiring specialized interventions such as mechanical circulatory support, heart transplantation, or palliative care.

NYHA Functional Class I

Heart failure functional status with no limitation of physical activity; ordinary physical activity does not induce undue fatigue, dyspnea, palpitations, or angina (can perform tasks requiring $\le 7\,\text{MET}$).

NYHA Functional Class II

Heart failure functional status with slight limitation of physical activity; comfortable at rest, but ordinary physical exertion results in fatigue, dyspnea, palpitations, or angina (can complete tasks requiring $\le 5\,\text{MET}$).

NYHA Functional Class III

Heart failure functional status with marked limitation of physical activity; comfortable at rest, but less than ordinary physical activity precipitates fatigue, dyspnea, palpitations, or angina (can complete tasks requiring $\le 2\,\text{MET}$).

NYHA Functional Class IV

Heart failure functional status characterized by the inability to perform any physical exertion without discomfort, with symptoms of heart failure or angina occurring even at rest (cannot complete tasks requiring $\ge 2\,\text{MET}$).

Beta-Adrenergic Desensitization

A homeostatic down-regulatory mechanism whereby chronic elevated sympathetic stimulation (norepinephrine) leads to G-protein coupled receptor kinase (GRK) phosphorylation of $\beta_1$-adrenergic receptors, recruitment of $\beta$-arrestin, uncoupling from $G_s$, endosomal internalization, and subsequent lysosomal degradation.

Neprilysin

A neutral endopeptidase enzyme that degrades endogenous vasoactive and counter-regulatory peptides, including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), bradykinin, angiotensin I, angiotensin II, and endothelin.

Acute Decompensated Heart Failure (ADHF)

A sudden or progressive worsening of baseline heart failure signs and symptoms (or new acute onset) driven by volume overload, tissue hypoperfusion, or both, necessitating urgent hospitalization and therapy.

Pulmonary Artery Catheter (Swan-Ganz Catheter)

A flow-directed, balloon-tipped diagnostic catheter inserted into a central vein and advanced through the right heart into a pulmonary artery branch to obtain hemodynamic measurements, notably pulmonary capillary wedge pressure (PCWP) and cardiac output.

Cardiac Index (CI)

A hemodynamic measure of cardiac performance normalized to patient body surface area ($\text{CI} = \frac{\text{Cardiac Output}}{\text{BSA}}$), where normal ranges between $2.5\,\text{L/min/m}^2$ and $3.5\,\text{L/min/m}^2$, and a threshold $< 2.2\,\text{L/min/m}^2$ designates clinical hypoperfusion ("cold").

Pulmonary Capillary Wedge Pressure (PCWP)

An indirect estimate of left atrial pressure and left ventricular end-diastolic pressure obtained via pulmonary artery catheter wedging; normal is $5\text{--}12\,\text{mmHg}$, while a level $> 18\,\text{mmHg}$ identifies pulmonary venous congestion ("wet").

Stevenson Hemodynamic Subset I (Warm and Dry)

ADHF clinical presentation characterized by adequate systemic perfusion ($\text{CI} > 2.2\,\text{L/min/m}^2$) and the absence of congestion ($\text{PCWP} \le 18\,\text{mmHg}$); managed by optimizing chronic oral medical therapy.

Stevenson Hemodynamic Subset II (Warm and Wet)

The most common ADHF hemodynamic presentation, characterized by preserved perfusion ($\text{CI} > 2.2\,\text{L/min/m}^2$) alongside pulmonary/systemic congestion ($\text{PCWP} > 18\,\text{mmHg}$); treated with intravenous loop diuretics and IV venodilators.

Stevenson Hemodynamic Subset III (Cold and Dry)

ADHF hemodynamic presentation defined by systemic hypoperfusion ($\text{CI} < 2.2\,\text{L/min/m}^2$) without pulmonary congestion ($\text{PCWP} \le 18\,\text{mmHg}$); managed by fluid administration if PCWP is $< 15\,\text{mmHg}$, or IV inotropic support.

Stevenson Hemodynamic Subset IV (Cold and Wet)

The most severe ADHF hemodynamic profile (cardiogenic shock), defined by concurrent systemic hypoperfusion ($\text{CI} < 2.2\,\text{L/min/m}^2$) and pulmonary congestion ($\text{PCWP} > 18\,\text{mmHg}$); managed with IV inotropes, diuretics, vasopressors, and mechanical circulatory support.

Four Pillars of Guideline-Directed Medical Therapy (GDMT)

The four foundational drug classes demonstrated to reduce morbidity and mortality in Stage C HFrEF: (1) ARNI (or ACEi/ARB), (2) evidence-based beta-blocker, (3) mineralocorticoid receptor antagonist (MRA), and (4) SGLT2 inhibitor.

Loop Diuretic Dosing Equivalency

The standardized clinical conversion ratios for loop diuretic agents: $40\,\text{mg}$ IV furosemide = $80\,\text{mg}$ oral furosemide = $20\,\text{mg}$ IV/oral torsemide = $1\,\text{mg}$ IV/oral bumetanide.

Sacubitril/Valsartan (Entresto)

A first-line Angiotensin Receptor-Neprilysin Inhibitor (ARNI) combining a neprilysin inhibitor (sacubitril) that enhances active natriuretic peptides and bradykinin with an $\text{AT}_1$ receptor antagonist (valsartan) to reduce cardiovascular death and hospitalizations in HFrEF.

ACE Inhibitor to ARNI Washout Period

A mandatory $36\text{-hour}$ drug-free interval required between the last dose of an ACE inhibitor and initiation of an ARNI (sacubitril/valsartan) to prevent the synergistic accumulation of bradykinin and avoid severe angioedema.

Evidence-Based Beta-Blockers for HFrEF

The three specific beta-blockers demonstrated in randomized clinical trials to reduce mortality in stable HFrEF: bisoprolol, carvedilol, and metoprolol succinate.

Target Digoxin Level in HFrEF

A narrow therapeutic serum concentration range of $0.5\text{--}0.9\,\text{ng/mL}$, which provides neurohormonal modulation and reduces heart failure hospitalizations without conferring the excess mortality seen with higher levels.

Ivabradine

A selective inhibitor of the hyperpolarization-activated cyclic nucleotide-gated ($I_f$) funny current in the sinoatrial node that slows heart rate without altering contractility or blood pressure, indicated in symptomatic stable HFrEF (LVEF $< 35\%$) with a resting heart rate $\ge 70\,\text{bpm}$ in sinus rhythm on maximally tolerated beta-blockers.

BiDil (Hydralazine / Isosorbide Dinitrate)

A fixed-dose combination combining an arterial vasodilator (hydralazine) and a venodilator (isosorbide dinitrate) indicated to reduce mortality and hospitalizations in self-identified Black/African American patients with NYHA Class III-IV HFrEF on optimal GDMT.

Finerenone

A nonsteroidal mineralocorticoid receptor antagonist (nsMRA) proven to reduce worsening heart failure events and cardiovascular death in patients with heart failure with mildly reduced or preserved ejection fraction (LVEF $\ge 40\%$), carrying a lower risk of hyperkalemia than steroidal MRAs.

Milrinone

A bipyridine phosphodiesterase-3 (PDE3) inhibitor that prevents cyclic AMP (cAMP) breakdown, functioning as an "inodilator" to increase cardiac contractility while inducing systemic arteriolar and venous vasodilation to reduce afterload and PCWP.

Dobutamine

A synthetic catecholamine inotropic agent that primarily stimulates $\beta_1$ and $\beta_2$ adrenergic receptors (with mild $\alpha_1$ activity), augmenting cardiac output and stroke volume with a modest increase in heart rate and potential attenuation of effect after $72\,\text{hours}$ due to receptor downregulation.

SLCO1B1 (OATP1B1)

A solute carrier organic anion transporter protein encoded by the SLCO1B1 gene on chromosome 12 that mediates the uptake of statins (especially simvastatin) from portal blood into hepatocytes.

SLCO1B1 *5 Allele (rs4149056 / c.521T>C)

A missense variant in the SLCO1B1 gene causing a p.Val174Ala amino acid substitution, leading to impaired hepatic statin uptake, elevated statin area under the curve (AUC), and a substantially increased risk of statin-associated muscle symptoms (SAMS).

CYP2C19 *2 and *3 Alleles

Non-functional ("no function") loss-of-function variant alleles of the CYP2C19 gene that diminish the metabolic bioactivation of clopidogrel into its active antiplatelet thiol metabolite, increasing the risk of adverse cardiovascular events and stent thrombosis.

CYP2C19 *17 Allele

A gain-of-function promoter variant ($c.-806C>T$) in the CYP2C19 gene that increases transcription, resulting in rapid or ultrarapid metabolism of clopidogrel and potentially increased active metabolite exposure and bleeding risk.

VKORC1 -1639G>A (rs9923231)

A single nucleotide polymorphism in the promoter region of the VKORC1 gene; presence of the A allele reduces vitamin K epoxide reductase synthesis, leading to decreased clotting factor carboxylation and lower warfarin maintenance dose requirements.

CYP4F2 (rs2108622 / V433M)

A genetic variant ($c.1297G>A$, p.Val433Met) in the CYP4F2 gene that reduces the oxidative clearance of reduced vitamin K, resulting in higher circulating levels of active vitamin K and requiring a $5\text{--}10\%$ increase in warfarin dose in carriers.