Congestive Heart Failure (CHF)

• Congestive heart failure (CHF) happens when the heart cannot pump enough blood to meet the body's needs due to a defect in the heart's excitation-contraction coupling machinery.

Types of Heart Failure:

• Acute CHF is caused by cardiac muscle exposure to toxic drug levels or coronary artery occlusion, with symptoms including tachycardia, shortness of breath, edema, and decreased exercise tolerance.
• Chronic CHF is caused by heart damage from conditions like hypertension or myocardial infarction, with symptoms including arrhythmias, hypertension, cardiomegaly, and edema.
• Common diseases contributing to CHF include cardiomyopathy, myocardial ischemia/infarction, hypertension, cardiac valve disease, congenital heart disease, and coronary artery disease, with CHF more prevalent in the elderly.
• Right ventricular heart failure ("backward failure") leads to high central venous and right atrial pressure, causing general venous congestion and symptoms like dyspnea, edema, and fatigue.
• Left ventricular heart failure ("forward failure") results in reduced cardiac output and blood pressure; linked with “backward failure” because of pulmonary congestion
• CHF causes the body to activate compensatory mechanisms to maintain cardiac output, activating baroreceptors due to hypotension from reduced cardiac output, increasing sympathetic nervous system activity, and triggering the renin-angiotensin-aldosterone system due to reduced renal perfusion.
• Endocrine function increases from CHF compensatory mechanisms, resulting in increased water retention, blood pressure, vascular/interstitial fluid volume, congestion/edema, and cardiac preload, leading to ventricular dilatation, increased volume/pressure, incomplete ventricle emptying, and increased left ventricular end-diastolic pressure.

Drugs for CHF

• Heart failure treatment entails pharmacological agents and lifestyle changes like sodium restriction, weight maintenance, avoiding alcohol, and exercise.

Drugs Affecting Renin-Angiotensin and Neutral Endopeptidase Pathways:

• Renin-angiotensin converting enzyme (ACE) inhibitors (captopril, enalapril, lisinopril, quinapril) inhibit angiotensin I conversion to angiotensin II, decreasing cardiac performance.
• Angiotensin II produces vasoconstriction, increases systemic vascular resistance (afterload), stimulates aldosterone production (increases sodium/water retention), and has trophic effects on cardiac/vascular tissues.
• ACE inhibition reduces angiotensin II levels, decreasing peripheral resistance and aldosterone release, with side effects including angioedema, dry cough, loss of taste, and orthostatic hypotension.
• ACE inhibitors are among the first-line therapies for CHF that prevent/slow heart failure progression while also reducing mortality and hospitalization, but are contraindicated in conditions of renal artery stenosis or hyperkalemia.
• Angiotensin II type1-receptor antagonists (losartan, candesartan) block angiotensin II effects on receptors, providing similar benefits to ACE inhibitors for patients intolerant to ACE inhibitors because of taste loss or cough.
• A neutral endopeptidase inhibitor combined with an Angiotensin II type1-receptor antagonist drug (sacubitril+valsartan) combines sacubitril (a neprilysin inhibitor) with valsartan (an angiotensin II receptor antagonist).
• This combination inhibits neprilysin, blocking the degradation of natriuretic peptides, bradykinin, and adrenomedullin and blocks angiotensin type1 receptors, is an effective treatment for heart failure.
• This results in reduced cardiovascular death and hospitalization risk for heart failure patients with reduced ejection fraction, also lowering cardiovascular mortality and slowing the progression of heart failure.
• The side effects of sacubitril+valsartan include hypotension, hyperkalemia, cough, elevated serum creatinine, and angioedema. Concurrent use with ACE inhibitors increases angioedema risk and should be avoided in hyperkalemia.

Nitrovasodilators:

• Nitrovasodilators (sodium nitroprusside, hydralazine and nitroglycerin) are used to reduce preload and afterload.
• Sodium nitroprusside reduces preload/afterload by venodilatation, increasing venous capacity, reducing left ventricular filling pressure and myocardial oxygen consumption.
• The side effects include liver metabolism to cyanide, which can accumulate with renal insufficiency; causing nausea, confusion, and convulsions.
• Hydralazine and Nitrates (sodium nitroprusside or nitroglycerin) combination therapy addresses preload/afterload, improves cardiac output, and increases life expectancy.
• The side effects of hydralazine include drug-induced systemic lupus erythematosus (rare at doses below 200 mg/day), and nitroglycerin include extensive hypotension.

Cardiac Glycosides:

• Cardiac glycosides (Digoxin) exert positive inotropic effects in both normal and diseased hearts, improving cardiac function and reducing sympathetic tone to the heart and vasculature as well overall oxygen demand.
• Digoxin decreases heart rate via improved cardiac function, indirect slowing of the sinus rate (vagomimetic actions), and direct depressant action on AV nodal conductivity (negative dromotropic effects).
• It can produce enhanced automaticity, decrease cardiac conduction velocity, and increase AV nodal refractory period.
• The basis is the inhibition of the sodium/potassium pump, accumulating sodium ions inside the myocytes. The increased concentration of calcium inside myocytes will contribute to a greater development of contractile force.
• Cardiac glycosides have a low therapeutic ratio, causing cardiac arrhythmias (toxicity), gastrointestinal disturbances, stimulating the vagal system and the chemoreceptor trigger zone, and causing nausea, vomiting, diarrhea, and anorexia.

β-Adrenoceptor Antagonists:

• β-Adrenoceptor antagonists (carvedilol, metoprolol, bisoprolol) treat heart failure by reducing excessive sympathetic stimulation.
• Sympathetic nerve stimulation in a failing heart results in tachycardia, increased myocardial oxygen demands, and, chronically, cardiac hypertrophy along with impaired myocyte function/death.
• Carvedilol, a β-adrenoceptor antagonist with vasodilator activity, reduces afterload to improve cardiac function, and reduces sympathetic nerve stimulation to reduce heart workload/oxygen demand.
• These also reduce arterial resistance (afterload) and sympathetic nerve activation (reducing renin release), resulting in reduced volume overload, with studies showing reduced mortality rates when treating patients with carvedilol, metoprolol, or bisoprolol.
• Side effects consist of bradycardia, worsening heart failure, and dizziness/light-headedness due to vasodilatation and decreased blood pressure.

Diuretics:

• Diuretics (Furosemide and chlorothiazide) reduce blood volume and venous pressure, increasing cardiac pumping efficiency and are used to reduce intravascular and extravascular fluid accumulation in CHF.
• The side effects consist of electrolyte imbalance resulting in hypokalemia which could precipitate ventricular arrhythmias
• Potassium-sparing diuretics can be used (spironolactone or triamterene.) Additionally, glucose and uric acid concentrations may increase in plasma, and furosemide's actions can be impaired by concomitant aspirin use.

Ivabradine:

• Ivabradine selectively inhibits If currents in cardiac pacemaker cells, reducing heart rate without affecting myocardial contractility, conduction, or coronary vascular resistance.
• It is used with standard treatment for chronic heart failure patients with a heart rate of 77 beats/minute or higher (normal sinus rhythm) and an ejection fraction ≤ 35%.
• The side effects are transient, dose-related visual symptoms (sensitivity to light) and modest reports of nausea/dizziness

Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors:

• Sodium-Glucose Cotransporter-2 Inhibitors (dapagliflozin, empagliflozin) are found to reduce cardiovascular risk, reducing hospitalization/death risk in heart failure patients (with reduced ejection fraction) regardless of diabetes status.
• SGLT2 Inhibitors produce osmotic diuresis, reduce blood pressure/vascular stiffness, as well as preload/afterload (reducing heart workload.)
• Contraindications consist of eGFR levels which includes less than 30 ml/min/1.73 m² (dapagliflozin) while also less than 20 ml/min/1.73 m² (empagliflozin), along with side effects of yeast infection, back pain, skin reactions (dapagliflozin), weakness, and lightheadedness (empagliflozin), with the potential to cause ketoacidosis.

Phosphodiesterase Inhibitors:

• Phosphodiesterase inhibitors (Amrinone) are reserved for refractory CHF patients, inhibiting phosphodiesterase (PDE 3) in cardiac/smooth muscle, increasing cyclic AMP concentration.
• Amrinone improves cardiac output, stroke volume, and reduces right atrial/pulmonary capillary wedge pressures and is administered acutely.
• The side effects of prolonged intravenous use consist of nausea/vomiting, supraventricular/ventricular tachycardia, so ECG monitoring is essential.

Evolution of Heart Failure:

• Risk factors for the evolution of heart failure consist of aging, hypertension, smoking, dyslipidemia, diabetes, obesity, genetics, and toxins, leading to cellular pathophysiology (hypertrophy, infarction, accelerated apoptosis, fibrosis) → Ventricular remodeling
• Stages A and B are structural heart disease without symptoms, and Stages C and D are symptomatic heart failure. LVH: Left Ventricular Hypertrophy