Discuss therapeutic targets and identify factors that affect prognosis of CHF.

Explain the rationale for diuretic therapy and the clinical implication of diuretic resistance.

Initiate evidence-based medical therapy and discuss the role of device therapy for patients with CHF.

Detail the differential diagnosis for patients with hyponatremia.

Describe the role of volume overload in the cascade of events leading to onset and progression of CHF.

Heart Failure
Andrew Boyle, MD, Associate Professor of Medicine, and Medical Director, Division of Cardiology, Heart Failure, and Transplantation, University of Minnesota Medical School, Minneapolis

Scope of problem: ≈5 million people in United States have congestive heart failure (CHF); >500000 new cases annually; 5-yr mortality rate as high as 50%; largest expense for Medicare; relatively few experts in advanced CHF, so primary care providers responsible for bulk of care; ≈1.5 million patients have moderate to advanced CHF (ie, shortness of breath at rest or with minimal exertion on daily basis)

Disease progression: left ventricular (LV) injury—most commonly caused by coronary artery disease; other causes include diabetes, valvular disease (eg, as result of chronic hypertension), and other cardiomyopathies (often unidentified); cardiac remodeling—LV injury activates variety of neurohormonal pathways, leading to pathologic changes; ventricle dilates and ejection fraction (EF) decreases; symptoms emerge; reverse remodeling—goal of therapy; shrinking ventricle improves prognosis; death—sudden cardiac death or progressive pump dysfunction

Targets of therapy: diuretics—reduce fluid volume (ie, cardiac preload); vasodilators—eg, nitroglycerin, hydralazine, angiotensin-converting enzyme (ACE) inhibitors; agents reduce cardiac preload and afterload; inotropic agents— increase contractility; long-term outcomes—improving cardiac output has little effect; decongestion important; patients discharged with high pulmonary capillary wedge pressures (PCWP) have poor outcomes, compared to those with normal PCWP

Decongestion: often insufficient; registry data from 105000 patients admitted to hospital for decompensated CHF show 16% of patients gained weight (ie, increased fluid volume) during stay, and 33% lost <5 lb; failure to adequately decongest patients increases risk for subsequent readmission; diuretic therapy—reduces fluid retention and improves exercise tolerance, but not shown to improve mortality from CHF; ACE inhibitors and β-blockers do improve mortality

Hospitalization: LV dysfunction not cause for hospitalization; may not correspond with symptoms or functional impairment; problems leading to hospitalization include noncompliance (with diet and/or medication) and diuretic resistance

Diuretic response: nephron requires threshold concentration of loop diuretic before excreting sodium, after which excretion dose-responsive; diuretic resistance—higher threshold concentration; larger doses required to achieve similar increases in sodium excretion (ie, nephrons less responsive); management strategy—illogical to continue increasing dose of agent to which patient resistant; switching strategies more likely to result in benefit

Nesiritide: recombinant B-type natriuretic peptide (rhBNP); endogenous BNP produced in left ventricle in response to stretch (volume overload); hemodynamic effects primarily result from vasodilation and reflexive increase in cardiac index because of afterload reduction; advantages—does not exacerbate neurohormonal cascade; does not increase heart rate (HR) or risk for arrhythmias; decreases PCWP, systolic blood pressure (BP), and mean right atrial pressure; study—fluid intake and output closely monitored; addition of nesiritide did not increase diuresis or sodium excretion; outpatient studies also show no benefit for decongestion

Vasopressin antagonists: stimulate diuresis without sodium excretion; study—compared to placebo, tolvaptan improved decongestion but had no effect on outcomes; clinical and research implications—sodium excretion (not simply fluid diuresis) important for improving outcomes; studies looking at diuretic agents (for management of CHF) should measure sodium excretion, not simply loss of weight or fluid

Ultrafiltration therapy: reserved for patients with diuretic resistance; associated with increased weight loss, compared to intravenous (IV) diuretic therapy; improves outcomes (eg, 90-day readmission rate); removes sodium and water; approach to decongestion—ultrafiltration good option for patients with true diuretic resistance; diuretic therapy often sufficient if patient excretes isotonic urine; if urine hypotonic, diuresis inefficient (consider ultrafiltration)

Cardiac resynchronization therapy (CRT): leads—right atrium; right ventricle (lead also has defibrillator coil); left ventricle; effect—coordinates timing of contraction of ventricles; study showed improved functional capacity (based on 6-min walk), increased EF (even small increases associated with improved prognosis), decreased LV end-diastolic dimension (ie, reverse remodeling), and decreased mitral regurgitation (associated with symptom improvement); indications—moderate to severe CHF (speaker recommends for patients with NYHA class III); widened QRS (indicator of ventricular dyssynchrony); systolic dysfunction; symptoms present despite maximized medical therapy (including β- blocker, ACE inhibitor or angiotensin receptor blocker [ARB] and diuretic, titrated to maximum tolerated doses); medical therapy after CRT—improvements in, eg, heart rhythm, HR, and BP, allow up-titration of medications to recommended doses

LV-assist devices (LVADs): used as bridge to transplantation and for patients who do not meet age criteria for transplantation; pump—placed beneath abdominal wall; drains blood from left ventricle and pumps it to ascending aorta; patients—require anticoagulation therapy (typically managed by primary care provider); outcomes—appropriate patient selection improves likelihood of success; candidates have NYHA class IV CHF and poor quality of life (QOL); successful implantation of LVAD results in durable improvement in functional capacity and QOL

New devices: use magnetic levitation technology, so rotor spins continuously without friction; preliminary results show 12-mo survival rates of ≥86%; advantages—anticipated to last 5 to 10 yr (compared to 15-18 mo for other LVADs); smaller; improved patient satisfaction; can be used in smaller patients (eg, women)

Stage-based approach to management: stage A—patients at risk for CHF but have no structural disease; treat risk factors (eg, hypertension, dyslipidemia); encourage lifestyle modification (eg, exercise, reduction of alcohol consumption); consider ACE inhibitors for appropriate patients (eg, diabetics); stage B—patients have structural heart disease (eg, hypertrophy, reduced EF) but asymptomatic; treat risk factors; initiate ACE inhibitor and β-blocker (lifelong therapy); stage C—structural heart disease; patient symptomatic (presently or previously); treat risk factors; initiate or continue ACE inhibitor and β-blocker; consider aldosterone receptor antagonist for patients with normal kidney function and no hyperkalemia (contraindicated in patients with creatinine >2 mg/dL or potassium >5 mEq/L); consider digitalis for patients with frequent visits to hospital; adjust diuretic therapy for decongestion; consider CRT for appropriate patients; stage D—patients with refractory CHF; in addition to therapies already mentioned, consider device therapy and cardiac transplantation; encourage palliative care (eg, continuous IV inotropic agents, hospice care) when appropriate

Hyponatremia in Heart Failure
Terrence X. O’Brien, MD, Professor of Medicine, Division of Cardiology, Medical University of South Carolina, Charleston

Volume overload: primary target in management of decompensated CHF; edema—sodium concentration affects volume of extracellular fluid (ECF); elevation of total-body sodium and total-body water results in volume overload and edematous states (eg, CHF, ascites, cirrhosis, nephrotic syndrome); sodium level may appear low (because of excess ECF), even when total sodium high

Signs and symptoms of hyponatremia: often asymptomatic; symptoms tend to emerge when sodium <120 mEq/L or drops quickly; generally nonspecific (eg, headache, lethargy); serious complications include seizure and coma

Work-up: history and physical examination—rule out liver and kidney disease, thyroid and adrenal disorders, syndrome of inappropriate secretion of antidiuretic hormone (SIADH; especially in patients with neurologic or pulmonary disease), and psychogenic causes; obtain drug history (prescription and recreational drugs); determine pregnancy status; assess volume status (orthostatics; HR; BP; skin turgor; mucous membranes); laboratory studies—serum osmolality; urine electrolytes and osmolality; thyrotropin and cortisol levels in new patients and those with unclear history; imaging—chest x-ray and computed tomography of head for patients with neurologic impairment

Osmolality: hypertonic—>300 mOsm/kg; assess for presence of osmotically active molecules (eg, glucose, mannitol) in serum; hypotonic—generally related to volume status

Volume status: hypervolemic hyponatremia—volume overload obvious; symptoms include pulmonary rales, jugular venous distention, pedal and sacrotesticular edema, and weight gain; urine sodium generally <10 mEq/L in patients with CHF, cirrhosis, or nephrosis (increases with advanced renal failure); hypo-volemic hyponatremia—low fluid and (sometimes) sodium levels may result from overdiuresis; extrarenal losses include gastrointestinal (GI) losses, third spacing, inadequate intake, and insensible losses; euvolemic hyponatremia—increased urine osmolality; causes include SIADH (decreased urine sodium, urine output, and serum urea nitrogen; associated with neurologic events, malignancy and metastasis, and some medications; often overlooked in older patients), adrenal insufficiency, hypothyroidism, psychogenic polydipsia, and low solute intake

General approach to treatment: goal—prevent cerebral edema and encephalopathy without causing central pontine myelinolysis (results from correcting sodium level too rapidly); general guideline—increase sodium by 1.5 to 2 mEq/L/ hr if serious cerebral dysfunction present; otherwise, increase by 10 to 12 mEq/L during first 24 hr and 18 mEq/L during first 2 days; standard therapies—fluid restriction (inexpensive; effective when monitored, but compliance difficult); demeclocycline and lithium rarely used because of toxicity and adverse effects; loop diuretics (appropriate in some patients; free water excretion must be greater than sodium and potassium excretion; balance must exist between diuretic action and salt ingestion); urea no longer used; hypertonic saline for patients with cerebral edema (rate of correction difficult to judge; patients require monitoring [eg, for myelinolysis] in intensive care unit)

Vasopressin antagonists: vasopressin—powerful vasoconstrictor; target receptors—vasopressin 1a (V1a ) receptors located on blood vessels; V2 receptors located on renal tubules; blocking V2 receptors results in water diuresis (ie, no salt excretion); advantages—no activation of neurohormonal cascade; no excretion of solute; no worsening of renal function; systemic levels of vasopressin remain within physiologic range

Conivaptan (Vaprisol): indications—symptomatic hyponatremia (hypervolemic or euvolemic); use—loading dose (20 mg) followed by infusion (40 mg/day) for 2 to 4 days; results—serum sodium levels increase to >130 mEq/L or by >12 mEq/ L over 24 hr; increased levels persist for 30 days; mechanism of action—blocks V1a and V2 receptors; results in diuresis without loss of electrolytes; contraindications—hypovolemia; use of medications that inhibit CYP3A system (eg, antifungal agents, some antiviral agents); interactions—other drugs metabolized by CYP3A system (eg, simvastatin, amlodipine); agents should be discontinued before initiating conivaptan therapy; precautions—avoid correcting serum sodium too quickly; important note—not indicated for management of CHF; adverse effects—common reactions include phlebitis and pain at infusion site, nausea, and GI complaints; in general, safety profile good

Congestion: patients often admitted because of symptoms related to volume overload; volume overload also contributes to neurohormonal activation and (eventually) decompensatory effects of CHF; presenting complaints (eg, decompensated CHF, hypertension, pulmonary edema) often related to volume overload; pathophysiology—increased tension on endocardium decreases subendocardial and coronary perfusion, impairing systolic and diastolic function; increased myocardial load leads to neurohormonal activation, systolic and diastolic failure, systemic effects of chronic CHF (including decreased threshold for arrhythmias), altered levels of electrolytes, and cardiac remodeling; remodeling results in decreased cardiac output, mitral and tricuspid regurgitation, and decreased renal perfusion

Clinical course: initial decompensation corrected with appropriate medical therapy; progressive remodeling results in subsequent hospitalizations for decompensation and in overall decline; factors affecting prognosis—if congestion not corrected during admission, mortality rate doubles; registry data show that hyponatremia increases length of stay, in-hospital mortality, and 1-yr mortality; outcomes related to severity of hyponatremia

Management of stage-C CHF: standard medical therapy includes diuretics, ACE inhibitors, and β-blockers; aldosterone antagonists, digitalis, and/or hydralazine and nitrates recommended for some patients; implantable cardioverter defibrillators or cardiac resynchronization for appropriate patients; exercise training

Diuretics: standard of care, but limited evidence of outcome benefit (level C evidence); adverse effects include volume depletion, electrolyte disturbance, neurohormonal activation, myocardial fibrosis (with chronic use), decreased glomerular filtration rate and worsening renal function, hyperglycemia (in diabetic patients), abnormal lipid profiles, and loss of water-soluble vitamins; no evidence that loop diuretics improve mortality rates, but important for correction of acute congestion

Aldosterone inhibitors: aldosterone contributes to neurohormonal activation and leads to electrolyte imbalances, increasing risk for arrhythmias; high levels of aldosterone associated with increased deposition of collagen (leading to fibrosis); large clinical trials show mortality benefit of aldosterone inhibitors; indications—patients with stage-C CHF with adequate renal function; combination with ACE inhibitor or ARB (but not both) acceptable; follow-up—monitor renal function and potassium levels

Tolvaptan: vasopressin antagonist with higher affinity for V2 receptors; clinical trials—pilot study (tolvaptan added to recommended medical therapy for patients with CHF) found no change in cardiac remodeling, but showed mortality benefit; Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) showed short- term benefit in symptoms but no mortality benefit; safety profile—generally well tolerated; adverse effects include dry mouth, thirst, and hypernatremia; electrolyte profile more favorable than with placebo; future—possible indication for short-term management of acute symptoms