Objectives Hyponatremia in Heart Failure: why it is important and what should we do about it? Pathophysiology of sodium and water retention in heart failure Hyponatremia in heart failure (mechanism and prognostic importance) Richard G. Kiel, M.D. Associate Clinical Professor of Medicine, UCSF Director, Advanced Heart Failure and Mechanical Circulator Support, UCSF-Fresno MEP How to treat volume overload in heart failure Aquaresis vs. diuresis in treating volume overload in patients with heart failure and hyponatremia Pathophysiology of Heart Failure Vicious Circle of Water Retention Schrier RW. J Am Coll Cardiol. 2006; 47: 1-8. Schrier RW. J Am Coll Cardiol. 2006; 47: 1-8. 1
Pathophysiology of hyponatremia in acute decompensated heart failure Dilutional Hyponatremia Increased sensitivity of osmotic AVP release lower osmo-checkpoint Increased nonosmotic AVP release Impaired AVP degradation Increased thirst Decreased distal nephron flow Verbrugge et al. J Am Coll Cardiol. 2015; 65: 480-492. Mechanism of action Baroreceptor activation/angtiotensin II Baroreceptor activation/angtiotensin II Liver/kidney dysfunction Baroreceptor activation/angtiotensin II Impaired glomerular filtration/increase reabsorption in proximal tubes Pathophysiology of hyponatremia in acute decompensated heart failure Depletional Hyponatremia Low sodium intake Exaggerated nonurinary sodium loss Exagerated natriuresis Sodium shift toward the intracellular compartment Verbrugge et al. J Am Coll Cardiol. 2015; 65: 480-492. Mechanism of action Salt-restricted diet Diarrhea, ascites Diuretics, osmotic diuresis Potassium and/or magnesium deficiency Differentiate dilutional verus depletion If volume overload you can assume at least a component of dilutional Urine osmolality should be depressed (<100 mosm/l) in depletional but not dilutional hyponatremia. Low urinary sodium (<50mEq/L) is a strong argument for electrolyte depletion Plasma hypotonicity Confirm plasma hypotonicity (<285 mosm/l) Pseudohyponatrmia: Elevated triglycerides, immunoglobulins, monoclonal gammanopathies can cause falsely low Na concentrations Presence of effective osmoles (e.g. hyperglycemia) can falsely increase serum Na concentrations 2
Role of Vasopressin in Heart Failure Free Water Excretion in Patients Without Heart Failure Dilutional hyponatremia, high BUN Verbrugge FH. J Am Coll Cardiol. 2015; 65: 480-492. Verbrugge FH. J Am Coll Cardiol. 2015; 65: 480-492. Free Water Excretion is Impaired in Heart Failure Hyponatremia in patients hospitalized for heart failure 20% with Na < 135 mmol/l Verbrugge FH. J Am Coll Cardiol. 2015; 65: 480-492. Gheorghiade M et al. Eur Heart J. 2007; 28: 980-988. 3
Sodium and Survival in Heart Failure BUN and Survival in Heart Failure Klein L et al. Circulation 2005; 111: 2454-2460. Klein L et al. Circ Heart Fail. 2008; 1: 25-33. Volume Management in Heart Failure Diuretics Loop; thiazide; acetazolamide Aquaretics (vaptans) Tolvaptan Inotropic agents Dopamine; dobutamine Vasodilators Nesiretide, nitroglycerin, nitroprusside Ultrafiltration Continuous; intermittent Diuretic Strategies Need combination (due to braking and tolerance) Loop + Thiazide + Acetazolamide Potency and protein binding Bumetanide > Torsemide > Furosemide High vs. Low dose High dose better (DOSE - HF trial) IV Bolus vs. IV Drip No difference (DOSE - HF trial) High dose vs. Low dose + Dopamine Dopamine improves renal blood flow and size of renal arteries 4
Aquaretics (Vaptans) Tolvaptan is the most studied V 2 antagonist Studied in chronic heart failure, acute heart failure Hemodynamic studies Remodeling studies Potential of improving volume status and serum sodium No increases in short or long term mortality No adverse effects on blood pressure, heart rate, renal function, electrolytes Hemodynamics Effects of Tolvaptan Slightly better reduction in filling pressures with tolvaptan Schrier RW et al. N Engl J Med. 2006; 355: 2099-2112; Udelson JE et al. J Am Coll Cardiol. 2008; 52: 1540-1545; Lehrich RW et al. J Am Soc Nephrol. 2008; 19: 1054-1058. Udelson JE et al. J Am Coll Cardiol. 2008; 52: 1540-1545. Effects of Tolvaptan on PCWP Effects of Tolvaptan on Urine Output Sustained reduction in filling pressures with tolvaptan Udelson JE et al. J Am Coll Cardiol. 2008; 52: 1540-1545. Better diuresis with single dose tolvaptan No changes in renal function and electrolytes Udelson JE et al. J Am Coll Cardiol. 2008; 52: 1540-1545. 5
Renal Effects of Tolvaptan * p < 0.05 Costello-Boerrigter et al. Am J Physiol Renal Physiol 2006; 290: F273-278 TLV compared to furosemide: Similar urine output No changes in electrolytes No changes in osmolality Preserved renal blood flow Effects of Tolvaptan vs. Furosemide TLV produced sustained decrease in body weight, increased urine volume, transient sodium increase (within normal range) and no change in potassium Udelson JE et al. J Card Fail. 2011; 17: 973-981. Change in Global Clinical Status During Hospitalization in EVEREST Dyspnea in Hospitalized Patients with Hyponatremia in EVEREST Gheorghiade M et al. JAMA. 2007; 297: 1332-1343. Hauptman PJ et al. J Card Fail. 2013; 19: 390-397. 6
Diuretics in Hospitalized Patients with Hyponatremia in EVEREST * p < 0.05 Body Weight and Sodium in EVEREST * p < 0.001 * p < 0.001 (in pts. with Na < 134 mmol/l) Hauptman PJ et al. J Card Fail. 2013; 19: 390-397. Konstam MA et al. JAMA. 2007; 297: 1319-1331. Body Weight and Sodium in EVEREST All-Cause Mortality in EVEREST Konstam MA et al. JAMA. 2007; 297: 1319-1331. Konstam MA et al. JAMA. 2007; 297: 1319-1331. 7
Event Analysis in EVEREST Hauptman PJ et al. J Card Fail. 2013; 19: 390-397. Managing Volume Overload in Heart Failure: Diuretics vs. Vaptans Vaptans Diuretics Urine Output ã ã Serum Sodium ã ä Serum Potassium No change ä Plasma Osmolality ã ä Blood Pressure No change ä BUN/Creatinine No change ã Renal Blood Flow ã ä GFR ã ä Renal vascular resistance ä ã Vasopressin level ã ã Norepinephrine level No change ã Plasma renin activity No change ã Aldosterone level No change ã Costello-Boerrigter et al. Am J Physiol Renal Physiol 2006; 290: F273-278 Conclusions Volume overload is the main reason for hospitalizations in pts. with HF Up to 20% of pts. develop dilutional hyponatremia Volume control is paramount Use diuretics, vaptans, inotropes, ultrafiltration Diuretics can lead to worse neurohormonal activity, renal function and hyponatremia Diuretic resistance leads to use of combination Tolvaptan: better symptomatic relief than diuretics in HFrEF pts. with hyponatremia No deleterious hemodynamic effects, preserves renal function and potassium, corrects hyponatremia 8