A 71-year-old woman comes to the emergency department due to progressive dyspnea and orthopnea for the last week. She has a history of myocardial infarction and systolic heart failure with a left ventricular ejection fraction of 15%. The patient is compliant with her medications, which include carvedilol, furosemide, aspirin, lisinopril, and atorvastatin. Blood pressure is 118/74 mm Hg and pulse is 72/min. Examination reveals elevated jugular venous pressure, bibasilar crackles, an S3 heart sound, and bilateral lower extremity pitting edema. The patient is started on dobutamine infusion, which provides significant symptom relief. Echocardiogram shows mild improvement in cardiac contractility. Which of the following is the likely mechanism underlying this patient's clinical improvement?

Question

A 71-year-old woman comes to the emergency department due to progressive dyspnea and orthopnea for the last week.  She has a history of myocardial infarction and systolic heart failure with a left ventricular ejection fraction of 15%.  The patient is compliant with her medications, which include carvedilol, furosemide, aspirin, lisinopril, and atorvastatin.  Blood pressure is 118/74 mm Hg and pulse is 72/min.  Examination reveals elevated jugular venous pressure, bibasilar crackles, an S3 heart sound, and bilateral lower extremity pitting edema.  The patient is started on dobutamine infusion, which provides significant symptom relief.  Echocardiogram shows mild improvement in cardiac contractility.  Which of the following is the likely mechanism underlying this patient's clinical improvement?

Quizplus · Accepted Answer

11ec160b_3ba0_871c_9249_89492041583c_MD0001_00 Dobutamine is a β-adrenergic agonist with predominant activity on β₁ receptors and weak activity on β₂ and α₁ receptors. Stimulation of β₁-adrenergic receptors causes G_s protein GTP binding, leading to activation of adenylyl cyclase and increased production of cAMP in the target cells. In cardiac myocytes, increased cAMP causes calcium channel activation and increased cytosolic Ca²⁺ concentration. This causes a conformational change in the troponin complex, facilitating actin-myosin binding and increasing myocardial contractility (positive inotropy). Increased cAMP also causes a rise in heart rate by increasing Na⁺ and Ca²⁺ channel activation in pacemaker cells (positive chronotropy). In the vasculature, α₁ agonist activity (vasoconstriction) balances the β₂ agonist effect (vasodilation) with resultant mild vasodilation. The net hemodynamic effects are an increase in cardiac contractility and a decrease in systemic vascular resistance without significant change in arterial blood pressure. This increase in cardiac output can improve symptoms and end-organ perfusion in patients with severe left ventricular systolic dysfunction and cardiogenic shock. (Choice A) Phosphodiesterase inhibitors (eg, milrinone) increase the intracellular levels of cAMP by preventing its enzymatic breakdown in cardiac and vascular tissues, and result in vasodilation and positive inotropic effects. (Choice C) Ranolazine is an anti-anginal drug that inhibits late-phase inward sodium channels in ischemic myocardial cells during cardiac repolarization. A decrease in intracellular sodium concentration enhances calcium efflux via the sodium-calcium exchanger, which reduces myocardial oxygen consumption. (Choice D) Digoxin acts by inhibiting the sodium-potassium ATPase pump. This increases intracellular sodium concentration, which in turn decreases activity of the sodium-calcium exchanger that exports calcium from myocardial cells. The corresponding rise in intracellular Ca²⁺ concentration leads to improved myocardial contractility. (Choice E) Nitrates provide free radical nitric oxide, which activates guanylate cyclase and increases cGMP levels. This in turn leads to dephosphorylation of myosin light chains and causes vascular smooth muscle relaxation. (Choice F) Calcium channel blockers (eg, verapamil, diltiazem) prevent calcium ions from traversing voltage-dependent calcium channels in vascular smooth muscle and myocardium, leading to vasodilation and a decrease in cardiac contractility. Educational objective: Dobutamine is a β-adrenergic agonist with predominant activity on β₁ receptors and weak activity on β₂ and α₁ receptors. Stimulation of β₁ receptors leads to an increased production of cAMP and increased cytosolic Ca²⁺ concentration. This facilitates the interaction between actin and myosin, resulting in increased myocardial contractility. __________ References: The pharmacology of dobutamine. (http://www.ncbi.nlm.nih.gov/pubmed/3310640) Inotropes and vasopressors: review of physiology and clinical use in cardiovascular disease. (http://www.ncbi.nlm.nih.gov/pubmed/18765387)

A 71-Year-Old Woman Comes to the Emergency Department Due to Progressive