Mechanical Circulatory Support in the Treatment of Advanced Heart Failure.

According to the Centers for Disease Control, heart failure (HF) remains a pervasive condition with high morbidity and mortality, affecting 5.8 million people in the United States and 23 million worldwide. For patients with refractory end-stage HF, heart transplantation is the "gold standard" for definitive treatment. However, the demand for heart transplantation has consistently exceeded the availability of donor hearts, with approximately 2331 orthotopic heart transplantations performed in the United States in 2015 despite an estimated 100 000 to 250 000 patients with New York Heart Association class IIIB or IV symptoms that are refractory to medical treatment, making such patients potential transplant candidates. As such, the need for mechanical circulatory support (MCS) to treat patients with end-stage HF has become paramount. In this review, we focus on the history, advancements, and current use of durable MCS device therapy in the treatment of advanced heart failure.

Angiotensin II type 1 receptor blockade with 80 and 160 mg valsartan in healthy, normotensive subjects.

BACKGROUND: An 80-mg dose once or twice daily is the dose of valsartan frequently administered for treatment of hypertension. The target dose selected for the Val-HeFT trial in patients with chronic heart failure is 160 mg twice daily. The level and time course of angiotensin II type 1 (AT(1))-receptor blockade achieved by 160 mg valsartan have not been reported. METHODS AND RESULTS: Seven normotensive healthy subjects were assigned in random order to receive a single dose of placebo, 80 mg valsartan, and 160 mg valsartan at 7- to 10-day intervals. AT(1)-receptor blockade level (%) was determined by the pressure response to administration of exogenous angiotensin II. The pressure response to angiotensin II was measured at baseline and 2, 6, 12, and 24 hours after oral administration of placebo, 80 mg valsartan, and 160 mg valsartan. Eighty and 160 mg valsartan resulted in a significant and similar level of AT(1)-receptor blockade at 2 and 6 hours compared with placebo. The 160-mg dose resulted in a significantly greater level of AT(1)-receptor blockade than 80 mg at 12 and 24 hours. CONCLUSIONS: During the first 6 hours after oral administration of 80 and 160 mg valsartan the level of AT(1)-receptor blockade is similar. However, only 160 mg valsartan provides sustained AT(1)-receptor blockade over 24 hours.

Dose-dependent blockade of the angiotensin II type 1 receptor with losartan in normal volunteers.

Losartan, an angiotensin II type 1 receptor (AT1) antagonist, was developed as a more specific alternative to angiotensin-converting enzyme (ACE) inhibitors. At a daily dose of 50 mg, losartan is currently evaluated in large outcome trials involving patients with hypertension and postmyocardial infarction. The current study evaluated the level and duration of blockade of a pressor response to angiotensin II by 50 and 150 mg of losartan, compared with 32 mg of candesartan. Eight normotensive volunteers were randomly assigned to a single dose of losartan 50 or 150 mg, candesartan 32 mg, or placebo. Subjects were re-randomized after a 2-week washout period to complete all four study arms. Radial artery systolic pressure response to exogenous angiotensin II was measured at 2, 6, 12, and 24 h after administration of drug. Losartan 50 mg reduced the pressure response to exogenous angiotensin II significantly only at 6 h. In contrast, candesartan and losartan 150 mg produced a greater reduction in the pressure response to angiotensin II throughout the 24-h period. This suppression was not paralleled by a reduction in resting systemic arterial pressure. Higher doses than 50 mg of losartan might be evaluated to elicit optimal clinical effects.

Current management of patients with pulmonary hypertension and right ventricular insufficiency.

Pulmonary hypertension is a pathologic condition characterized by elevated pulmonary artery pressures and an associated vasculopathy. Primary pulmonary hypertension (PPH) is a rare condition with a sporadic occurrence and a familial form of the disorder. Abnormal vasomotor tone in the pulmonary vasculature results from an imbalance of the action of various vasoconstrictors/ vascular proliferative agents (endothelin and thromboxane) versus vasodilators /anti-proliferative agents (prostacyclin and nitric oxide). The mainstay of outpatient therapy has been the use of digitalis, diuretics, oxygen, and coumadin and the judicious use of vasodilator therapy. Calcium channel blockers in a select group and intravenous prostacyclin have dramatically improved survival for those with primary pulmonary hypertension. Use of prostaglandin I2 (PGI2) in other forms of chronic pulmonary arterial hypertension is not as clear, although evidence of initial beneficial response is promising. Importantly, over the next few years both pharmacologic and nonpharmacologic treatment modalities for pulmonary hypertension may rapidly change as we focus more on the abnormal pulmonary vascular biology and concomitant hemodynamic and neurohormonal milieu.