Faculty Bibliography

BACKGROUND: Incomplete suppression of the renin-angiotensin system during long-term ACE inhibition may contribute to symptomatic deterioration in patients with severe congestive heart failure (CHF). Combined angiotensin II type I (AT1) receptor blockade and ACE inhibition more completely suppresses the activated renin-angiotensin system than either intervention alone in sodium-depleted normal individuals. Whether AT1 receptor blockade with losartan improves exercise capacity in patients with severe CHF already treated with ACE inhibitors is unknown. METHODS AND RESULTS: Thirty-three patients with severe CHF despite treatment with maximally recommended or tolerated doses of ACE inhibitors were randomized 1:1 to receive 50 mg/d losartan or placebo for 6 months in addition to standard therapy in a multicenter, double-blind trial. Peak aerobic capacity (V(O2)) during symptom-limited treadmill exercise and NYHA functional class were determined at baseline and after 3 and 6 months of double-blind therapy. Peak V(O2) at baseline and after 3 and 6 months were 13.5+/-0.6, 15.1+/-1.0, and 15.7+/-1.1 mL. kg-1. min-1, respectively, in patients receiving losartan and 14.1+/-0.6, 14.3+/-0.9, and 13.6+/-1.1 mL. kg-1. min-1, respectively, in patients receiving placebo (P<0.02 for treatment group-by-time interaction). Functional class improved by at least one NYHA class in 9 of 16 patients receiving losartan and 1 of 17 patients receiving placebo. CONCLUSIONS: Losartan enhances peak exercise capacity and alleviates symptoms in patients with CHF who are severely symptomatic despite treatment with maximally recommended or tolerated doses of ACE inhibitors

Transcutaneous ultrasonography is a non-invasive technique with the ability to measure the volumetric blood flow of the peripheral circulation. Peripheral blood flow can be determined by high-resolution imaging of vessel diameter coupled with Doppler assessment of flow velocity. This method, however, has not been validated in vivo. Accordingly, brachial artery flow in response to intraarterial infusion of vasodilators was assessed by ultrasonography in 16 healthy subjects and compared to values obtained simultaneously by venous occlusion plethysmography. Blood flow calculated from ultrasound-derived vessel diameter and flow velocity was found to highly correlate with plethysmographic flow, with r values ranging from 0.83 to 0.99. Using this ultrasound technique combined with plethysmography, the response of conduit and resistance vessels to endothelium-mediated vasodilation was characterized. Doppler velocity rose dramatically with endothelium-dependent acetylcholine (970%), but only modestly with endothelium-independent vasodilators, nitroglycerin (292%) and nitroprusside (340%). Despite eliciting the greatest overall forearm flow response, acetylcholine resulted in a smaller increase in conduit diameter (15.4%) than nitroglycerin (21.8%), and only a comparable change than nitroprusside (14.6%). Taken together, these results suggest that acetylcholine acts predominantly on resistance vessels, whereas nitrovasodilators affect mainly conduit vessels. In summary, transcutaneous ultrasonography can be used reliably to assess flow changes in the peripheral circulation. Combined with plethysmography, this technique is useful for determining the relative contribution of conduit and resistance vessels to peripheral flow, particularly in the assessment of endothelium-mediated vasodilation

Valgus instability of the elbow joint is a clinical diagnosis. However, many authors describe valgus stress radiographs as an aid in making this diagnosis. We studied valgus stress radiographs of 20 men (40 elbows) and 20 women (40 elbows), none with a history of elbow trauma or instability. The medial ulnohumeral distance was measured with no stress, valgus stress by gravity, and an applied valgus stress of 25 N (approximately 5 pounds). Measurements were made with the elbow positioned in extension and in 30 degrees of flexion. The increase in medial ulnohumeral gapping with either gravity or 5 pounds of stress was statistically significant at both extension and 30 degrees of flexion compared with the unstressed condition. The difference in ulnohumeral gapping between gravity stress and 5 pounds of valgus stress in extension and in 30 degrees of flexion was also significant. We found no differences with regard to hand dominance or sex. We conclude that uninjured elbows have significant medial ulnohumeral gapping on valgus stress radiography. Although this is an important tool in diagnosing valgus instability of the elbow, it may yield a false-positive assessment of valgus instability. Valgus stress radiographs comparing contralateral elbows may reduce the false-positive rate since there appears to be no significant difference in medial ulnohumeral gapping between the two elbows

Congestive heart failure (CHF) is a common cardiovascular disorder that is characterised, in part, by a decreased cardiac output reserve. Accordingly, there is ongoing interest in the role of positive inotropic agents (e.g. adrenergic agonists and phosphodiesterase type III inhibitors, which mediate their cardiovascular effects via a cyclic adenosine monophosphate-dependent mechanism) in the treatment of CHF. However, enthusiasm for positive inotropic therapy in CHF has been dampened by the results of clinical trials, which have shown that these drugs are associated with an increased risk of mortality. Calcium sensitising agents are a heterogeneous group of positive inotropic agents that mediate their cardiovascular actions (at least in part) by increasing the sensitivity of the contractile elements to calcium. Increased sensitivity to calcium may be related to changes in calcium binding to troponin C, or to direct effects on the actin-myosin complex. In addition, the inhibition of phosphodiesterase type III may contribute to the positive inotropic action of calcium sensitising agents. Five agents with calcium sensitising properties (pimobendan, levosimendan, MCI-154, EMD-53998 and CGP-48506) have been studied as possible therapies for CHF. All of these agents have demonstrated a positive inotropic action in isolated cardiac tissue and in animal models of CHF. In clinical trials, pimobendan, the most extensively studied of these drugs, was well tolerated and was associated with improved exercise tolerance during the first 6 months of therapy; however, it was also associated with a nonsignificant trend towards increased mortality. Because many of the calcium sensitising agents also inhibit phosphodiesterase type III activity, the long term safety of these agents is uncertain. Large-scale survival trials are required to determine the long term safety and efficacy of these agents before their role in the treatment of CHF can be defined

Forearm blood flow (ml/min/100 ml) was determined with strain-gauge venous occlusion plethysmography at rest and in response to handgrip exercise in 7 patients with congestive heart failure and in 9 normal subjects before and after regional administration of endothelin-1 in the brachial artery. Administration of endothelin-1 significantly decreased forearm blood flow at rest and during exercise in normal subjects but did not change it at rest or during exercise in patients with congestive heart failure

Combined therapy with an angiotensin-II type I receptor (AT1) antagonist and an angiotensin-converting enzyme (ACE) inhibitor results in more complete suppression of the renin-angiotensin system. Accordingly, the blood-pressure response and safety of combining AT1-receptor blockade with losartan for ACE inhibition were evaluated in patients with congestive heart failure who were already treated with maximally recommended or tolerated doses of an ACE inhibitor. Forty-three patients with symptomatic congestive heart failure were evaluated biweekly for 1 month before addition of losartan and weekly during administration of losartan at a daily dose of 25 mg for the first week and 50 mg for the second week. Systolic blood pressure, which remained unchanged before addition of losartan, decreased from 122 +/- 18 mm Hg to 112 +/- 17 and 107 +/- 17 mm Hg (p < 0.001) after 1 week of 25 mg and 1 week of 50 mg losartan, respectively. Diastolic blood pressure also significantly decreased. The decreases in blood pressure were well tolerated by all patients, even by those in whom symptomatic hypotension developed during uptitration of ACE inhibition. Serum potassium and sodium and parameters of renal function remained unchanged. Combining AT1-receptor blockade with losartan to maximally recommended or tolerated ACE inhibition appears safe and leads to further vasodilatation in symptomatic patients with congestive heart failure

The effects of physical training on endothelium-dependent vasodilation in skeletal muscle resistance vessels were investigated in patients with heart failure. Forearm blood flows (ml.min-1.100 ml-1) in response to brachial arterial administration of acetylcholine (5 x 10(-5) and 5 x 10(-4) M at 1 ml/min) and nitroglycerin (5 x 10(-6) and 5 x 10(-5) M at 1 ml/min) were determined by strain-gauge venous occlusion plethysmography before and after 8 wk of daily handgrip exercise in 12 patients with chronic heart failure. After 8 wk of daily handgrip exercise, the vasodilatory responses to acetylcholine significantly increased from pretraining values, i.e., 16.6 +/- 2.0 vs. 8.6 +/- 1.3 ml.min-1.100 ml-1 (P < 0.05) and 27.5 +/- 1.5 vs. 14.6 +/- 1.7 ml.min-1.100 ml-1 (P < 0.05), respectively, whereas the vasodilatory responses to nitroglycerin did not change. Handgrip exercise training appears to specifically enhance endothelium-dependent vasodilation in the forearm skeletal muscle circulation of patients with heart failure

The pathogenesis of heart failure is determined by the ventricular and vascular responses to myocellular injury. Experimental and clinical studies suggest that the vascular endothelium may play an important role in modulating progression of ventricular and vascular remodeling in heart failure. Endothelial cell dysfunction has been described in the coronary and skeletal muscle circulations of patients with heart failure and appears to be characterized by decreased endothelial synthesis of nitric oxide and increased production of endothelin-1. The pathogenesis of endothelial dysfunction in heart failure is unknown, but may be related to increased oxidative stress, abnormal regional flow conditions, and cytokine and neurohormonal activation. The specific role of endothelial dysfunction in the pathogenesis of heart failure remains to be determined. If endothelial dysfunction does contribute to progression of disease in early heart failure, specific therapies to enhance endothelial dysfunction may improve long-term morbidity and mortality

BACKGROUND: Long-term beta-adrenergic blockade does not appear to be associated with drug-induced training in patients with congestive heart failure (CHF); whether exercise training can increase peak aerobic capacity in patients with CHF who are treated with beta-adrenergic blockers is currently unknown. METHODS AND RESULTS: We studied 23 patients with CHF who were treated with carvedilol or propranolol in addition to ACE inhibitors, furosemide, and digoxin. Of the patients treated with carvedilol, 8 underwent exercise training and 8 remained sedentary. All 7 patients treated with propranolol underwent exercise training. Peak oxygen consumption (mL.kg-1.min-1) was serially measured in trained and sedentary patients. Peak reactive hyperemia (mL.min-1.100 mL-1) was determined in the calf and forearm immediately before and after 12 weeks of training. The peak oxygen consumption of trained patients treated with either carvedilol or propranolol increased from 12.9 +/- 1.4 to 16.0 +/- 1.6 (P < .001) and 12.4 +/- 1.0 to 15.7 +/- 0.9 (P < .001) mL.kg-1.min-1, respectively, whereas it did not change in the sedentary patients. Peak reactive hyperemia increased significantly in the calves but not the forearms of trained patients. CONCLUSIONS: Long-term, nonselective beta-adrenergic blockade with carvedilol or propranolol does not prevent patients with CHF from deriving systemic and regional benefits from physical training

BACKGROUND: Whether increased cardiac output during chronic circulatory support with a left ventricular assist device (LVAD) is associated with improved metabolic vasodilation in the peripheral circulation of patients with congestive heart failure is unknown. METHODS: Forearm blood flow, determined by venous occlusion plethysmography, mean arterial pressure, and cardiac output were measured at rest and after 5 minutes of arterial occlusion (a maximal metabolic vasodilatory stimulus) in 14 patients with severe heart failure before LVAD implantation, and in the early (<4 weeks) and late (8 to 12 weeks) postoperative recovery phases after LVAD implantation. Nine normal subjects served as controls. Vascular conductance was calculated as the ratio of forearm blood flow and mean arterial pressure. RESULTS: Mean arterial pressure and cardiac output increased to normal values in the early and late recovery phases after LVAD implantation. Resting forearm blood flow and vascular conductance were similar to normal subjects in the early and late recovery phases after LVAD implantation. Peak forearm blood flow and vascular conductance were significantly less than control subjects in the early preoperative recovery phase (p < 0.05) but were similar to control subjects in the late postoperative recovery phase after LVAD implantation. CONCLUSIONS: In spite of early normalization of cardiac output, mean arterial pressure, and resting forearm blood flow during chronic circulatory support with the LVAD, peak forearm blood flow, and peak vascular conductance did not increase to values similar to those observed in normal subjects until the late postoperative recovery period. The delayed effect of the LVAD on metabolic vasodilation may be related to flow-dependent changes in the peripheral vasculature of patients with heart failure