Faculty Bibliography

The current study was undertaken to determine prospectively the risk of cerebral thromboembolism and the prognostic significance of left ventricular thrombus in ambulatory patients with chronic congestive heart failure. A total of 264 ambulatory patients (mean age 62 years, mean left ventricular ejection fraction 27%) were followed prospectively for 24 +/- 9 months to determine the incidence of nonhemorrhagic stroke, transient ischemic attack, and mortality. Two-dimensional echocardiographic studies, performed for clinical indications other than previous systemic thromboembolism in 109 patients, were analyzed to relate the presence of left ventricular thrombus to subsequent outcome. Nine cerebral thromboembolic events occurred in 264 patients during the two-year mean follow-up period, yielding a rate of 1.7 thromboembolic events per 100 patient-years of follow-up. Known risk factors for stroke (hypertension, diabetes mellitus, and/or atrial fibrillation) were present in all nine patients with cerebral thromboembolic events. The 109 patients with echocardiographic studies had more severe heart failure than patients without echocardiographic studies (functional class 2.6 vs 2.1, p < 0.01), greater risk of a thromboembolic event (2.4 vs 1.4 events/100 patient-years of follow-up, p < 0.01), and higher mortality (21.3 vs 5.5 deaths/100 patient-years, p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND. The vasodilatory response to intra-arterial administration of acetylcholine is reduced in patients with congestive heart failure compared with that of normal subjects. The reduced response to acetylcholine may be related to decreased endothelial release of nitric oxide, interaction with peripheral alpha-adrenergic transmission, or production of cyclooxygenase-dependent vasoconstricting substances. The extent to which each of these mechanisms contributes to the reduced vasodilatory response to acetylcholine in patients with congestive heart failure is not known. METHODS AND RESULTS. Thirty-one patients with congestive heart failure (New York Heart Association functional class II-III) and five age-matched normal subjects were studied. Regional vascular responses in the forearm to infusions of acetylcholine, an endothelium-dependent vasodilator (10(-7) to 10(-5) mol/L) and nitroglycerin, an endothelium-independent vasodilator (10(-6) mol/L) in the brachial artery were determined with venous occlusion plethysmography before and after regional alpha-adrenergic blockade with intra-arterial phentolamine (25 micrograms/min) and systemic cyclooxygenase with oral indomethacin (50 mg). Administration of phentolamine significantly increased resting baseline forearm blood flow in 11 patients with congestive heart failure (2.9 +/- 0.4 to 5.4 +/- 0.8 mL.min-1.100 mL-1) and normal subjects (4.6 +/- 0.3 to 11.3 +/- 2.1 mL.min-1.100 mL-1). Before administration of phentolamine, intra-arterial infusions of acetylcholine 10(-7), 10(-6), and 10(-5) mol/L increased forearm blood flow to 4.0 +/- 1.0, 6.0 +/- 1.7, and 16.1 +/- 4.0 mL.min-1.100 mL-1, respectively, in patients with congestive heart failure and to 14.7 +/- 6.2, 20.2 +/- 4.7, and 38.7 +/- 7.9 mL.min-1.100 mL-1, respectively, in normal subjects. After administration of phentolamine, the vasodilatory responses to intra-arterial infusions of acetylcholine and nitroglycerin did not change in either patients or normal subjects. Administration of indomethacin did not alter resting forearm blood flow in 15 patients with congestive heart failure (2.7 +/- 0.4 to 2.7 +/- 0.4 mL.min-1.100 mL-1) or normal subjects (4.6 +/- 0.3 to 5.4 +/- 0.8 mL.min-1.100 mL-1). Administration of indomethacin significantly increased the vasodilatory response to infusion of acetylcholine by an average of 39% in patients with congestive heart failure but did not change the vasodilatory response to acetylcholine in normal subjects. In patients with congestive heart failure, baseline forearm blood flow and the vasodilatory responses to intra-arterial infusions of acetylcholine and nitroglycerin were significantly less than those of normal subjects both before and after administration of phentolamine and indomethacin. CONCLUSIONS. The reduced vasodilatory response to intra-arterial infusion of acetylcholine in patients with congestive heart failure probably results from several coexistent abnormalities in peripheral vascular function, including abnormal production of cyclooxygenase-dependent vasoconstricting factor, impaired endothelial release of nitric oxide, and decreased vascular smooth muscle responsiveness to cyclic GMP-mediated vasodilation

Clinicopathologic features of 13 women with peripartum cardiomyopathy were compared to 13 women aged 19 through 38 with idiopathic dilated cardiomyopathy. No presenting clinical or pathologic variable distinguished either group. However, the clinical course differed between the groups. Eleven of 13 patients with idiopathic dilated cardiomyopathy had a poor clinical outcome, defined as persistent heart failure or death. Patients in this group succumbed one year or more after disease onset. Five of 13 patients with peripartum cardiomyopathy had poor outcome, with death occurring 9 months or less after disease onset. The clinical course of peripartum cardiomyopathy appears distinct from that of idiopathic dilated cardiomyopathy in young women

As a sequel to our previous descriptions of the pathological changes induced by hydrocephalus in the infantile cerebral cortex, the study presented here has evaluated the effects of surgical decompression on cortical cytology and cytoarchitecture. Hydrocephalus was induced in 14 kittens by the intracisternal injection of kaolin at 4 to 11 days of age. Nine of these hydrocephalic animals received low-pressure ventriculoperitoneal shunts at 9 to 15 days after kaolin injection; these animals were monitored preoperatively and postoperatively by ultrasound and were killed at various postshunt intervals up to 30 days. Five normal or saline-injected animals served as age-matched controls. At the time of shunt placement, the ventricular index confirmed that all recipient animals had attained moderate or severe degrees of ventriculomegaly. Within 3 days after shunt placement, the size of the lateral ventricles had decreased to control levels and was accompanied by rapid and dramatic improvements in behavior and skull ossification. When the animals were killed, gross inspection revealed that about half of the animals exhibited mild to moderate ventriculomegaly, with cortical mantles 50 to 80% their normal thickness. Tissue from frontal (primary motor), parietal (association), and occipital (primary visual) cortical areas was processed for light microscopic analysis. Pyknotic or dark shrunken neurons, which are found typically in hydrocephalic brains, were observed only occasionally in the cortex of shunted animals. Gliosis and mild edema were prevalent, however, in the periventricular white matter. The laminae of the cerebral cortex could be identified in all shunted animals. In those animals with mild residual ventriculomegaly, the entire cortical mantle was somewhat compressed, as evidenced by an increased packing density of neurons. Furthermore, the somata of some neurons were disoriented. Overall, these results indicate that most of the morphological characteristics of the cerebral cortex are preserved after surgical decompression and suggest that ventriculoperitoneal shunts may prevent neuronal damage and/or promote neuronal repair

BACKGROUND. In addition to depressed cardiac reserve, peripheral factors may contribute to limit maximal exercise capacity in patients with congestive heart failure (CHF). To investigate the role of reduced active skeletal muscle mass, peak oxygen uptake (VO2, milligrams per kilogram per minute) was determined during maximal symptom-limited exercise involving the lower limbs (LL) alone and the lower limbs and upper limbs (LL+UL) combined in patients with CHF and in normal subjects of similar age and sex. METHODS AND RESULTS. LL bicycle exercise was performed upright with a ramp protocol and continuous expired gas analysis. When respiratory exchange ratio (RER) reached 1.0, UL exercise was initiated at constant load with the use of a cranking device positioned at shoulder level. LL exercise alone and combined LL+UL exercise were performed on separate days in randomized order by 24 patients with CHF and seven normal subjects. In patients with CHF, peak VO2 was greater during combined LL+UL exercise than during LL exercise alone, i.e., 15.8 +/- 0.8 versus 14.2 +/- 0.9 ml.kg-1.min-1 (p < 0.001), whereas in normal subjects, maximal VO2 was similar during the two tests, i.e., 26.7 versus 26.2 ml.kg-1.min-1 (NS). The increase in peak VO2 during combined LL+UL exercise relative to LL exercise alone was almost exclusively observed in patients with peak VO2 < 15 ml.kg-1.min-1 (mean increase, 21.7 +/- 4.1%). Peak VO2 during combined LL and UL exercise did not increase relative to LL exercise alone in patients with peak VO2 > 15 ml.kg-1.min-1 and in normal subjects of similar age and sex, i.e., 0.1 +/- 4.0% and 2.0 +/- 2.3% respectively. CONCLUSIONS. In contrast to normal subjects and patients with moderate CHF, patients with severe CHF do not exhaust their cardiopulmonary reserve during symptom-limited maximal LL exercise on a bicycle

Anaerobic threshold measurements determined either invasively by analysis of arterial lactate concentration (lactate threshold) or noninvasively by respiratory gas exchange analysis (ventilatory threshold) were compared in patients with chronic congestive heart failure. Sixteen patients performed symptom-limited maximal exercise on a bicycle ergometer using a continuous ramp protocol with measurement of arterial lactate concentration at 1 minute intervals, and continuous breath-by-breath analysis of respiratory gas exchange. A specific lactate threshold point was detected in only 7 patients. These 7 patients had significantly greater peak oxygen uptake than did the 9 in whom no specific lactate threshold point was detected (15.9 +/- 1.0 vs 10.5 +/- 0.5 ml/kg/min; p less than 0.05). Ventilatory threshold significantly correlated with lactate threshold in these 7 patients. In the remaining 9 patients, neither lactate nor ventilatory threshold could be reliably determined with methods used in the present study

Impaired endothelial-dependent vasodilation has been demonstrated in two animal models of congestive heart failure and in the coronary circulation of patients with idiopathic dilated cardiomyopathy. To determine whether this impairment contributes to the abnormal peripheral vasomotor tone in patients with congestive heart failure, the local vascular response to intraarterial infusions of graded concentrations (10(-8) M to 10(-5) M) of acetylcholine (an endothelial-dependent vasodilator) and nitroglycerin (a direct-acting vasodilator) was studied in the superficial femoral artery of 19 patients with congestive heart failure (New York Heart Association classes I to IV) and 6 age-matched normal control subjects. The local vascular response was determined from the arterial blood flow velocity pattern obtained by transcutaneous Doppler ultrasonography. Acetylcholine, 10(-5) M, induced a pattern characteristic of vasodilation in all six normal subjects; mean blood flow velocity for the group significantly increased from 11.9 +/- 2.7 to 44.8 +/- 20.9 cm/s (p less than 0.05). In contrast, the same dose of acetylcholine induced a blood flow velocity pattern characteristic of vasodilation in only 4 of the 19 patients with congestive heart failure. Group mean blood flow velocity did not change significantly. Nitroglycerin, 10(-7) M, induced vasodilation in all 6 normal subjects but in only 1 of 19 patients. Nitroglycerin, 10(-5) M, was administered to 10 patients; all 10 demonstrated a pattern characteristic of vasodilation. Thus, acetylcholine-mediated endothelial-dependent vasodilation appears to be impaired in the peripheral vasculature of patients with congestive heart failure. Both endothelial dysfunction and abnormal vascular smooth muscle responsiveness may contribute to abnormal peripheral vasomotor tone

BACKGROUND. The vasodilatory response to local specific type III phosphodiesterase inhibition with amrinone was evaluated before and immediately after local administration of digoxin in 14 patients with severe congestive heart failure (CHF). METHODS AND RESULTS. A 3F polyethylene catheter was inserted into the common femoral artery for drug administration and pressure monitoring. Mean blood flow velocity (MBFV) was continuously determined in the superficial femoral artery by transcutaneous Doppler ultrasonography. After intra-arterial administration of 10 mg amrinone, group MBFV increased from 7.7 +/- 1.4 to 16.0 +/- 2.1 cm/sec (p less than 0.05, n = 10). Local administration of 20 micrograms digoxin, which was infused over 20 minutes, did not alter group MBFV (i.e., 8.2 +/- 1.6 versus 7.6 +/- 1.5 cm/sec; p = NS, n = 10). The second administration of 10 mg amrinone, which immediately followed completion of local digoxin infusion, increased group MBFV but to a lesser extent than that produced by the first amrinone administration (i.e., 11.9 +/- 1.9 versus 16.0 +/- 2.1 cm/sec; p less than 0.05, n = 10). When placebo was administered instead of digoxin, group MBFV was similar after the first and second administrations of amrinone (i.e., 15.3 +/- 3.3 versus 15.6 +/- 3.8 cm/sec; p = NS, n = 4). CONCLUSIONS. Although local administration of digoxin did not significantly alter baseline vascular tone in patients with CHF, it substantially decreased the direct vasodilatory effect induced by specific type III phosphodiesterase with amrinone

Pimobendan, a new oral cardiotonic and vasodilator agent, increases myocardial contractile force through specific inhibition of phosphodiesterase type III and increased calcium sensitivity of the myocardial contractile elements. The effects of pimobendan on left ventricular performance and maximal exercise capacity were studied in a multicenter, randomized, double-blind, placebo-controlled trial involving 52 patients with severe congestive heart failure despite diuretics, digoxin, and angiotensin-converting enzyme inhibitors. The acute hemodynamic evaluation included three single doses of 2.5, 5.0, and 10.0 mg of oral pimobendan, which was subsequently administered at a daily dose of 5 or 10 mg for 4 weeks. Acute administration of pimobendan significantly increased the resting cardiac index and lowered pulmonary capillary wedge pressure in a dose-dependent manner, whereas heart rate and systemic arterial pressure were not substantially altered. Patients receiving pimobendan, 5 and 10 mg daily, had a significantly greater increase in maximal exercise duration than those receiving placebo, that is, 144 +/- 30 and 124 +/- 33 seconds versus 58 +/- 25 seconds (p = 0.05). Peak oxygen uptake increased by 1.7 +/- 0.8 and 2.2 +/- 1.3 ml/kg/min in patients receiving pimobendan at a daily dose of 5 and 10 mg, respectively, whereas it decreased by 0.1 +/- 0.6 ml/kg/min in patients receiving placebo (p = 0.06). Thus pimobendan acutely improves resting left ventricular performance and chronically increases exercise duration and peak oxygen uptake in patients with severe congestive heart failure concomitantly treated with digoxin, diuretics, and angiotensin-converting enzyme inhibitors

Derangements of the peripheral circulation play a major role in the pathophysiology of congestive heart failure. Their appearance coincides with that of the symptoms and signs that characterize the full-blown clinical syndrome. Long-term therapy with ACE inhibitors partially reverses these abnormalities, but the pathologic mechanisms are still poorly understood