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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.

A reliable multipurpose measurement of maximal physical performance is not available in normal subjects or patients with left ventricular (LV) systolic dysfunction/congestive heart failure (CHF), since maximal physical performance depends on the task at hand. Thus, although general indices of cardiopulmonary reserve are extremely helpful to measure the level of physical fitness, they do not predict physical performance for a each specific activity. To be reliable, a quantitative assessment should be specifically obtained for activity, an approach that is highly cumbersome in describing the physical profile of a given individual. When concerned with aerobic activities, measurement of maximal oxygen consumption, i.e., max VO2 (ml/kg/min) can be considered as good an index as any to predict maximal performance of normal subjects. Determination of max VO2 is rarely obtained in patients with LV systolic dysfunction/CHF, since symptoms preclude patients from reaching a true plateau in VO2. Nevertheless, patients with LV systolic dysfunction/CHF reach a peak VO2, which is a semiobjective index of cardiac and vascular reserve.

BACKGROUND Tumor necrosis factor-alpha (TNF alpha), which we and others have shown to be elevated in patients with severe congestive heart failure (CHF), is involved in the regulation of nitric oxide metabolism. Whether increased concentrations of TNF alpha affect nitric oxide-mediated vasodilation in patients with CHF has not been studied previously. METHODS AND RESULTS Serum concentrations of TNF alpha, interleukin-1 (IL-1), interleukin-2 (IL-2), and interleukin-6 (IL-6) were determined in venous blood (pg/mL) from 17 patients with stable New York Heart Association classes II and III CHF (mean age, 58 +/- 11 years; mean left ventricular ejection fraction, 19.5 +/- 7.3) and 17 age-matched normal subjects with enzyme-linked immunosorbent assays (detection limit of assays, 20 pg/mL). Forearm blood flows were determined with plethysmography (mL/min per 100 mL) in 17 patients and 7 normal subjects in response to brachial artery administration of graded concentrations of acetylcholine (10(-6) mol/L and 10(-5) mol/L) and nitroglycerin (10(-7) mol/L and 10(-6) mol/L). Serum concentrations of TNF alpha were above the detection limits of the assay in 10 of 17 patients with CHF (mean serum concentration, 39.4 +/- 3.8 pg/mL). Forearm blood flow responses to acetylcholine and nitroglycerin were significantly greater in these 10 patients than in the 7 patients without detectable serum TNF alpha and were closely correlated with TNF alpha serum concentrations (r > or = .81, P < .01 and r > or = .65, P < .05 respectively). In 1 of 17 normal subjects, the serum concentration of TNF alpha was just above the detection limit of the assay. Serum concentrations of IL-2 were above the detection limit of the assay in 14 of 17 patients with CHF (mean serum concentration, 112 +/- 19 pg/mL). IL-2 was not detected in the serum of normal subjects. Serum concentrations of IL-1 and IL-6 were below the detection limit of the assays in all patients and normal subjects assayed. CONCLUSIONS Increased TNF alpha concentrations are closely correlated with forearm blood flow responses to regional administration of acetylcholine and nitroglycerin. The significant correlation between serum concentrations of TNF alpha and forearm blood flow responses to acetylcholine and nitroglycerin suggests that both the inducible and the constitutive forms of nitric oxide synthase are involved in the regulation of peripheral vasomotor tone in patients with CHF.

Systemic and lower limb skeletal muscle lactate metabolism was studied in 10 men with congestive heart failure by use of a primed continuous intravenous infusion of L-(+)-[U-14C]lactate. Arterial and deep femoral venous blood samples were obtained at rest and during 30 min of submaximal exercise. Systemic lactate metabolic turnover rate (Rd) was determined using Steele's isotopic steady-state equation (Rd = isotopic infusion rate/arterial specific activity). Plasma lactate concentrations in the artery and deep femoral vein did not change significantly from resting values during exercise (1.11 +/- 0.13 vs. 1.26 +/- 0.12 and 1.27 +/- 0.12 vs. 1.30 +/- 0.12 mM, respectively), whereas Rd increased from 22.5 +/- 1.8 to 41.6 +/- 4.8 mumol.kg-1.min-1 (P < 0.005). Rd did not significantly correlate with arterial lactate concentration during rest or exercise. Because of simultaneous uptake and release of lactate in skeletal muscle, arterial and deep femoral venous lactate concentrations are not closely related to either systemic or lower limb skeletal muscle lactate metabolism in patients with congestive heart failure.

The ability of the skeletal muscle vasculature to meet the high metabolic requirements of the active skeletal muscle probably represents the most striking adaptation of the cardiovascular system to heavy exercise. Indeed, up to 90% of the increased cardiac output, which can reach 25–30 L/min, is distributed to the lower limbs during maximal treadmill or bicycle exercise [1]. Thus, while the cardiac output increases from rest by a factor of 4 to 5, blood flow to the skeletal muscle involved in exercise increases by a factor ranging from 15 to 20. In normal and diseased states, blood flow to skeletal muscle involved in exercise closely correlates with peak aerobic capacity. Moreover, measurement of skeletal muscle blood flow (SMBF) is critical to study the metabolism of the skeletal muscles [2]. However, studies of SMBF in man are few and only a handful of laboratories have been active in this area over the years [3, 4, 5, 6, 7, 8, 9]. This, by far, does not stem from a lack of interest in the skeletal muscle vasculature, but reflects the difficulties in measuring SMBF in normal subjects and in patients with cardiac disease. In addition, determination of SMBF during exercise has been hampered by our inability to quantify the amount of skeletal muscle mass actively participating in exercise. If 50% of the total muscle mass is active, the flow per 100 g or per kg is considerably lower than if only 30% of the total muscle is active. Thus, prior to reviewing the data currently available on SMBF in man, the advantages and limitations of the techniques used to measure SMBF will be briefly discussed.

OBJECTIVES We sought to investigate the effect of angiotensin-converting enzyme (ACE) inhibition

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.

The advantages and inadequacies of the currently available techniques to measure regional blood flow in the lower limbs are being reviewed. Thermodilution technique and local 133xenon washout technique have the advantage of allowing determination of blood flow during exercise, while venous occlusion plethysmography and pulsed-Doppler duplex ultrasonography only allow determination of blood flow at rest. Overall, measurements of lower limb blood flow are not highly reproducible by any technique, and the variability in measurements of regional blood flow should lead to careful interpretation of derived parameters such as vascular conductance and resistance. Determination of vascular input impedance by Fourier analysis of pressure data, recorded with high fidelity catheter, and flow velocity measurements obtained transcutaneously by Doppler ultrasonography, may offer a more accurate quantitative analysis of the characteristics of the lower limb vascular system.

Flosequinan is an oral arterial and venous vasodilator that is currently under investigation for the treatment of congestive heart failure. The effects of flosequinan on ventricular performance and myocardial contractility were studied in 10 patients with severe congestive heart failure during right and left cardiac catheterization. Sixty minutes after a 100 mg oral dose of flosequinan, the peak rate of rise in left ventricular pressure (dP/dt) increased from 940 +/- 180 to 1050 +/- 240 mm Hg/sec (p less than 0.05), while left ventricular end-diastolic pressure decreased from 32 +/- 5 to 26 +/- 8 mm Hg (p less than 0.05), and cardiac index increased (2.1 +/- 0.4 to 2.3 +/- 0.5 L/min/m2, (p less than 0.05). The mean pulmonary artery pressure and vascular resistance decreased from 40 +/- 8 to 33 +/- 12 mm Hg (p less than 0.05) and from 330 +/- 240 to 290 +/- 170 dyne-sec/cm5 (p less than 0.05), respectively. Heart rate, mean aortic pressure, right atrial pressure, systemic vascular resistance, and serum norepinephrine levels did not change significantly. The increase in left ventricular peak dP/dt that was concomitant with a decrease in left ventricular end-diastolic pressure, and no change in systemic arterial pressure or sympathetic tone, argue for a direct positive inotropic effect of flosequinan.

Conventional high level exercise training at a workload consistent with 75% of peak oxygen consumption (pVO 2 , ml/min/kg) in patients with congestive heart failure (CHF) improves peak aerobic capacity and limb vasodilatory capacity. However, training at this workload may promote left ventricular dilatation in patients with CHF by prolonged exposure to substantially elevated filling pressure (PCWP). Whether training at low level, I.e., at a workload consistent with l50% pVO 2 , would result in limited increases in PCWP while still improving peak aerobic capacity and peripheral vasodilatory function is unknown. Accordingly, 15 patients with stable advanced CHF underwent measurement of 1) the PCWP response to low vs high level exercise, and 2) the change in peak aerobic capacity and limb vasodilatory capacity resulting from participation in a low level training program. PCWP was measured by right heart catheterization at rest, and during low and high level exercise. Patients then performed 12 weeks of low level training, utilizing a semi-recumbent bicycle. Pre- and post-training evaluations included pVO 2 , calf and forearm peak hyperemic blood flow (PHBF, ml/min/100 ml), and resting heart rate (HR, b/min). Results 1)PCWP rose to 20 mmHg during low level exercise (Δ54% vs rest), and 34 mmHg during high level exercise (Δ162% vs rest). 2)Pre- and post-training data are as follows: pVO 2 calf PHBF forearm PHBF HR pre-train 99 18 23 99 post-train 14.1 36 20 80 p value 0.02 l0.01 NS 0.02 Conclusions 1) The rise in PCWP is significantly less during low level exercise than during high level exercise. 2) Training at a workload consistent with ≤50% of pVO 2 significantly improves peak aerobic capacity. 3) PHBF in the trained calf increases 100% from baseline, while it does not change in the untrained forearm. Enhanced vasodilatory responses in exercising muscle may be an important contributor to improved peak aerobic capacity. Thus, low level training produces benefits similar to high level training with only a moderate rise in PCWP, and may therefore provide less of a stimulus for ventricular dilatation.

ContextCardiogenic shock (CS) is the leading cause of death for patients hospitalized with acute myocardial infarction (AMI).ObjectiveTo assess the effect of early revascularization (ERV) on 1-year survival for patients with AMI complicated by CS.DesignThe SHOCK (Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock) Trial, an unblinded, randomized controlled trial from April 1993 through November 1998.SettingThirty-six referral centers with angioplasty and cardiac surgery facilities.PatientsThree hundred two patients with AMI and CS due to predominant left ventricular failure who met specified clinical and hemodynamic criteria.InterventionsPatients were randomly assigned to an initial medical stabilization (IMS; n = 150) group , which included thrombolysis (63% of patients), intra-aortic balloon counterpulsation (86%), and subsequent revascularization (25%), or to an ERV group (n = 152), which mandated revascularization within 6 hours of randomization and included angioplasty (55%) and coronary artery bypass graft surgery (38%).Main Outcome MeasuresAll-cause mortality and functional status at 1 year, compared between the ERV and IMS groups.ResultsOne-year survival was 46.7% for patients in the ERV group compared with 33.6% in the IMS group (absolute difference in survival, 13.2%; 95% confidence interval [CI], 2.2%-24.1%; P

Numerous large, double-blind, randomized trials have demonstrated that, overall, angiotensin converting enzyme (ACE) inhibition improves survival of patients after acute myocardial infarction (AMI). However, several practical issues concerning ACE inhibition in the presence of AMI have not yet been answered. These include whether ACE inhibition should be initiated in all patients with AMI, how soon ACE inhibition should be attempted in relation to onset of pain and possibly thrombolysis, and, lastly, how long ACE inhibition should be maintained after the acute event. Each of these issues is addressed, and recommendations are made on the basis of the results from recent randomized trials in AMI and congestive heart failure.

SUMMARY Theeffects ofcombined administration oflow-dose amrinone (100mg)andhydralazine (75-100 mg)on resting hemodynamics andexercise capacity werestudied inninepatients with severecongestive heart failure. Five patients wereinNewYorkHeartAssociation (NYHA)functional class IVandfour wereinclass III.Cardiac index increased from1.92 ± 0.36I/min/m' (mean SD)to3.23 ± 0.63I/min/m' (p< 0.001); pulmonary wedge pressuredecreased from23.6 ± 4.1to15.1i 4.7mm Hg(p< 0.001) and systemic vascular resistance from1666 ± 210to1063 189dyn-sec-cm-' (p

In patients with chronic congestive heart failure (CHF), skeletal muscle blood flow can be measured directly by the continuous thermodilution technique and by the xenon 133 clearance method. The continuous thermodilution technique requires retrograde catheterization of the femoral vein and, thus, cannot be repeated conveniently in patients during evaluation of pharmacologic interventions. The xenon 133 clearance, which requires only an intramuscular injection, allows repeated determination of skeletal muscle blood flow. In patients with severe CHF, a fixed capacity of the skeletal muscle vasculature to dilate appears to limit maximal exercise performance. Moreover, the changes in peak skeletal muscle blood flow noted during long-term administration of captopril, an angiotensin-converting enzyme inhibitor, appears to correlate with the changes in aerobic capacity. In patients with CHF, resting supine deep femoral vein oxygen content can be used as an indirect measurement of resting skeletal muscle blood flow. The absence of a steady state complicates the determination of peak skeletal muscle blood flow reached during graded bicycle or treadmill exercise in patients with chronic CHF. Indirect assessments of skeletal muscle blood flow and metabolism during exercise performed at sub-maximal work loads are currently developed in patients with chronic CHF.

Left ventricular performance was studied during isometric exercise in 17 patients with severe congestive heart failure, combining invasive hemodynamic and echo-Doppler techniques. Isometric exercise at 30% of maximum resulted in a decrease in stroke volume index (27.4 +/- 7.1 to 22.7 +/- 7.4 ml/m2), with a significant increase in heart rate from 81 +/- 10 to 92 +/- 14 beats/min and in systemic vascular resistance from 1827 +/- 527 to 2372 +/- 737 dyne.sec.cm-5. A significant rise in pulmonary capillary wedge pressure (18 +/- 9 to 31 +/- 10 mm Hg) was associated with a marked increase in mitral regurgitant volume (14 +/- 11 to 27 +/- 15 ml), calculated as the difference between total stroke volume obtained by two-dimensional echocardiography and forward stroke volume measured by pulsed Doppler at the aortic anulus. During isometric exercise, left ventricular end-diastolic and end-systolic volumes did not change markedly, but the total stroke volume tended to increase from 62 +/- 13 to 67 +/- 13 ml. The increase in mitral regurgitant volume induced by isometric exercise was correlated with the fall in forward stroke volume (r = 0.7, p less than 0.01). Thus a rise in systemic arterial pressure induced by isometric exercise is associated with a decrease in cardiac performance attributable to redistribution of total left ventricular output with an increase in mitral regurgitation and a simultaneous decrease in forward cardiac output.

The effects of dobutamine and intravenous milrinone on systemic hemodynamics, coronary blood flow and myocardial metabolism were studied in 11 patients with severe congestive heart failure. Although milrinone and dobutamine similarly increased cardiac index from 1.9 +/- 0.4 to 2.5 +/- 0.4 liters/min per m2 (p less than 0.001) and from 1.9 +/- 0.4 to 2.8 +/- 0.8 liters/min per m2 (p less than 0.001), respectively, milrinone decreased left ventricular end-diastolic pressure to a greater extent than dobutamine, that is, from 26 +/- 6 to 12 +/- 8 mm Hg (p less than 0.001) versus 26 +/- 8 to 20 +/- 8 mm Hg (p less than 0.001). In contrast to dobutamine, milrinone significantly reduced mean systemic arterial and right atrial pressures. Dobutamine increased the first derivative of left ventricular pressure (dP/dt) from 1,013 +/- 309 to 1,360 +/- 538 mm Hg/s (p less than 0.01) but milrinone did not. Similarly, blood flow and myocardial oxygen consumption were increased by dobutamine from 152 +/- 87 to 187 +/- 118 ml/min (p less than 0.05) and from 17.7 +/- 10.9 to 21.5 +/- 14.9 ml O2/min (p less than 0.05), respectively, but were unchanged by milrinone. Both drugs significantly decreased coronary vascular resistance and myocardial oxygen extraction but did not change myocardial lactate extraction. Thus, dobutamine and milrinone produce similar improvement in cardiac index. However, dobutamine increases myocardial oxygen consumption, whereas milrinone does not. This difference can probably be explained by the substantial vasodilating properties of milrinone.

In 11 dogs ischemic left ventricular failure characterized by a 30 percent reduction in cardiac output and a left ventricular end-diastolic pressure of 18 mm Hg or more was produced by proximal occlusion of the left anterior descending coronary artery followed by serial occlusions of the distal left circumflex coronary artery. Administration of amrinone in an intravenous bolus injection followed by a constant infusion produced improvements in cardiac output (from 1.62 +/- 0.50 to 2.19 +/- 0.52 liters/min [mean +/- standard deviation], p less than 0.05), left ventricular end-diastolic pressure (from 21.6 +/- 3.5 to 11.0 +/- 5.4 mm Hg, p less than 0.05) and peak positive rate of rise of left ventricular pressure [dP/dt] (from 1,264 +/- 241 to 1,800 +/- 458 mm Hg.s-1, p less than 0.05). These improvements were maintained throughout the 20 minute period of therapy. No significant alteration in heart rate or arterial pressure was noted. In parallel with the hemodynamic improvement myocardial oxygen consumption improved to 0.094 +/- 0.05 and 0.092 +/- 0.04 vol.min-1.g-1 after 2 and 20 minutes, respectively, of amrinone compared with 0.124 +/- 0.05 during left ventricular failure (both p less than 0.05). The effects of amrinone on left ventricular failure are due to augmented contractility and mild systemic vasodilatation. The reduction in myocardial oxygen consumption during amrinone-treated left ventricular failure presumably results from a reduction in ventricular wall tension that more than offsets the effect of an increase in contractility.

The prevalence of ventricular arrhythmias was evaluated in 35 patients with severe congestive heart failure (CHF) in New York Heart Association functional class III to IV. The etiology of CHF was equally distributed between ischemic and nonischemic cardiomyopathy. The severity of cardiac dysfunction was evidenced by left ventricular ejection fraction of less than 20%, mean cardiac index of 1.75 +/- 0.40 L/min/m2, pulmonary capillary wedge pressure of 28.1 +/- 7.1 mm Hg, and mean exercise capacity of 6.0 +/- 3.6 minutes. During 24-hour ambulatory Holter monitoring, 71% of these patients demonstrated repetitive episodes of ventricular tachycardia (VT), 92% had multifocal ventricular ectopic beats, and 88% had greater than or equal to 10 ventricular ectopy/1000 normal heart beats. Within 1 to 72 weeks of the Holter monitoring 25 patients died. Death could be attributed to VT in only one patient. In all the others, death was secondary to worsening CHF. Thus, although asymptomatic malignant ventricular arrhythmia occurred frequently in our patients, sudden death was rarely observed.

Milrinone is a new bipyridine inotrope that has shown promise in initial clinical testing when administered intravenously or orally. The present multicenter study was designed to evaluate the clinical effectiveness and safety of sustained (48 hour) intravenous infusions of different doses of milrinone, as would be used clinically, in a controlled fashion using invasive hemodynamic monitoring. Entry was limited to adult patients with chronic heart failure of functional class III or IV, with a cardiac index ≤2.5 liters/min per m2or a pulmonary capillary wedge pressure ≥15 mm Hg, or both. After stable baseline hemodynamic recordings were obtained, milrinone was given as loading (μg/kg per 10 min) and maintenance infusions (μg/kg per min) to 189 patients in one of four loading/maintenance dosage regimens: 37.5/0.375 (low dose, n = 26), 50/0.50 (intermediate dose, n = 95), 75/0.75 (high dose, n = 15) and 50/0.25 (lowest dose, n = 53). The lowest dose was shown to be ineffective for maintenance therapy. Effective individual patient responses were defined as ≥20% increase in cardiac index or decrease in pulmonary capillary wedge pressure, or both. During early therapy (≤3 hour), 99% of patients showed an effective maximal response, and 90% an effective mean response. An effective mean response was observed during days 1 and 2 in 80% of patients, with a positive dose-response trend (69% response, low dose; 80%, intermediate dose; 93%, high dose; day I). Each loading regimen was effective, with maximal mean response occurring at 15 minutes. Cardiac index initially increased by an average of 24 to 42% for all patients in the three groups, whereas pulmonary capillary wedge pressure decreased by 24 to 33%. Initial decreases in systemic vascular resistance averaged 15 to 31%. Initial changes in heart rate ( + 4 to +13%) and mean arterial pressure (− 2 to −13%) were modest. Significant mean hemodynamic responses were maintained over the 48 hours. Increases in cardiac index for days 1 and 2 averaged 38 and 39% for those completing constant low dose drug, 34 and 37% for intermediate dose and 73 and 44% for high dose. Decreases in pulmonary capillary wedge pressure for all patients averaged 18 to 32% on days 1 and 2, with little dose response. Heart rate changes were modest and variable, averaging − 9 to 9%. Mean arterial pressure decreased slightly (2 to 6%) for the lower doses and moderately (8 to 16%) for the high dose. Reductions in systemic vascular resistance averaged 20 to 25%. Calculated stroke work index remained substantially augmented (21 to 58%). Milrinone was well tolerated: sustained ventricular tachycardia occurred in only one patient (0.5%) and thrombocytopenia was not problematic. Thus, milrinone infusions of 0.375 to 0.75 μg/kg per min are associated with an excellent rate of hemodynamic response that is maintained for at least 48 hours, and with generally excellent safety and tolerance in patients with advanced chronic heart failure.

The effects of amrinone, dobutamine, and a combination of the two drugs on peak positive left ventricular dP/dt and left ventricular performance were evaluated in 11 patients with chronic congestive heart failure. When administered alone, both dobutamine (10.9 micrograms/kg/min) and intravenous amrinone (1.9 mg/kg/min) significantly increased left ventricular dP/dt and performance. When compared with dobutamine alone, the addition of amrinone resulted in further increases in left ventricular dP/dt and cardiac index (to 1319 +/- 419 from 1202 +/- 376 mm Hg/sec, p less than .002, and to 3.56 +/- 0.78 from 3.04 +/- 0.67 liters/min/m2, p less than .01, respectively). The combination also induced a further reduction in left ventricular end-diastolic pressure (to 15.3 +/- 11.3 from 18.2 +/- 10.3 mm Hg, p less than .05) when compared with amrinone alone. The combination of dobutamine and amrinone increased heart rate slightly when compared with either drug alone, but did not further reduce systemic arterial pressure when compared with amrinone alone. The dose-response curve of left ventricular dP/dt and performance during titration of dobutamine with and without the addition of intravenous amrinone was evaluated in seven patients. The addition of amrinone to any dose of dobutamine produced higher cardiac index and lower systemic vascular resistance than dobutamine or amrinone alone. Thus, when compared with dobutamine alone in patients with chronic congestive heart failure, the addition of intravenous amrinone to dobutamine results in an additive improvement in left ventricular performance throughout the dose range.

The visualization of vegetations by M-mode echocardiography in patients with infective endocarditis has been suggested to imply a poor prognosis regarding the development of major systemic emboli, congestive heart failure and the need for early surgical intervention. The question of using the finding of vegetations by echocardiography as an indication for surgery is controversial. To answer this question, 30 patients with the clinical diagnosis of endocarditis were studied by echocardiography. In 17 of the 30 (57 per cent) vegetations were present (aortic eight, mitral four, both mitral and aortic five), whereas in 13 (43 per cent) no vegetations were visualized. Infecting organisms were similar in each group; Streptococcus viridans being the most common. The patients with echocardiographically demonstrable vegetations had a higher incidence of congestive heart failure compared to the patients without (14 of 17 versus six of 13, p

The pathophysiology of the syndrome of congestive heart failure (CHF) includes 2 major components that closely interact. The first one is a reduction in ventricular performance, which is manifested initially during exercise and is later present at rest. The second one involves abnormalities of the peripheral circulation and organs, which become gradually more prominent and lead ultimately to symptoms. The exercise capacity of patients with chronic CHF is limited not only by an inadequate increase in cardiac output and an excessive increase in ventricular filling pressure, but also by a fixed vasodilatory response to exercise. Although the role of increased activity of the sympathetic and renin-angiotensin-aldosterone systems in the derangements of the peripheral circulation has been extensively investigated, the structural abnormalities of the arterial wall have received little emphasis in patients with CHF. Chronic reduction of the cardiac output may lead to endothelium-dependent reduction in arterial diameter and vasomotor response, which may in turn increase systemic vascular resistance and further reduce cardiac output. Therapeutic agents should be characterized by their acute and chronic effects not only on ventricular performance, but also on the peripheral circulation. More specifically, when one is concerned with the effect of a therapeutic intervention on exercise capacity, evaluation of its direct and indirect effects on the skeletal muscle vasculature is particularly important. Accordingly, the effects of phosphodiesterase inhibition on vascular smooth muscle tone and skeletal muscle vasculature are reviewed. In addition, the potential of phosphodiesterase inhibition to reverse structural abnormalities of the arterial wall is discussed.

The benefits derived from inhibition of the renin-angiotensin system in chronic heart failure are mediated through multiple mechanisms that can be directly related to the pathophysiology of the syndrome of congestive heart failure. At the stage of myocardial failure, angiotensin-converting enzyme inhibition may reverse myocardial hypertrophy and lower left ventricular filling pressure, and decrease ventricular size, thereby reducing ventricular wall remodeling. At the later stages of congestive heart failure, the cardiac effects of angiotensin-converting enzyme inhibition may have added benefits in the periphery. Normalization of the vasodilatory response to exercise, increase in renal blood flow, and possibly urinary sodium excretion, as well as prevention of hypokalemia tend to improve exercise capacity, quality of life, and survival in patients with severe congestive heart failure.

Seven patients with decompensated chronic heart failure and functional mitral regurgitation were studied before and during administration of nitroglycerin at a mean dose of 42 micrograms/min (range 20 to 90 micrograms/min). Forward aortic flow obtained by pulsed Doppler increased significantly from 35 +/- 8 to 45 +/- 9 ml/beat (p less than 0.001) and correlated well with the cardiac output measured by thermodilution technique (r = 0.8). Whereas regurgitant mitral volume calculated from the difference between echocardiographic total stroke volume and forward aortic flow decreased significantly from 19 +/- 9 to 3 +/- 3 ml/beat (p less than 0.001), peak velocity of mitral regurgitant flow increased from 4.1 +/- 0.9 to 4.4 +/- 1.0 m/sec (p less than 0.05). The decrease in effective mitral regurgitation area derived from a modified Gorlin formula average 80%. Accordingly, in patients with decompensated chronic heart failure and functional mitral regurgitation, nitroglycerin decreases mitral regurgitant area substantially, and thus almost abolishes mitral regurgitation despite an increase in systolic pressure gradient between left ventricle and atrium. Moreover, the increase in forward flow can be entirely accounted for by the reduction in mitral regurgitant flow.

The hemodynamic and clinical effects of parenteral and oral CI-930, a new phosphodiesterase type III inhibitor with combined vasodilator and inotropic properties, were studied in 12 patients with severe congestive heart failure refractory to therapy including captopril. The maximum response to dobutamine was also determined. Intravenous CI-930 increased cardiac index from 1.73 +/- 0.48 to 2.38 +/- 0.55 L/min/m2, and reduced pulmonary capillary wedge pressure from 19.2 +/- 7.9 to 12.5 +/- 6.4 mm Hg, mean right atrial pressure from 7.5 +/- 6.3 to 3.6 +/- 4.0 mm Hg, and systemic vascular resistance from 2288 +/- 860 to 1711 +/- 611 dynes . sec . cm-5 (p less than 0.001 for all). Heart rate and mean systemic arterial pressure were unchanged. The increment in cardiac index produced by dobutamine was higher than for CI-930, 2.68 +/- 0.55 vs 2.38 +/- 0.55 L/min/m2, p less than 0.001. However, reduction in pulmonary capillary wedge pressure tended to be less with dobutamine, 15.7 +/- 7.9 vs 12.5 +/- 6.4 mm Hg (NS). Hemodynamic benefits of oral CI-930 were equivalent to that of the parenteral drug. Duration of action was 9 to 12 hours. Chronic therapy resulted in subjective improvement in approximately 50% of patients. Exercise capacity, assessed by maximum oxygen consumption, was unchanged, 8.4 +/- 3.3 vs 9.8 +/- 3.4 ml/kg/min (NS). No overt laboratory manifestations of toxicity were observed.

Angiographic results in patients with mitral regurgitation suggest that up to 50% of the regurgitant volume occurs during the preejection period. This contrasts markedly with the electromagnetic measurements of mitral regurgitant flow in anesthetized dogs, which suggest that only 5% of mitral regurgitant flow occurs during the preejection period. Therefore, we used two-dimensional and Doppler echocardiography to quantify mitral regurgitation during aortic ejection and in the preejection and postejection periods in eight patients with severe heart failure. Mitral regurgitant volume (RV) was calculated as the difference between total stroke volume (by two-dimensional echocardiography) and forward aortic flow (by pulsed Doppler). Regurgitant velocity (V) and time (RT) were measured by continuous-wave Doppler, and the mean regurgitant area (RAm) was calculated from the RT and mean regurgitant velocity (Vm): RAm = (RV/RT)/Vm. As a first approximation, the RA was assumed to be constant during systole, and the regurgitant volume during aortic ejection and during the preejection and postejection periods was calculated from: RVi = (Vmi) (RTi) (TAm), where Ti represents the duration of the appropriate period. Percentages of total regurgitant volume occurring during the preejection, ejection, and postejection periods were 13 +/- 4%, 79 +/- 5%, and 8 +/- 5%, respectively. Thus, in contrast to previously reported angiographic studies, mitral regurgitation occurs predominantly during the aortic ejection period. These results were not substantially changed by assuming a 20% reduction in effective regurgitant orifice area between the preejection and ejection periods and are consistent with data from chronically instrumented dogs with mitral regurgitation.(ABSTRACT TRUNCATED AT 250 WORDS)

The dynamics between mitral anulus motion, and, thus, motion of the base of the heart, and filling of the left atrium and ventricle were studied by Doppler echocardiography in 12 normal subjects and 28 patients with dilated cardiomyopathy. The normal motion of the mitral anulus is associated with two phases of inflow from the pulmonary veins. The first phase (J) of pulmonary venous inflow occurs during ventricular systole, concomitant with the descent of the mitral anulus toward the ventricular apex, the extent of which is 12.8 +/- 1.4 mm. The end of the descent of the anulus occurs at the cessation of aortic ejection. About 100 msec later, a rapid recoil of the mitral anulus toward the atrium coincides with the onset of transmitral filling. This rapid recoil contributes to the displacement of blood from the atria into the ventricles in early diastole. The second phase (K) of pulmonary venous flow begins in early diastole, with its peak occurring about 50 msec after the peak of transmitral flow. During atrial contraction, the mitral anulus moves slightly (2.4 +/- 0.7 mm) toward the atrium and then returns toward its initial position within 120 msec. This motion coincides with the A wave of transmitral flow. In patients with dilated cardiomyopathy, pulmonary venous flow and mitral anulus motion are markedly altered in comparison with normal subjects. In all patients, motion of the mitral anulus is either reduced or absent.(ABSTRACT TRUNCATED AT 250 WORDS)

The relative efficacies of oral verapamil, a calcium-entry blocking drug, and propranolol, a beta-adrenergic blocking drug, were compared in 12 patients who had both stable angina pectoris and mild to moderate systemic hypertension, using a placebo-controlled, double-blind, randomized crossover protocol. Compared with placebo, both propranolol and verapamil decreased the frequency of anginal attacks and the number of nitroglycerin tablets consumed, and increased exercise duration and total work; there were no significant differences in the antianginal effect of the two drugs. Both verapamil and propranolol reduced the supine and standing systolic and diastolic blood pressure measured at rest; compared with propranolol, however, verapamil had greater effects on standing diastolic blood pressure (p less than 0.002). Resting heart rate was reduced from placebo baseline with large doses of both drugs; compared with verapamil, however, propranolol exerted greater effects on resting heart rate and rate-pressure product. Plasma renin activity was increased from placebo baseline with verapamil (p less than 0.05), but was reduced with propranolol (p less than 0.05); no significant change in plasma aldosterone was seen with either drug. Verapamil appears to be a safe and effective treatment alternative to propranolol for relieving anginal symptoms, improving exercise tolerance, and reducing elevated systemic blood pressure in patients with both angina pectoris and mild to moderate systemic hypertension.

The effects of oral labetalol, an alpha-beta adrenoceptor blocker, were evaluated in 10 patients with angina pectoris and hypertension. After 3 weeks of placebo, increasing doses of labetalol (300 to 1,200 mg/day) were given over 4 weeks followed by a rapid drug withdrawal phase. The frequency of anginal attacks and exercise tolerance were measured as were noninvasive indexes of left ventricular function (echocardiography, systolic time intervals), plasma renin activity and platelet function (aggregability). Compared with placebo, during labetalol therapy the frequency of anginal attacks was reduced, exercise time increased (from 351.6 ± 56.2 to 463.2 ± 45.2 seconds , P kilopond - meters , p mm Hg (mean ± Standard error of the mean) (p mm Hg (p beats / min (p mm Hg (p mm Hg (P beats / min (p

The hemodynamic effects of captopril (SQ 14225), an oral inhibitor of angiotensin-converting enzyme, were measured in 10 patients with severe chronic heart failure poorly controlled by digitalis and diuretics. After administration of a 25 mg dose, the cardiac index increased from 1.82 +/- 0.14 to 2.28 +/- 0.30 liters/min/m2 (p less than 0.05) while pulmonary capillary wedge pressure decreased from 22.7 +/- 2.0 to 14.7 +/- 4.7 mm Hg (p less than 0.05). Mean blood pressure and systemic vascular resistance decreased from 85.7 +/- 6.7 to 71.2 +/- 12.0 mm Hg (p less than 0.001) and from 1,909 +/- 246 to 1,362 +/- 347 dynes-s-cm5 (p less than 0.001), respectively. Heart rate did not change significantly. There was an inverse relation between maximal augmentation in cardiac index and maximal reduction in pulmonary capillary wedge pressure (r = -0.82, p less than 0.01). While most patients demonstrated a constant hemodynamic benefit after repeated administration of captopril, some exhibited a triphasic response with attenuation of effects after the second dose and restoration of effects after the third dose. These hemodynamic benefits were observed in patients with stable chronic heart failure whose plasma renin activity was within normal range (1.1 to 7.3 ng/ml/hour).

Amrinone was given to 14 patients with congestive heart failure as an intravenous bolus (1 mg/sec) at doses ranging from 0.5 to 3.5 mg/kg. Simultaneous determinations of cardiac index were made by thermodilution and of amrinone plasma concentration by high-performance liquid chromatography. A relationship between improvement in cardiac index and increasing plasma concentrations of amrinone was demonstrated for 13 of the 14 patients. The percentage increase in cardiac index correlated with amrinone plasma concentration (r = 0.81; p < 0.001). Amrinone was given to four patients as an intravenous bolus dose of 1.5 mg/kg followed by a constant infusion of 10 µg/kg/min for 10 hr; simultaneous determinations of cardiac index and circulating levels of amrinone indicated that both declined after the initial rise. The plasma concentration of amrinone remained relatively constant during the infusion at about 1.7 µg/ml. In all cases, despite the relatively constant plasma levels there was a decline in cardiac index after about 4 to 5 hr of infusion, although the cardiac index remained above the baseline; during the constant infusion the cardiac index rose again and was maintained at a reasonably constant level for the last 3 hr. Seven patients received oral doses of amrinone of about 3 mg/kg, and simultaneous determinations of cardiac index and plasma concentration showed a relationship between amrinone level and rise in cardiac index (p < 0.05). In 16 patients after amrinone orally sufficient blood samples were taken to estimate the apparent first-order terminal elimination t½. The t½ as estimated by log-linear regression ranged from about 3 to 15 hr; x ± SEM value was 8.3 (±1.1) hr. Clinical Pharmacology and Therapeutics (1981) 29, 723–728; doi:10.1038/clpt.1981.102

The renin-angiotensin system is thought to maintain elevated systemic vascular resistance in heart failure. The hemodynamic effects of captopril (SQ 14225), an oral inhibitor of angiotensin-converting enzyme, were measured in 10 patients with stable congestive heart failure poorly controlled by digitalis and diuretics. At single daily doses of 25 to 150 mg, the cardiac index rose from 1.75 +/- 0.18 to 2.27 +/- 0.39 (mean +/- S.D.) liters per minute per square meter (P less than 0.001), and pulmonary-wedge pressure fell from 26.5 +/- 7.5 to 17.3 +/- 6.1 mm Hg (P less than 0.01). Systemic vascular resistance decreased from 2006 +/- 300 to 1393 +/- 238 dyne seconds per centimeter (P less than 0.001), and mean arterial pressure fell from 83.7 +/- 7.0 to 70.3 +/- 9.9 mm Hg (P less than 0.001) (mean +/- S.D.). Heart rate did not change appreciably. Hemodynamic alterations peaked at 90 minutes and persisted for three to four hours. Control plasma renin activity ranged from 1.1 to 7.3 ng per milliliter per hour and did not correlate with changes in hemodynamic values. Three patients on long-term treatment maintained clinical improvement. Although its mechanism of action has not been completely elucidated, captopril may prove useful in the treatment of chronic congestive heart failure.

The acute hemodynamic and metabolic effects of dobutamine administered during exercise were studied in 8 patients with severe chronic heart failure. Exercise was performed on an upright bicycle ergometer using a graded protocol. During exercise performed without administration of dobutamine, exhaustion occurred after 4.5 +/- 1.2 minutes of exercise. The cardiac index increased from 1.61 +/- 0.25 to 2.67 +/- 0.59 liters/min/m2 (p less than 0.001), the arteriovenous oxygen difference from 7.8 +/- 1.7 to 12.5 +/- 2.4 ml/100 ml (p less than 0.001), and oxygen uptake from 7.9 +/- 3.0 to 41.2 +/- 15.7 mg/100 ml (p less than 0.001). During exercise performed with the administration of dobutamine, the cardiac index was significantly greater than during the control state, 3.23 +/- 0.78 versus 2.67 +/- 0.59 liters/min/m2 (p less than 0.001), while the arteriovenous oxygen difference was significantly lower, 11.2 +/- 2.1 vs 12.5 +/- 2.4 ml/100 ml (p less than 0.01). The arterial lactate level was not significantly changed, 45.3 +/- 17.6 versus 41.2 +/- 15.7 mg/100 ml. Although the dobutamine level tended to increase maximal oxygen uptake compared with the control period of exercise, 9.1 +/- 1.2 versus 8.5 +/- 1.4 ml/kg/min (p less than 0.05), it did not significantly increase exercise capacity, 4.8 +/- 1.5 versus 4.5 +/- 1.2 min. Thus administration of dobutamine in patients with severe chronic heart failure increased the cardiac index during maximal exercise but failed to increase exercise capacity. Since arteriovenous oxygen difference is reduced, dobutamine probably increases blood flow to the nonexercising tissues and not to the actively metabolizing muscles.