Robert J. Cody

Arrhythmias in ischemic and nonischemic dilated cardiomyopathy: Prediction of mortality by ambulatory electrocardiography

To test the hypothesis that ventricular arrhythmias detected by ambulatory electrocardiography can stratify mortality risk in patients with ischemic and those with nonischemic dilated cardiomyopathy, clinical, hemodynamic and neurohumoral findings were evaluated in 31 patients. By Kaplan-Meier analysis, the total population had 51% survival at 12 months and 19% survival at 25 months. Subgroups based on peak complexity of ventricular arrhythmias included 9 patients with simple ventricular arrhythmias (peak Lown grades 1 to 3) and 22 patients with complex ventricular arrhythmias (peak Lown grades 4 or 5). Clinical variables and baseline catecholamine levels and renin-angiotensin system activity were similar in the simple and complex arrhythmia subgroups. Patients with simple and those with complex arrhythmias were comparable by all hemodynamic indexes except for a higher mean pulmonary capillary wedge pressure in the complex arrhythmia subgroup. Survival was strikingly related to arrhythmias: mortality was 11% (1 of 9) in the simple ventricular arrhythmia subgroup and 59% (13 of 22) in the complex ventricular arrhythmia subgroup (p less than 0.025 by log-rank test). Twelve patients died suddenly and 2 patients died in circulatory failure, and the risk of death was not affected by the etiology of cardiomyopathy. The higher mortality among the patients with complex arrhythmia could not be explained by the presence of elevated filling pressures alone. Thus, ambulatory electrocardiography can stratify mortality risk among patients with severe ischemic and nonischemic dilated cardiomyopathy.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative accuracy of Doppler echocardiographic methods for clinical stroke volume determination.

Numerous Doppler echocardiographic methods to measure stroke volume have been proposed in experimental or clinical studies, but their relative accuracy in patients compared with an invasive reference standard remains uncertain. Accordingly, we compared Doppler with thermodilution stroke volume measurement in 18 hospitalized patients, 16 with an acute manifestation of coronary artery disease and two with chronic cardiomyopathies. Doppler time-velocity integrals were measured by darkest line (modal velocity) and the leading edge (maximal velocity) techniques at the aortic annular plane, the mitral orifice, and the mitral annular plane. Two-dimensional echocardiography was used to measure cross-sectional areas (M-mode-corrected at the mitral orifice). The combination of aortic annular cross-sectional area and the leading edge technique of measuring the time-velocity integral of blood flow at this site provided the most accurate measure of stroke volume (r = 0.87, p less than 0.0001, standard error of estimate = 11 cm3; mean difference from thermodilution = 2.8 ml +/- 8.9 ml, p = NS). It also resulted in the most accurate measurement of cardiac output (r = 0.88, p less than 0.0003; mean difference from thermodilution = 0.11 L/min +/- 0.69 L/min, p = NS). Other methods yielded values that correlated less closely and deviated systematically from thermodilution measurements. We therefore conclude that of the six common methods evaluated, the aortic annular leading edge method measures stroke volume with the best accuracy and is most suitable for clinical application.

Identification of normal neurohormonal activity in mild congestive heart failure and stimulating effect of upright posture and diuretics

To characterize further the pathophysiology of the neurohormonal vasoconstrictor pathways in congestive heart failure (CHF), plasma renin activity, plasma norepinephrine, blood pressure, blood volume and renal hemodynamics were measured in 12 patients with mild to moderate CHF. In addition, the response to the gravitational stress of head-up tilt and the influence of 3 weeks of furosemide treatment as stimuli of neurohormonal activity were assessed. Supine plasma renin activity before diuretics was relatively normal at 1.94 +/- 1.6 ng/ml/hr and was significantly increased to 3.9 +/- 2.7 ng/ml/hr after diuretics. During tilt, there was a significant reflex increase in plasma renin activity both before and after diuretics. Plasma norepinephrine was also relatively normal before diuretics (325 +/- 211 pg/ml), did not increase after diuretics, but showed significant increases during tilt both before and after diuretics. Diuretic administration led to decreases in both systolic and diastolic blood pressures, but there was no change in body weight or total blood volume. In addition, diuretic administration did not result in any significant changes of renal blood flow (546 +/- 119 to 634 +/- 204 ml/min/1.73m2), glomerular filtration rate (81 +/- 22 to 90 +/- 27 ml/min/1.73m2) or filtration fraction (0.26 to 0.25). The present study demonstrates that the renin-angiotensin system and the sympathetic nervous system were not activated in the early symptomatic stages of CHF and that baroreceptor stimulation of these pathways during head-up tilt was relatively preserved. Renin secretion increased during diuretic administration, suggesting that the macula densa signal for renin release was also preserved in patients with relatively mild CHF.

Plasma atrial natriuretic factor in essential hypertension: Relation to cardiac size, function and systemic hemodynamics

To evaluate determinants of elevated plasma atrial natriuretic factor levels in patients with hypertension, immunoreactive plasma atrial natriuretic factor in 54 normal subjects and 40 untreated hypertensive patients was compared with echocardiographic measurements of cardiac size, function and systemic hemodynamics. In normal subjects, plasma atrial natriuretic factor was related to age, systolic blood pressure and left atrial and ventricular chamber sizes, but only age and ventricular size were independent predictors. In untreated hypertensive patients, atrial natriuretic factor was directly related to age, atrial size, systolic pressure, peripheral resistance and ventricular systolic performance; age, atrial size and peripheral resistance were independent predictors. Eight patients with elevated atrial natriuretic factor values (greater than 25 fmol/ml) were significantly (p less than 0.01) older and had greater atrial and ventricular size and higher systolic pressure and function than normal subjects or patients with normal natriuretic factor levels. Plasma atrial natriuretic factor was inversely related to peak diastolic filling rate in normal subjects (r = -0.59; p less than 0.001), whereas it was positively related to the proportional contribution of atrial systole to left ventricular filling in hypertensive patients (r = 0.77; p less than 0.001). These findings suggest that in normal subjects, impairment of ventricular relaxation with age may contribute to atrial natriuretic factor secretion by increasing left atrial afterload; the correlation with left ventricular size may reflect physiologic fluctuations in plasma volume. In patients with uncomplicated hypertension, left atrial enlargement and consequent stronger atrial contraction contributed to increased atrial natriuretic factor release, whereas no independent relation existed with left ventricular hypertrophy or systolic function. Because ventricular relaxation was normal and ventricular size and systolic performance were increased in hypertensive patients with high atrial natriuretic factor levels, the observed increase in left atrial size and atrial contribution to ventricular filling might reflect a primary increase in venous return in this subset of hypertensive patients.

Clinical and hemodynamic experience with enalapril in congestive heart failure.

The renin-angiotension system is activated in many patients with congestive heart failure (CHF), resulting in angiotensin-mediated vasoconstriction and aldosterone-mediated sodium and water retention. To evaluate the effectiveness of enalapril, a new converting enzyme inhibitor, enalapril was administered to patients either orally or intravenously in a single dose, and hemodynamic and hormonal responses were measured. Patients were then placed on oral enalapril therapy for 1 month, and treadmill exercise duration and invasive hemodynamics were compared with baseline pretreatment data. With single-dose administration, both oral and intravenous enalapril reduced systemic vascular resistance and increased cardiac output. However, the effects of oral enalapril were not manifest for 3 to 4 hours, because oral enalapril is a pro-drug form that requires hepatic deesterification. In contrast, intravenous enalapril resulted in significant hemodynamic and hormonal changes 15 to 30 minutes after administration. During long-term therapy, enalapril was associated with improved symptomatology, increase of treadmill exercise duration and sustained hemodynamic improvement. Enalapril was effective therapy for chronic CHF. Optimal short-term response may require coadministration of both intravenous and oral preparations of enalapril; however, the magnitude of the short-term response was comparable for both preparations. Long-term therapy is most effective when the drug is administered as a twice-daily regimen.

Effect of nicardipine on rest and exercise hemodynamics in chronic congestive heart failure

The hemodynamic response to vasodilation induced by the new calcium channel antagonist nicardipine was studied in 10 patients with severe, chronic congestive heart failure. Rest and exercise hemodynamics were evaluated in the baseline state and after 1 week of oral nicardipine therapy (30 mg 3 times daily). In addition, respiratory gas exchange and arteriovenous oxygen difference were measured to assess changes in oxygen utilization. The responses of the sympathetic nervous system were evaluated by measuring plasma norepinephrine concentrations at rest and during maximal exercise. At rest, nicardipine administration was associated with significant reductions in mean systemic arterial pressure, systemic vascular resistance, pulmonary artery wedge pressure and pulmonary arterial pressure, and significant increases in cardiac index and stroke volume index. These effects were maintained during exercise. In contrast to findings with other calcium channel antagonists, no negative inotropic effect of nicardipine was identified. Nicardipine administration was associated with reduction of arteriovenous oxygen difference. Nicardipine had no effect on plasma norepinephrine concentrations, suggesting absence of reflex sympathetic nervous activation. Thus, nicardipine-mediated vasodilation leads to significant improvements in both rest and exercise cardiac performance.

Milrinone in congestive heart failure: Observations on ambulatory ventricular arrhythmias

Milrinone is a potent non-catecholamine, non-glycoside inotropic agent that can improve hemodynamic performance and functional capacity in patients with severe congestive heart failure. However, the potential effect of chronic inotropic stimulation on ventricular arrhythmias in patients with heart failure requires evaluation. We compared 24-hour ambulatory ECGs before and 2 to 4 weeks after initiation of chronic milrinone therapy in 20 patients with severe congestive heart failure (mean cardiac index 1.79 +/- 0.43 L/min/m2). A greater than tenfold increase in simple ventricular premature complex (VPC) density, a greater than tenfold increase in complex VPC form density, or an increase from 0 to greater than 5 episodes per 24 hours of any complex VPC form occurred in 35% (7 of 20) of patients. A greater than tenfold reduction in simple VPC density was noted in 5% (1 of 20), while 60% (12 of 20) of the study group had no significant change in ventricular arrhythmia profile on milrinone. The hemodynamic and functional response to milrinone, as well as entry hemodynamic profiles, were unrelated to the change in frequency or complexity of ventricular arrhythmias during therapy. Thus, milrinone therapy in congestive heart failure may be associated with the development of VPC complexity and with a significantly increased density of complex VPC forms.

Association of hyponatremia with increased renin activity in chronic congestive heart failure: impact of diuretic therapy.

A correlation between hyponatremia and increased plasma renin activity (PRA) has been reported in patients with severe congestive heart failure (CHF), implying both clinical and pathophysiologic significance. To determine the impact of diuretic therapy on this relation, we evaluated the correlation of serum sodium, prerenal azotemia (blood urea nitrogen/creatinine ratio [BUN/Cr] ), and PRA in 44 patients with severe CHF who were maintained on diuretic therapy. Serum sodium level was inversely related to PRA (r = -0.389, p less than 0.02). However, a significant correlation also existed between the BUN/Cr ratio and PRA (r = 0.365, p less than 0.025) and an inverse correlation between serum sodium level and the BUN/Cr ratio (r = 0.332, p less than 0.025). Multiple regression analysis of the 3 variables yielded significant interdependence (p less than 0.01). To evaluate the effect of diuretic therapy, 12 patients with severe CHF discontinued diuretic therapy and received, for 1 week each, 10 and 100 mEq sodium diets in balance studies. PRA ranged from 0.14 to 16 ng/ml/h. Despite this range, there was no significant correlation between either serum sodium or BUN/Cr ratio and PRA. It is concluded that the presence of marked hyponatremia and prerenal azotemia in patients with diuretic-treated CHF may suggest increased PRA. However, substantial patient-to-patient variability limits the predictive value of these correlations. Although some clinical value may be derived from such correlations, they should not be used to draw major inferences regarding the severity of CHF or the pathophysiology of water balance in CHF.

Ability of left ventricular stress-shortening relations, end-systolic stress/volume ratio and indirect indexes to detect severe contractile failure in ischemic or idiopathic dilated cardiomyopathy

The ability of several proposed indirect and direct indexes of left ventricular LV) systolic performance and contractility to detect clinically important LV dysfunction was evaluated in 42 patients with refractory dilated cardiomyopathy studied with right-sided heart catheterization and M-mode echocardiography. Hemodynamic evaluation demonstrated elevated filling pressure (mean pulmonary artery wedge pressure 24 +/- 6 mm Hg) and depressed function (cardiac index 1.68 +/- 0.43 liters/min/m2). Echocardiographic LV end-diastolic dimension (7.3 +/- 1.0 cm), mass (182 +/- 60 gm/m2) and end-systolic stress (163 +/- 44 x 10(3) dynes/cm2) were increased whereas fractional shortening was depressed in all (mean 12 +/- 4%). During follow-up 88% of patients died at a median interval of 16 months after study. Indirect measurements of LV function (mitral E point-septal separation and the ratio of preejection period to LV ejection time) were abnormal in 100 and 88% of patients, respectively. Contractility was classified as depressed in 36 (86%) patients by the end-systolic stress volume index ratio and in 31 (74%) by the relation between fractional shortening and end-systolic stress. In contrast, the relation between end-systolic stress and velocity of circumferential shortening identified only 7 (17%) patients as having subnormal contractility and classified 9 (21%) as having supernormal contractility. Rate correction of velocity of circumferential shortening only modestly improved the ability of the relation to identify depressed contractility (abnormal in 16 patients or 38 percent).

A substrate analog inhibitor of renin that is effective in vivo

Summary A potent inhibitor of primate renin effective in vivo has been synthesized. The peptide, Pro-His-Pro-Phe-His-Phe-Phe-Val-Tyr-Lys, is an analog of the amino acid sequence found between residues 6 and 13 of renin natural substrate (angiotensinogen). The inhibitor is eight times more soluble at physiologic pH and is cleared from circulation about two-orders of magnitude more slowly than earlier substrate analog inhibitors which were not active in vivo. Infusion of the inhibitor into the monkey (M. fascicularis) blocks the rise in mean arterial pressure caused by exogenous human renin, but not by angiotensin I or II. When injected into a salt-depleted monkey, the peptide lowers blood pressure in a dose-dependent manner about as effectively as the converting enzyme inhibitor, teprotide.