Vasodilator therapy for congestive heart failure. Lessons from mortality trials.

Congestive heart failure is a major clinical and public health problem affecting between 2 and 3 million people in the United States. Whereas myocardial dysfunction assumes a central pathophysiologic role in the development of chronic heart failure, alterations in the peripheral vasculature and neurohormonal systems serve to modulate the heart failure state. Short-term studies of nonspecific vasodilators and angiotensin-converting enzyme inhibitors demonstrate a beneficial effect of these agents on left ventricular function, hemodynamics, exercise tolerance, and quality of life in patients with congestive heart failure and depressed left ventricular systolic function. More recently, several large-scale multicenter trials have documented improved survival in patients with heart failure who received vasodilating agents. These studies, in conjunction with hemodynamic and functional studies, argue strongly for the widespread use of vasodilator therapy, notably the angiotensin-converting enzyme inhibitors, for congestive heart failure and left ventricular systolic dysfunction.

Determination of Fura-2 dissociation constants following adjustment of the apparent Ca-EGTA association constant for temperature and ionic strength.

The accurate calibration of Fura-2 fluorescence in living cells is dependent upon the apparent dissociation constant (Kd) of Fura-2 for Ca2+. If Ca-EGTA calibration buffers are used to construct an in vitro calibration curve, then the calculated value of the apparent Ca-EGTA association constant (K'CaEGTA) will have an important influence on the Kd of Fura-2 and thus the calculated free [Ca2+] in cells. In order to simulate experimental conditions, the individual proton and Ca2+ association constants for EGTA in these experiments were adjusted for both ionic strength and temperature using a semi-empirical form of the Debye-Huckel limiting law and the Van't Hoff isochore, respectively, as described by Harrison and Bers. The modified individual binding constants were then employed in the calculation of K'CaEGTA using the SPECS computer program of Fabatio. At pH = 7.05, ionic strength = 0.15 M, temp = 20 degrees C, K'CaEGTA = 3.232 x 10(6) M-1; at pH = 6.84, temp = 36 degrees C, K'CaEGTA = 1.652 x 10(6) M-1. These values differed substantially from those obtained with unadjusted individual association constants. Calibration buffers of varying [Ca2+] were prepared using the corrected values of K'CaEGTA, and Fura-2 fluorescence ratios were measured during superfusion of these buffers in the experimental chamber at both 20 degrees C and 37 degrees C. The Kd of Fura-2 for Ca2+ was determined to be 236 nM at 20 degrees C and 285 nM at 37 degrees C, utilizing the value of K'CaEGTA adjusted by the method of Harrison and Bers.(ABSTRACT TRUNCATED AT 250 WORDS)

Prognosis in survivors of acute myocardial infarction occurring at age 70 years or older.

To identify prognostic factors in elderly persons who have survived acute myocardial infarction, 113 patients, aged 70 to 91 years (median 76), were followed for an average of 122 months (range 94 to 170). Eighty-four patients died, 61 (73%) from coronary artery disease. Overall mortality rates were 20.4% at 1 year, 30.1% at 2 years, 31.9% at 3 years, 45.1% at 4 years, 51.3% at 5 years and 69% at 10 years. Almost half (44%) of all deaths from coronary causes occurred in the first 2 years. Univariate analysis of 21 historical and clinical variables found several of prognostic significance: age, prior myocardial infarction, previous diastolic hypertension, history of diabetes mellitus, history of heart failure, presence of rales above the scapula, ventricular gallop, Killip class, cardiomegaly on admission chest x-ray and prescribing digitalis or diuretic at discharge. When these prognostic factors were entered into multivariate analysis, only Killip class (p less than 0.001) emerged as an independent predictor of survival.

Once-daily vs. continuous aminoglycoside dosing: efficacy and toxicity in animal and clinical studies of gentamicin, netilmicin, and tobramycin.

The dosing frequency of aminoglycoside antibiotics may alter efficacy and toxicity independent of total daily dose. Once-daily tobramycin dosing was compared with continuous infusion in three models of efficacy. Acute pneumonia due to Pseudomonas aeruginosa in guinea pigs responded better to once-daily dosing, and chronic pneumonia in rats and endocarditis in rabbits responded equally to both regimens. Dogs given gentamicin, tobramycin, or netilmicin once daily, with maximum serum concentrations of greater than 100 mg/liter, had less nephrotoxicity than dogs given continuous infusions. Tobramycin was given once daily or continuously to 52 patients with cystic fibrosis who in 10 days had no change in creatinine clearance or hearing despite maximum serum tobramycin concentrations of 40 mg/liter. Intermittent dosing of aminoglycosides, causing infrequent large maximum serum concentrations, may be less toxic and equally efficacious as frequent dosing.