Search

A new unstable beta globin chain variant associated with methemoglobin (Met-Hb) phenotype was found in a Caucasian infant. Molecular analysis of the beta globin gene using polymerase chain reaction (PCR) amplification and sequencing led to the detection of a new in frame deletion in exon-1. Direct sequencing of the PCR product revealed a 3 bp deletion (-GTG) between codons 25/26, which resulted in the loss of a single amino acid (-Gly). We propose that this newly discovered unstable M-hemoglobin (M-Hb) variant, named Hb Dothan [GGT/GAG-->GAG//Gly/Glu-->Glu], is caused by a shift in the amino acid sequence and altered packing of the B and E helices during beta globin synthesis, and also changes the orientation of the critical proximal and distal histidine in the F and E helices respectively. Phenotype/Genotype features and molecular characteristics of this new beta chain are presented in this communication.

As part of a large-scale mutagenesis screen of the zebrafish genome, we have identified 58 mutations that affect the formation and function of the cardiovascular system. The cardiovascular system is particularly amenable for screening in the transparent zebrafish embryo because the heart and blood vessels are prominent and their function easily examined. We have classified the mutations affecting the heart into those that affect primarily either morphogenesis or function. Nine mutations clearly disrupt the formation of the heart. cloche deletes the endocardium. In cloche mutants, the myocardial layer forms in the absence of the endocardium but is dysmorphic and exhibits a weak contractility. Two loci, miles apart and bonnie and clyde, play a critical role in the fusion of the bilateral tubular primordia. Three mutations lead to an abnormally large heart and one to the formation of a diminutive, dysmorphic heart. We have found no mutation that deletes the myocardial cells altogether, but one, pandora, appears to eliminate the ventricle selectively. Seven mutations interfere with vascular integrity, as indicated by hemorrhage at particular sites. In terms of cardiac function, one large group exhibits a weak beat. In this group, five loci affect both chambers and seven a specific chamber (the atrium or ventricle). For example, the weak atrium mutation exhibits an atrium that becomes silent but has a normally beating ventricle. Seven mutations affect the rhythm of the heart causing, for example, a slow rate, a fibrillating pattern or an apparent block to conduction. In several other mutants, regurgitation of blood flow from ventricle to atrium is the most prominent abnormality, due either to the absence of valves or to poor coordination between the chambers with regard to the timing of contraction. The mutations identified in this screen point to discrete and critical steps in the formation and function of the heart and vasculature.

Twenty-nine patients with chronic congestive heart failure underwent symptom-limited maximal exercise to define the determinants and predictors of exercise capacity in this condition. Clinically, the combination of age, cardiothoracic ratio, and left ventricular displacement was moderately predictive of exercise capacity (R2 = 0.44, p = 0.004). Noninvasive and angiographic measurements of ventricular performance failed to predict maximal exercise duration. Resting systemic and pulmonary arteriolar resistances correlated modestly with maximal effort tolerance (supine: R2 = 0.25, p = 0.02; upright: R2 = 0.38, p = 0.002). At a predetermined level of submaximal exercise, changes in heart rate and pulmonary arteriolar resistance plus the absolute value of systemic arteriolar resistance correlated moderately with exercise duration (R2 = 0.44, p = 0.003). For all parameters examined, exercise capacity was most reliably determined during the transition from submaximal to maximal exercise through the combination of changes in heart rate and stroke volume and the exercise end point value of systemic arteriolar resistance (R2 = 0.87, p = 0.0001). Exercise capacity in chronic cardiac failure appears to be best explained by the patient's ability to increase heart rate and stroke volume beyond a set submaximal stage of exercise. Excessive vascular resistances may further restrain cardiac performance and the delivery of blood to exercising structures during exhaustive exercise.

Twelve patients with moderately severe congestive heart failure underwent the simultaneous determination of central and regional hemodynamics after administration of placebo and enoximone. The regions examined hemodynamically included renal, hepatic-splanchnic and upper limb. Enoximone was studied in 2 doses, 1 and 2 mg/kg, and administered in a double-blind, placebo-controlled, crossover design. At these doses enoximone elicited a significantly greater increase in cardiac output and a greater decrease in systemic vascular resistance than placebo. Systemic blood pressure was not significantly altered. Enoximone did not significantly change the flow or resistance of renal or hepatic-splanchnic vascular beds. Limb vascular resistance decreased modestly after enoximone with a significant augmentation (+12% to 17%) of limb blood flow compared with placebo. The initial oral administration of the 1 and 2 mg/kg doses of enoximone improved central hemodynamic parameters with apparent preferential reduction of limb vascular resistance and augmentation of blood flow to the limb region (peripheral musculoskeletal system).

Diastolic perfusion time is an important determinant of coronary blood flow and subendocardial perfusion. It has been proposed that subendocardial ischemia may exacerbate and perpetuate left ventricular dysfunction in congestive heart failure. Diastolic perfusion time in relation to heart rate was analyzed in 29 digitalized (group 1) and 12 nondigitalized patients (group 2) with heart failure and in 58 normal control subjects. In group 1 there was a strong negative exponential correlation (r = -0.85) and in group 2 a strong negative logarithmic correlation (r = -0.95) between heart rate and diastolic time; both regressions differed significantly from normal control. There was a 9% increase of diastolic time at a heart rate of 60 bpm in group 1 and a 7% increase in group 2 (both p less than 0.05) compared with normal subjects. The curves intersected the regression line of normal subjects at a heart rate of 98 bpm in group 1 and 93 bpm in group 2. At 120 bpm there was a 10% decrease in diastolic time for both groups with heart failure (both p less than 0.05). Changes in diastolic perfusion time relative to heart rate are more pronounced in congestive heart failure such that at faster heart rates this relationship may further impede subendocardial blood flow.

Twelve patients with congestive heart failure underwent a double-blind, placebo-controlled study for the purpose of examining the central and regional hemodynamic effects of first-dose (1 and 2 mg/kg) oral enoximone, a new phosphodiesterase III inhibitor. Enoximone augmented cardiac output, generally through a positive chronotropic response. Indices of left ventricular contractility, specifically stroke volume, delta P/delta t, fractional shortening rate, and the duration of the preejection period, were only modestly enhanced by enoximone. At 2 mg/kg, systemic vascular resistance fell below baseline values without affecting systemic blood pressure; these parameters were not altered by the 1 mg/kg dose. Both pulmonary artery pressure and pulmonary vascular resistance dropped below baseline and below placebo control for the 2 mg/kg dose. Enoximone at 2 mg/kg lowered right and left heart filling pressures below baseline. Examination of regional hemodynamic responses to both doses demonstrated a reduction in limb vascular resistance and an increase in limb blood flow proportional to the concomitant increase in cardiac output. Renal and hepatic-splanchnic blood flow and vascular resistances were not altered by enoximone. First-dose oral enoximone (1 and 2 mg/kg) alters hemodynamics in heart failure by predominant vasodilatation, particularly of limb-musculoskeletal and pulmonary vascular beds, some positive chronotropism, and modest positive inotropism.