NOS1AP variant associated with incidence of type 2 diabetes in calcium channel blocker users in the Atherosclerosis Risk in Communities (ARIC) study.

AIMS/HYPOTHESIS: To validate the reported association between rs10494366 in NOS1AP (the gene encoding nitric oxide synthase-1 adaptor protein) and the incidence of type 2 diabetes in calcium channel blocker (CCB) users and to identify additional NOS1AP variants associated with type 2 diabetes risk. METHODS: Data from 9 years of follow-up in 9,221 middle-aged white and 2,724 African-American adults free of diabetes at baseline from the Atherosclerosis Risk in Communities study were analysed. Nineteen NOS1AP variants were examined for associations with incident diabetes and fasting glucose levels stratified by baseline CCB use. RESULTS: Prevalence of CCB use at baseline was 2.7% (n = 247) in whites and 2.3% (n = 72) in African-Americans. Among white CCB users, the G allele of rs10494366 was associated with lower diabetes incidence (HR 0.57, 95% CI 0.35-0.92, p = 0.016). The association was marginally significant after adjusting for age, sex, obesity, smoking, alcohol use, physical activity, hypertension, heart rate and electrocardiographic QT interval (HR 0.63, 95% CI 0.38-1.04, p = 0.052). rs10494366 was associated with lower average fasting glucose during follow-up (p = 0.037). No other variants were associated with diabetes risk in CCB users after multiple-testing correction. No associations were observed between any NOS1AP variant and diabetes development in non-CCB users. NOS1AP variants were not associated with diabetes risk in either African-American CCB users or non-CCB users. CONCLUSIONS/INTERPRETATION: We have independently replicated the association between rs10494366 in NOS1AP and incident diabetes among white CCB users. Further exploration of NOS1AP variants and type 2 diabetes and functional studies of NOS1AP in type 2 diabetes pathology is warranted.

Prevention of abnormal sarcoplasmic reticulum calcium transport and protein expression in post-infarction heart failure using 3, 5-diiodothyropropionic acid (DITPA).

Heart failure of diverse causes is associated with abnormalities of sarcoplasmic reticulum (SR) Ca(2+)transport. The purpose of this study was to determine whether the thyroid hormone analogue, 3,5-diiodothyropropionic acid (DITPA), prevents abnormal Ca(2+)transport and expression of SR proteins associated with post-infarction heart failure. New Zealand White rabbits were randomly assigned to circumflex artery ligation or sham operation, and to DITPA administration (3.75 mg/kg/day) or no treatment in a two-by-two factorial design. After 3 weeks, echo-Doppler and LV hemodynamic measurements were performed. From ventricular tissue, single myocyte shortening and relaxation were determined, and Ca(2+)transport was measured in homogenates and SR-enriched microsomes. Levels of mRNA and protein content were determined for the SR Ca(2+)-ATPase (SERCA2a), phospholamban (PLB), cardiac ryanodine receptor (RyR-2) and calsequestrin. The administration of DITPA improved LV contraction and relaxation and improved myocyte shortening in infarcted animals. The improvements in LV and myocyte function were associated with increases in V(max)for SR Ca(2+)transport in both homogenates and microsomes. Also, DITPA prevented the decrease in LV protein density for SERCA2a, PLB and RyR-2 post-infarction, without measurable changes in mRNA levels. The thyroid hormone analogue, DITPA, improves LV, myocyte and SR function in infarcted hearts and prevents the downregulation of SR proteins associated with post-infarction heart failure. The specific effects of DITPA on post-infarction SR Ca(2+)transport and the expression of SR proteins make this compound a potentially useful therapeutic agent for LV systolic and/or diastolic dysfunction.

Thyroid hormone and thyroid hormone analogues in the treatment of heart failure.

The thyroid hormone analogue DITPA is a promising potential new treatment for heart failure. Although the mechanism of action is incompletely determined, it is clear that DITPA improves systolic as well as diastolic function. It is also clear that the effects of DITPA are intrinsic to the muscle and not the result of changes in the structure or geometry of the left ventricle. On the basis of these experimental studies, we applied to the USA Food and Drug Administration for an Investigational New Drug application to study the use of DITPA in patients. These studies are currently in progress. While we await the outcome of these clinical trials, it is important to emphasize that even if the end-point is not a new drug to treat heart failure, our investigations are based on a systematic evaluation integrating biochemistry and physiology. We believe that this is the way to approach the problem of developmental pharmacology.

Increased intraventricular velocities: an unrecognized cause of systolic murmur in adults.

OBJECTIVES: The purpose of this study was to determine the frequency, clinical features and echocardiographic characteristics of increased intraventricular velocities (IIVs) in patients referred to the echocardiography laboratory for systolic murmur. BACKGROUND: A subset of patients referred to the echocardiography laboratory for evaluation of a systolic murmur have IIVs in the absence of other recognized causes of systolic murmur. METHODS: We prospectively studied echocardiograms from 108 consecutive patients referred for evaluation of a systolic murmur. Clinical data were obtained from patient examinations and medical records. RESULTS: The sole explanation for systolic murmur was IIVs in 16.7% of referred patients. Compared with those without IIVs, patients with IIVs had a higher ejection fraction (EF) (58.7+/-7.8% vs. 51.1+/-12.5%, p < 0.001), percent fractional shortening (42.3+/-9.7% vs. 31.0+/-11.4%, p < 0.0001), left ventricular (LV) mass index (181+/-70 vs. 152+/-48 g/m2, p=0.046) and prevalence of hypertension (73.3% vs. 51.7%, p=0.043) and a lower prevalence of segmental wall motion abnormalities (2.2% vs. 39.3%, p < 0.001). CONCLUSIONS: Increased intraventricular velocities are a common cause of systolic murmur in this group of patients and should be included in the differential diagnosis of systolic murmurs in adults. The association of IIVs with LV hypertrophy should be a clinical consideration when these murmurs are identified.

Echocardiographic changes after myocardial infarction in a model of left ventricular diastolic dysfunction.

To determine the early and late effects of myocardial infarction on left ventricular (LV) diastolic function in the rabbit postinfarction model, male New Zealand White rabbits were randomly assigned to ligation of the circumflex artery or sham operation. Serial echocardiographic and Doppler studies were performed on both groups of animals at baseline and 1 h and 3 wk after surgery (n = 10 for each group) after verification of the reproducibility and repeatability of the measurements. At 1 h postinfarction, decreases in early mitral inflow velocity (E wave) and mitral inflow velocity with atrial contraction (A wave) and increases in the mean pulmonary venous systolic-to-diastolic ratio and A wave reversal velocities were observed, without changes in LV geometry. By 3 wk postinfarction, increases in the mitral E-to-A ratio (1.1 +/- 0.3 vs. 2.9 +/- 0.9, P < 0.001) and left atrial area (131 +/- 23 vs. 510 +/- 72 mm2, P < 0.001) and decreases in the pulmonary venous systolic-to-diastolic ratio (0.56 +/- 0.20 vs. 0.79 +/- 0.14, P = 0.008) were consistent with severe diastolic abnormalities (restricted physiology). The findings of this study demonstrate that coronary artery ligation in the rabbit provides a reproducible echocardiographic and Doppler model of LV diastolic dysfunction that is consistent with abnormalities found in humans with previous myocardial infarction, symptoms of heart failure, and preserved LV systolic function.