Physiological significance of early deceleration time prolongation in asymptomatic elderly subjects.

BACKGROUND: Alterations in Doppler-derived diastolic filling patterns are common among elderly persons, but their physiological and prognostic significance remains uncertain, particularly in asymptomatic older persons without overt cardiac disease. This study was designed to determine whether early mitral inflow deceleration time (DT) prolongation is of physiological significance in asymptomatic elderly subjects. METHODS AND RESULTS: In 15 asymptomatic patients aged 60 to 93 years with no history of heart failure (HF) or edema, we performed two-dimensional and Doppler echocardiography and 60-minute head-out, isothermic water immersion to produce circulatory volume expansion. Plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were measured immediately before and after water immersion. Seven of 15 patients had a normal mitral early DT (160 to 240 milliseconds; group 1) and 8 of 15 patients had DT prolongation (> 240 milliseconds; group 2). Group 2 subjects had significantly smaller chamber sizes and increased relative wall thickness without increased left ventricular mass. Head-out water immersion produced greater increases in plasma ANP levels in group 2 subjects with longer DTs despite similar degrees of circulatory volume expansion in each group. In contrast, plasma BNP levels did not increase significantly with water immersion in either group. CONCLUSION: Early DT prolongation in asymptomatic elderly subjects is associated with increased relative wall thickness and enhanced ANP increments after central volume expansion. Such exaggerated responses suggest that, in the elderly, a prolonged DT has physiological significance and may represent a precursor to symptomatic diastolic HF, a condition known to be associated with advancing age.

Differential expression of c-jun and junD in end-stage human cardiomyopathy.

The proto-oncogenes c-jun and junD are closely related transcriptional factors with opposing actions on cell growth and division. Expression of c-jun rapidly increases as cells enter the cell cycle. Levels of c-jun are also increased in the early stages of experimental cardiac hypertrophy and failure but expression decreases with time. In contrast, junD accumulates in quiescent cells. Expression in end-stage cardiomyopathy has not been studied. Steady-state levels of c-jun and junD mRNA were determined in failing human myocardium (obtained at the time of cardiac transplantation) and in control myocardium from patients who died of noncardiac causes. Relative expression was normalized for glyceraldehyde-3-phosphate dehydrogenase expression. Levels of junD were almost four-fold depressed in myocardium from myopathic hearts (2.1 +/- 0.27, x +/- SE; n = 20) vs. the controls (7.7 +/- 1.1; n = 3). Levels of c-jun were similar in both myopathic and control hearts. Relative expression of beta-myosin heavy chain was the same in both myopathic and control hearts. Levels of junD were still found to be depressed in the myopathic hearts after normalization for myosin heavy chain gene expression. We conclude that c-jun and junD are differentially regulated in end-stage human cardiomyopathy with expression of junD being decreased while relative levels of c-jun mRNA remain unchanged. Further studies are needed to determine the role of junD down-regulation in the development and/or maintenance of the abnormalities present in end-stage heart disease.

c-myc gene expression is localized to the myocyte following hemodynamic overload in vivo.

Expression of the proto-oncogene c-myc increases in the hemodynamically overloaded heart, but expression by cardiac myocytes has not been shown. To address this issue, right ventricular overload was induced in cats by pulmonary artery banding. Expression of c-myc and alpha-skeletal actin mRNA were determined by Northern analysis. Immuno-reactive Myc protein was identified by histochemical staining. Steady state levels of c-myc mRNA peaked within 2 h after banding. Levels of alpha-skeletal actin mRNA were maximally increased 48 h-1 week after banding and were still elevated at 1 month. Prominent staining of myocyte nuclei for immunoreactive Myc protein was detected 48 h after banding although a few interstitial nuclei were also positive. These studies show that c-myc and alpha-skeletal actin gene expression are upregulated in a large animal model of hemodynamic overload. The localization of the immunoreactive Myc protein to right ventricular myocyte nuclei after pulmonary artery banding supports the hypothesis that c-myc induction is part of a general response in cardiac hypertrophy that is common to many mammalian species.

Progressive feline pressure-overload: noninvasive assessment correlates with abnormalities in single cells.

Serial echocardiography and Doppler were used to monitor the progression of pressure-overload produced by banding the ascending aortas of young cats. The peak Doppler gradient across the band increased (as the animals grew in size) from 42 +/- 4.2 mmHg at 1 wk to 78 +/- 4.5 mmHg at 2-3 mos. Echocardiographic measurements of septal wall thickness increased significantly at 1 wk. Global ventricular function was unaltered in banded cats versus shams at each time point. However, in the subgroup of animals with an aortic-constricted area of < 0.025 cm2 at 1 wk, fractional shortening decreased by 40% at 2-3 mos. Contractile abnormalities were present in isolated myocytes from hypertrophied hearts. Mechanical function was more profoundly depressed in cells from hearts with echocardiographic evidence of ventricular decompensation. Echocardiographic and Doppler studies assessed cardiac size and function and identified indexes predictive of global and cellular myocardial dysfunction. The use of noninvasive techniques as a predictor of failure makes the feline model of progressive left ventricular pressure-overload useful for studies of cellular and molecular factors regulating not only the development of cardiac hypertrophy but also the transition from compensated hypertrophy to myocardial failure.

Mechanical properties of adult feline ventricular myocytes in culture.

The contractile and electrophysiological properties of cultured adult feline ventricular myocytes were studied. Cells were field stimulated and contraction was measured using a video-based edge detector. The magnitude of contraction decreased by 36% and the rate of contraction decreased by 52% 2 h after the cells were plated on laminin-coated cover slips. The magnitude and rate of contraction then remained stable for 1 wk. The duration of contraction prolonged and a second component to the twitch frequently, but not invariably, developed after 5 days in culture. This was associated with prolongation of the action potential duration. After 7 days in culture, cells could be divided into two groups based on resting membrane potential. Norepinephrine increased the magnitude of contraction for 5 days after plating. Cultured ventricular myocytes became unresponsive to the effects of norepinephrine after 7 days. Adult cardiac myocytes maintained in primary culture continue to respond to field stimulation and retain many contractile properties for up to 7 days; however, the functional characteristics of these cells do not remain uniform during this time period.

Effects of diabetes on cardiac contractile proteins in rabbits and reversal with insulin.

In rats, chronic diabetes is associated with depressed cardiac myosin ATPase activity and a shift from the predominant V1 isoenzyme to V3, correlating with depressed contractility. Rabbit myocardium consists mostly of the V3 isoenzyme, and therefore a switch to even more V3 isoenzyme in diabetes might not be possible and therefore not explain the mechanical abnormalities observed. To explore this, rabbits were made diabetic with 140-150 mg/kg of alloxan, and their hearts were studied 3 days, 1 mo, 3 mo, and 6 mo later. Ca2+-myosin-ATPase activity was decreased in the diabetic rabbit at 1, 3, and 6 mo, correlating with increased percent V3. Actin-activated Mg2+-ATPase activity was not significantly decreased in diabetics, but myofibrillar ATPase activity was decreased in 6-mo diabetic animals. When 3- to 4-mo diabetic animals were administered insulin for 3-4 additional months, myosin-ATPase activity and isoenzyme distribution normalized. These results correlate well with mechanical changes in papillary muscle from these same hearts. They suggest that in rabbit, as in rat, changes in cardiac contractile function are at least partially mediated by changes in myosin isoenzyme composition and are reversible with insulin.