Citations

Background— Thin filament mutations are reported to cause ≈20% of cases of hypertrophic cardiomyopathy (HCM), and they have been associated with specific phenotypes. However, the frequency of these mutations and their associated phenotype(s) from a large tertiary referral center population are unknown. Methods and Results— DNA was obtained from 389 unrelated patients with HCM. A mutational analysis of all protein coding exons of cardiac troponin T, cardiac troponin I, α-tropomyosin, and cardiac actin was performed using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing. The clinical data were extracted from patient records and maintained independent of the patient genotype. Overall, only 18 patients (4.6%) harbored isolated thin filament mutations: 8 had troponin T mutations, 6 had troponin I mutations, 3 had α-tropomyosin mutations, and 1 had an actin mutation. Of the 12 unique missense mutations identified, 9 (75%) were novel mutations. As a group, patients with thin filament mutations were not significantly different from the rest of the cohort in age at diagnosis, left ventricular wall thickness, left ventricular outflow tract obstruction, or family history of HCM or sudden cardiac death. Conclusions— Mutations in genes encoding thin filament proteins are less prevalent in HCM than previously estimated. Patients with mutations in troponin T, troponin I, α-tropomyosin, and actin do not invariably present with any distinct clinical feature, thus limiting the utility of gene status for risk stratification or of clinical phenotype in guiding individual genetic screening at this time.

Background— We postulated that the variability of the phase shift between blood pressure and heart rate fluctuation near the frequency of 0.10 Hz might be useful in assessing autonomic circulatory control. Methods and Results— We tested this hypothesis in 4 groups of subjects: 28 young, healthy individuals; 13 elderly healthy individuals; 25 patients with coronary heart disease; and 19 patients with a planned or implanted cardioverter-defibrillator (ICD recipients). Data from 5 minutes of free breathing and at 2 different, controlled breathing frequencies (0.10 and 0.33 Hz) were used. Clear differences ( P <0.001) in variability of phase were evident between the ICD recipients and all other groups. Furthermore, at a breathing frequency of 0.10 Hz, differences in baroreflex sensitivity ( P <0.01) also became evident, even though these differences were not apparent at the 0.33-Hz breathing frequency. Conclusions— The frequency of 0.10 Hz represents a useful and potentially important one for controlled breathing, at which differences in blood pressure–RR interactions become evident. These interactions, whether computed as a variability of phase to define stability of the blood pressure–heart rate interaction or defined as the baroreflex sensitivity to define the gain in heart rate response to blood pressure changes, are significantly different in patients at risk for sudden arrhythmic death. In young versus older healthy individuals, only baroreflex gain is different, with the variability of phase being similar in both groups. These measurements of short-term circulatory control might help in risk stratification for sudden cardiac death.

Background and Purpose— Mortality after cerebral infarction (CI) has remained unchanged during the past 20 years, despite advances in neurologic care. Key factors affecting survival may be underrecognized. The purpose of this study was to determine the rate and cause of mortality after first CI. Methods— In this case-control, population-based study, all available medical records were reviewed for Rochester (Minnesota) residents with a first CI between 1985 and 1989 to identify morbidities and cause of death. Predictors for mortality were analyzed. Results— First CI was recorded for 444 patients. Survival was 83% at 1 month, 71% at 1 year, and 46% at 5 years. The most frequent causes of death were cardiovascular events (22%), respiratory infection (21%), and initial stroke complications (14%). Recurrent stroke and cancer accounted for 9% and 7.5% of deaths, respectively. In the first month after CI, 51% of deaths were attributed to the initial CI, 22% to respiratory infections, and 12% to cardiovascular events. During the first year, 26% of deaths resulted from respiratory infections and 28% from cardiovascular disease. Mortality was higher among patients than controls for at least 2 years after CI. Age, cardiac comorbid conditions, CI severity, stroke recurrence, seizures, and respiratory and cardiovascular morbidities were independent predictors of death. Conclusions— In the first month after CI, mortality resulted predominantly from neurologic complications. Later mortality remained high because of respiratory and cardiovascular causes. To improve long-term survival after CI, aggressive management of pulmonary and cardiac disease is as important as secondary stroke prevention.

ABSTRACT Activation of cyclic nucleotide‐dependent signaling pathways leads to phosphorylation of the small heat shock‐related protein, HSP20, on serine 16, and relaxation of vascular smooth muscle. In this study, we used an enhanced protein transduction domain (PTD) sequence to deliver HSP20 phosphopeptide analogs into porcine coronary artery. The transduction of phosphoHSP20 analogs led to dose‐dependent relaxation of coronary artery smooth muscle. Peptides containing the protein transduction domain coupled to a random orientation of the same amino acids did not. Direct fluorescence microscopy of arterial rings incubated with fluorescein isothiocyanate (FITC)‐PTD or FITC‐PTD‐HSP20 peptides showed a diffuse peptide uptake. Mass spectrometric immunoassays (MSIAs) of smooth muscle homogenates were used to determine whether the phosphopeptide analogs affected the phosphorylation of endogenous HSP20. Treatment with the phosphodiesterase inhibitor papaverine led to a mass shift of 80 Da. However, there was no mass shift of HSP20 in muscles treated with phosphoHSP20 analogs. This suggests that the PTD‐phosphoHSP20 peptide alone is sufficient to inhibit force maintenance and likely has a direct effect on the target of phosphorylated HSP20. These results suggest that transduction of phosphopeptide analogs of HSP20 directly alters physiological responses of intact muscles. The data also support a direct role for phosphorylated HSP20 in mediating vasorelaxation.

ABSTRACT Maternal diabetes during pregnancy is responsible for the occurrence of diabetic embryopathy, a spectrum of birth defects that includes heart abnormalities, neural tube defects, and caudal dysgenesis syndromes. Here, we report that mice transgenic for the homeodomain transcription factor Isl‐1 develop profound caudal growth defects that resemble human sacral/caudal agenesis. Isl‐1 is normally expressed in the pancreas and is required for pancreas development and endocrine cell differentiation. Aberrant regulation of this pancreatic transcription factor causes increased mesodermal cell death, and the severity of defects is dependent on transgene dosage. Together with the finding that mutation of the pancreatic transcription factor HLXB9 causes sacral agenesis, our results implicate pancreatic transcription factors in the pathogenesis of birth defects associated with diabetes.

Carbon monoxide (CO) is proposed as a physiological messenger. CO activates cGMP and has a direct effect on potassium channels. Both actions of CO lead to hyperpolarization of a cell's resting membrane potential, suggesting that CO may function as a hyperpolarizing factor, although direct evidence is still lacking. Here we take advantage of the known membrane potential gradient that exists in the muscle layers of the gastrointestinal tract to determine whether CO is an endogenous hyperpolarizing factor. We find that heme oxygenase-2-null mice have depolarized smooth muscle cells and that the membrane potential gradient in the gut is abolished. Exogenous CO hyperpolarizes the membrane potential. Regions of the canine gastrointestinal tract that are more hyperpolarized generate more CO and have higher heme oxygenase activity than more depolarized regions. Our results suggest that CO is a critical hyperpolarizing factor required for the maintenance of intestinal smooth muscle membrane potential and gradient.