A truncated cardiac troponin T molecule in transgenic mice suggests multiple cellular mechanisms for familial hypertrophic cardiomyopathy.

Mutations in multiple cardiac sarcomeric proteins including myosin heavy chain (MyHC) and cardiac troponin T (cTnT) cause a dominant genetic heart disease, familial hypertrophic cardiomyopathy (FHC). Patients with mutations in these two genes have quite distinct clinical characteristics. Those with MyHC mutations demonstrate more significant and uniform cardiac hypertrophy and a variable frequency of sudden death. Patients with cTnT mutations generally exhibit mild or no hypertrophy, but a high frequency of sudden death at an early age. To understand the basis for these distinctions and to study the pathogenesis of the disease, we have created transgenic mice expressing a truncated mouse cTnT allele analogous to one found in FHC patients. Mice expressing truncated cTnT at low (< 5%) levels develop cardiomyopathy and their hearts are significantly smaller (18-27%) than wild type. These animals also exhibit significant diastolic dysfunction and milder systolic dysfunction. Animals that express higher levels of transgene protein die within 24 h of birth. Transgenic mouse hearts demonstrate myocellular disarray and have a reduced number of cardiac myocytes that are smaller in size. These studies suggest that multiple cellular mechanisms result in the human disease, which is generally characterized by mild hypertrophy, but, also, frequent sudden death.     

Parkinson''s disease: an open label trial of pergolide in patients failing bromocriptine therapy.

Sixty-three patients with Parkinson's disease who failed bromocriptine therapy for various reasons were treated in an open-label trial of pergolide. The data were evaluated in a retrospective manner. Forty-six percent had a good response and tolerated the pergolide. A comparison of the outcomes regarding response and toxicity revealed that bromocriptine and pergolide act differently in individual patients. A trial of pergolide in Parkinsonian patients failing bromocriptine therapy may be therapeutically useful.     

Psychiatric nursing roles in a community mental health center

We describe the addition of medication monitoring to the duties of nurses working as case managers in a day treatment program for the chronically mentally ill. The nurses used their medical and behavioral knowledge to form a more complete picture of the patient than either a visiting psychiatrist or a case-manager who was not a nurse could do. This improved the integration of medication and other patient management decisions. It also improved cooperation between psychiatrists and nurses, better using the time and skills of both.     

Percutaneous transluminal angioplasty of the femoropopliteal artery: initial and long-term results

Patients with dilated stenoses and recanalized occlusions were evaluated to assess the initial and long-term results of percutaneous transluminal angioplasty (PTA) in the femoropopliteal artery. The follow-up period was at least 1 year. The initial success rate was 84% (128/164). The initial results were influenced by the radiologist's experience, catheter selection, and type of lesion. The 5- and 7-year cumulative patency rates were 70% and 60%. There was no difference in long-term patency between initially successful stenoses and short (less than 3 cm) occlusions. Both the morphology and location of the stenotic lesion influenced the long-term results. Although many factors influence the initial and long-term success rate, results of this study justify PTA in the femoropopliteal artery. Patients with localized stenoses and short occlusions are best suited for this treatment.     

Intrinsic connective tissue abnormalities in the heart muscle of cardiomyopathic Syrian hamsters.

Significant connective tissue abnormalities occurring in hearts of cardiomyopathic Syrian hamsters are reported. These abnormalities include a pronounced loss of the intrinsic connective tissue skeletal framework around foci of myocytolytic necrosis within the non-necrotic myocardium. These changes were demonstrated by a silver impregnation technique, and they were confirmed by scanning electron microscopy. Quantitation demonstrated more than a twofold increase in the area of ventricular wall affected by pathologic changes, when the connective tissue alterations were included with the myocardial necrosis. In addition, the authors also observed focal, thick "tethering" connective tissue fibers at the termini of necrotic lesions, seemingly connecting them to normal muscle. These connective tissue abnormalities may contribute to the progressive loss of ventricular function that occurs in this model of cardiomyopathy. They may permit greater wall thinning than would occur with focal necrosis alone, and they may increase focal mural stiffness in the tethered regions. Further investigation of the pathogenesis of these changes and their mechanical significance is indicated.     

Limited myocardial muscle necrosis model allowing for evaluation of angiogenic treatment modalities

The currently accepted model for creating infarcted cardiac tissue in a rat model involves ligation of the left anterior descending artery (LAD), either proximally or at the bifurcation level. This procedure requires significant technical expertise and, even in skilled hands, commonly results in a 30% to 60% animal mortality. The authors propose a new model for creating a limited area of myocardial muscle necrosis that can be effectively studied. It involves a distal electrocautery occlusion of the LAD terminal branches and coagulation of the surrounding muscle. The model is consistently reproducible and decreases the morbidity of the study animals. It provides a cardiac muscle necrosis model not dependent on survival, while allowing study of the post injured state of the muscle and surrounding scar. This allows researchers to evaluate neovascularization and healing of the scar and peri-necrotic muscle, to assess improving blood flow with treatment by techniques designed to improve and stimulate angiogenesis, and to measure the outcome of stem-cell transplants for potential clinical use.     

Catecholamine-induced myocardial necrosis in experimental diabetes mellitus

The pathogenesis of the cardiomyopathy associated with diabetes mellitus is unknown. Among several suggested mechanisms, myocardial necrosis induced by endogenous catecholamines may play a role. Therefore, the sensitivity of the heart to the effect of varying doses of isoproterenol hydrochloride and norepinephrine bitartrate was examined in diabetic and control rats given streptozocin. The dose of isoproterenol hydrochloride ranged from 0.008 to 30 mg/kg of body weight. Norepinephrine bitartrate was given in doses from 0.2 to 1.0 mg/kg of body weight. Each dose was given twice, 24 hours apart. Animals were killed 48 hours after the first dose, and their hearts were examined pathologically. Diabetes did not significantly alter the pathological response of the heart to either drug. We conclude that the diabetic heart is not intrinsically hypersensitive to catecholamines.     

Intralysosomal lipid in long-term maintenance transplant atherosclerosis.

Intralysosomal accumulation of lipid has been implicated as an important mechanism in the pathogenesis of atherosclerosis. Although atherosclerosis develops frequently in organ transplants maintained on a long-term basis, to our knowledge no studies to date have demonstrated the intracellular localization of the lipid in this setting. Light and electron microscopic study of a renal artery branch from a transplanted kidney maintained for 3 1/2 years demonstrates that the lipid is sequestered within intimal smooth muscle cell lysosomes. The features of the atherosclerotic plaque in long-term transplantation appear to be identical to spontaneous lesions or those induced experimentally.