Citations

Previous studies in this series demonstrated structural changes in the pulmonary vascular bed as the result of mitral valvular disease and other cardiac disorders. The present study demonstrates changes in the lungs as the result of chronic left ventricular failure; these changes were like those produced by mitral stenosis. The most pronounced disturbance was medial hypertrophy. The exact mechanism is not known, but it probably is related to increased pulmonary venous pressure.

Background —Idiopathic restrictive cardiomyopathy is a poorly recognized entity of unknown cause characterized by nondilated, nonhypertrophied ventricles with diastolic dysfunction resulting in dilated atria and variable systolic function. Methods and Results —Between 1979 and 1996, 94 patients (61% women) 10 to 90 years old (mean, 64 years) met strict morphological echocardiographic criteria for idiopathic restrictive cardiomyopathy, mainly dilated atria with nonhypertrophied, nondilated ventricles. None had known infiltrative disease, hypertension of >5 years’ duration, or cardiac or systemic conditions associated with restrictive filling. Nineteen percent were in NYHA class I, 53% in class II, and 28% in class III or IV. Atrial fibrillation was noted in 74% of patients and systolic dysfunction in 16%. Follow-up (mean, 68 months) was complete for 93 patients (99%). At follow-up, 47 patients (50%) had died, 32 (68%) of cardiovascular causes. Four had heart transplantation. The death rate compared with actuarial statistics was significantly higher than expected ( P <0.0001). Kaplan-Meier 5-year survival was 64%, compared with expected survival of 85%. Multivariate analysis using proportional hazards showed that the risk of death approximately doubles with male sex (hazard ratio [HR] =2.1), left atrial dimension >60 mm (HR=2.3), age >70 years (HR=2.0), and each increment of NYHA class (HR=2.0). Conclusions —Idiopathic restrictive cardiomyopathy or nondilated, nonhypertrophic ventricles with marked biatrial dilatation, as defined morphologically by echocardiography, affects predominantly elderly patients but can occur in any age group. Patients present with systemic and pulmonary venous congestion and atrial fibrillation and have a poor prognosis, particularly men >70 years old with higher NYHA class and left atrial dimension >60 mm.

BACKGROUND Although recent investigations report the elevation of plasma endothelin (ET) in congestive heart failure (CHF), it remains unclear if this elevation is that of the biologically active peptide ET-1 or of its precursor big-ET. Furthermore, it is unclear if such elevation is associated with increased myocardial ET and if the molecular form from cardiac tissue is altered ET. Last, it remains to be established whether circulating ET is increased at the earliest stage of CHF in patients with asymptomatic left ventricular dysfunction and correlates with the magnitude of ventricular dysfunction. METHODS AND RESULTS The present study was designed to investigate concentrations and molecular forms of ET in plasma and cardiac tissue in healthy subjects and CHF patients with New York Heart Association (NYHA) class I through IV using cardiac radionuclide angiogram, cardiac myocardial biopsy, radioimmunoassay, gel permeation chromatography (GPC), and immunohistochemical staining (IHCS). Plasma ET was increased only in patients with moderate (NYHA class III) or severe (NYHA class IV) CHF compared with healthy subjects and individuals with asymptomatic (NYHA class I) or mild (NYHA class II) CHF. The elevation of circulating ET in CHF showed a negative correlation with left ventricular ejection fraction and cardiac index and a positive correlation with functional class and left ventricular end-diastolic volume index. GPC demonstrated that immunoreactive plasma ET was ET-1 in healthy subjects and both mature ET-1 and its precursor big-ET in severe CHF patients, with big-ET the predominant molecular form. Cardiac tissue concentrations and IHCS revealed ET presence in healthy atrial and ventricular tissue, which were not different in severe CHF. GPC revealed that the molecular form of cardiac ET was ET-1 in both healthy and CHF hearts. CONCLUSIONS The present study establishes for the first time that the elevation of plasma ET in severe human CHF represents principally elevation of big-ET. Second, ET is present in healthy and failing myocardia, and its activity by both immunohistochemistry and radioimmunoassay is not changed in CHF. Furthermore, the elevated plasma ET is characteristic of severe CHF and not asymptomatic or mild CHF. In addition, the degree of plasma elevation of ET correlates with the magnitude of alterations in cardiac hemodynamics and functional class. The present study confirms and extends previous investigations of ET in human CHF and establishes the evolution of circulating and local cardiac ET in the spectrum of human CHF.

Progressive histologic changes occur in the pulmonary arteries and arterioles, as a complication of chronically elevated pulmonary arterial blood pressure, in patients with congenital septal defects of the heart. This progression is so stereotyped as to allow a division of the structural effects into 6 grades. The histologic features of each grade are described in detail in this communication. These results afford a basis for comparing the magnitude of these changes to the clinical findings.

Context— Posttransplant quality of life can be significantly affected by personality characteristics identified before transplant. Objective— Although overall quality of life in heart transplant patients improves after transplant, many studies reveal poorer mental health outcomes after transplant. We aimed to determine whether transplant recipients with an optimistic explanatory style had improved quality of life, fewer depressive symptoms, and increased survival. Design— We reviewed 68 patients who had completed a Minnesota Multiphasic Personality Inventory a mean of 2 years before transplant and examined associations between scores on the Optimism-Pessimism scale, survival rates, and results from the Health Status Questionnaire nearly 4 years after transplant. Results— Optimism was significantly associated with higher quality of life even after age (at the time of transplant), sex, depression score before transplant, time from the personality inventory to transplant, and time from transplant to the Health Status Questionnaire were controlled for. Furthermore, a pessimistic explanatory style was significantly associated with self-reported depressive symptoms, even after depression before transplant was adjusted for. Neither optimism nor pessimism was associated with length of survival. Conclusions— Pretransplant patients with a pessimistic explanatory style reported depressive symptoms nearly 5 years later. Furthermore, over the same time span, patients with an optimistic explanatory style described a significantly higher quality of life than the pessimists described.

Background— We retrospectively analyzed the potential of sirolimus as a primary immunosuppressant in the long-term attenuation of cardiac allograft vasculopathy progression and the effects on cardiac-related morbidity and mortality. Methods and Results— Forty-five cardiac transplant recipients were converted to sirolimus 1.2 years (0.2, 4.0) after transplantation with complete calcineurin inhibitor withdrawal. Fifty-eight control subjects 2.0 years (0.2, 6.5 years) from transplantation were maintained on calcineurin inhibitors. Age, sex, ejection fraction, and time from transplantation to baseline intravascular ultrasound study were not different ( P >0.2 for all) between the groups; neither were secondary immunosuppressants and use of steroids. Three-dimensional intravascular ultrasound studies were performed at baseline and 3.1 years (1.3, 4.6 years) later. Plaque index progression (plaque volume/vessel volume) was attenuated in the sirolimus group (0.7±10.5% versus 9.3±10.8%; P =0.0003) owing to reduced plaque volume in patients converted to sirolimus early (<2 years) after transplantation ( P =0.05) and improved positive vascular remodeling ( P =0.01) in patients analyzed late (>2 years) after transplantation. Outcome analysis in 160 consecutive patients maintained on 1 therapy was performed regardless of performance of intravascular ultrasound examinations. Five-year survival was improved with sirolimus (97.4±1.8% versus 81.8±4.9%; P =0.006), as was freedom from cardiac-related events (93.6±3.2% versus 76.9±5.5%; P =0.002). Conclusions— Substituting calcineurin inhibitor with sirolimus as primary immunosuppressant attenuates long-term cardiac allograft vasculopathy progression and may improve long-term allograft survival owing to favorable coronary remodeling. Because of the lack of randomization and retrospective nature of our analysis, the differences in outcome should be interpreted cautiously, and prospective clinical trials are required.

AbstractThe contributions of the host microenvironment to the pathogenesis of multiple myeloma, including progression from the non-malignant disorder monoclonal gammopathy of undetermined significance, are poorly understood. In the present study, microarray analysis of a murine model requiring a unique host microenvironment for myeloma development identified decreased host-derived adiponectin compared with normal mice. In support, clinical analysis revealed decreased serum adiponectin concentrations in monoclonal gammopathy of undetermined significance patients who subsequently progressed to myeloma. We investigated the role of adiponectin in myeloma pathogenesis and as a treatment approach, using both mice deficient in adiponectin and pharmacologic enhancement of circulating adiponectin. Increased tumor burden and bone disease were observed in myeloma-bearing adiponectin-deficient mice, and adiponectin was found to induce myeloma cell apoptosis. The apolipoprotein peptide mimetic L-4F was used for pharmacologic enhancement of adiponectin. L-4F reduced tumor burden, increased survival of myeloma-bearing mice, and prevented myeloma bone disease. Collectively, our studies have identified a novel mechanism whereby decreased host-derived adiponectin promotes myeloma tumor growth and osteolysis. Furthermore, we have established the potential therapeutic benefit of increasing adiponectin for the treatment of myeloma and the associated bone disease.

A model of proliferative human restenosis was developed in domestic pigs by using deep injury to the coronary arterial media. Metal wire coils were delivered percutaneously to the coronary arteries of 11 pigs with an oversized, high-pressure (14 atm) balloon and were left in place for times ranging from 28 to 70 days. During placement, the balloon expanded the coils and delivered them securely within the arterial lumen. Light microscopic examination of the vessels confirmed fracture of the internal elastic lamina by the coil. An extensive proliferative response occurred in 10 of the 11 pigs and was associated with a luminal area narrowing of at least 50% in all but one pig. The histopathologic features of the proliferative response were identical to those observed in human cases of restenosis after angioplasty. Immunohistochemical studies confirmed the prominence of smooth muscle cells in the proliferative tissue. A similar response was obtained in two of five porcine coronary arteries in which balloon inflation only was performed, without coil implant. This model is practical and inexpensive and closely mimics the proliferative portion of human restenosis both grossly and microscopically. Thus, it may be useful for understanding human restenosis and for testing therapies aimed at preventing restenosis after balloon angioplasty or other coronary interventional procedures.

Neointimal hyperplasia occurs in the coronary arteries after percutaneous revascularization procedures and is a reparative response that frequently causes recurrent stenosis. Prior animal studies have shown that neointimal tissue thickness is proportional to the depth of arterial injury. Because animal models are increasingly used to test therapeutic strategies against restenosis, the purpose of this study was to evaluate the degree of neointimal thickening formed in the coronary arteries of pigs compared with dogs in response to severe injury. Fourteen coronary arteries in six mongrel dogs and 18 coronary arteries in nine pigs underwent severe arterial injury using tantalum metal coils delivered on oversized angioplasty balloons. Animals were killed after 4 weeks, and all coronary arteries were pressure perfusion fixed. Mean histological injury scores and neointimal thicknesses for dogs were 1.9 +/- 0.3 and 0.30 +/- 0.11, respectively, compared with 2.1 +/- 0.7 and 0.71 +/- 0.36 for pigs. Thus, there was significantly less neointimal thickening in dogs compared with pigs (P < .001) despite no differences in injury (P = NS). The neointimal thickening differences translated into significantly different percent area stenoses: 55 +/- 24% for pigs versus 27 +/- 13% for dogs (P < .001). Linear regression modeled neointimal thickness versus injury assessed by an ordinal injury score proportional to the depth of injury for each species. This analysis confirmed the differences across multiple injury levels. The slope of the regression line for dogs was small, suggesting that no relation may exist between injury and neointimal thickness in this species. The pig may be a more appropriate model for the study of the genesis of stenosing neointima.(ABSTRACT TRUNCATED AT 250 WORDS)