H.O. Ventura

Safety, tolerability, and efficacy of cyclosporine microemulsion in heart transplant recipients: A randomized, multicenter, double-blind comparison with the oil-based formulation of cyclosporine: Results at 24 months after transplantation

BACKGROUNDnThe widespread use of cyclosporine has improved the survival of cardiac transplant patients as a result of reduced morbidity and mortality from rejection and infection. The original oil-based form of cyclosporine demonstrated unpredictable absorption resulting in an increased frequency of acute and chronic rejection in patients with poor bioavailability. The primary end. points of the present, prospective, randomized multicenter, double-blind trial were to compare the efficacy of the micro-emulsion form of cycolsporine (CsA-NL) with the oil-based formulation as determined by cardiac allograft and recipient survival and the incidence and severity of the acute rejection episodes and to determine the safety and tolerability of CsA-NL compared with Sandimmune CsA-(SM) in the study population. The 6-month analysis of the study showed reduced number of CsA-NL patients requiring antilymphocyte antibody therapy for rejection, fewer International Society of Heart and Lung Transplantation grade > or =3A rejections in female patients and fewer infections. Our report represents the final analysis of the results 24 months after transplantation.nnnMETHODSnA total of 380 patients undergoing de novo cardiac transplants at 24 centers in the United States, Canada, and Europe were enrolled in this double-blind, randomized trial evaluating the efficacy and safety of CsA-NL versus CsA-SM. Acute allograft rejection was diagnosed by endomyocardial biopsy and graded according to the International Society of Heart and Lung Transplantation nomenclature. Kaplan-Meier analysis and Fishers exact test were used for comparisons between groups.nnnRESULTSnAfter 24 months, allograft and recipient survival were identical in both groups. There were fewer CsA-NL patients (6.9%) requiring antilymphocyte antibody therapy for rejection than in the CsA-SM-treated patient group (17.7%, P=0.002). There were fewer discontinuations of study drug for treatment failures in the CsA-NL groups (7; 3.7%) compared with the CsA-SM group (18; 9.4%, P=0.037). The average corticosteroid dose was lower in the CsA-NL group (0.37 mg/kg/day) compared with the CsA-SM group (0.48 mg/kg/day, P=0.034) over the 24-month study period. Overall, there was no difference in blood pressure or creatinine between the two study groups.nnnCONCLUSIONSnThe final results of this multi-center, randomized study of two forms of cyclosporine confirmed that there were fewer episodes of rejection requiring antilymphocyte antibodies and fewer study discontinuations for treatment failures in CsA-NL-treated patients compared to those treated with CsA-SM. The use of CsA-NL did not predispose these patients to a higher risk of adverse events.

Ventilation/carbon dioxide production ratio in early exercise predicts poor functional capacity in congestive heart failure.

OBJECTIVES: To evaluate whether changes in the ventilation/carbon dioxide production ratio during early exercise could reliably serve as a surrogate marker for maximal oxygen consumption in heart failure patients. Maximal oxygen consumption is an important determinant of the severity of congestive heart failure with values > 14 ml/kg/min conferring a good 2-year survival. However, many patients undergoing cardiopulmonary exercise testing cannot exercise maximally because of other functional limitations. METHODS: Ventilation/carbon dioxide production ratio was assessed at rest, anaerobic threshold, and peak exercise in 75 patients with chronic heart failure and in 12 healthy controls. Patients were divided into two groups on the basis of heart failure severity as judged by maximal oxygen consumption. RESULTS: Patients with mild-moderate heart failure had a 20% reduction in the ventilation/carbon dioxide production ratio at anaerobic threshold similar to that in healthy controls. Patients with severe heart failure failed to reduce this ratio at anaerobic threshold. Furthermore, a reduction in the ventilation/carbon dioxide production ratio in early exercise of less than 10% predicted a maximal oxygen consumption of < 14 ml/kg/min with a positive predictive value of 96% and a negative predictive value of 88%. CONCLUSIONS: A reduction of the ventilation/carbon dioxide production ratio of less then 10% with early exercise reliably predicts poor functional capacity in congestive heart failure. Changes in this ratio during early exercise may be used as a surrogate for maximal oxygen consumption in patients who cannot exercise maximally.

Obesity and cardiovascular diseases.

Obesity is increasingly more common in postindustrial societies, and the burden of childhood obesity is increasing. The major effects of obesity on cardiovascular (CV) health are mediated through the risk of metabolic syndrome (insulin-resistance, dyslipidemia, and hypertension), such that an absence of these risk factors in obese individuals may not be associated with increased mortality risk. In individuals already diagnosed with chronic CV disease (CVD), the overweight and class I obese have significant associations with improved survival. However, this effect is attenuated by increases in cardiorespiratory fitness. The negative effects of obesity on CV health manifest as accelerated progression of atherosclerosis, higher rates of ventricular remodeling and a higher risk of associated diseases, including stroke, myocardial infarction, and heart failure. The most effective therapies at reversing CVD risk factors associated with obesity have been dietary changes with exercise, especially through structured exercise programs, such as cardiac rehabilitation.

Obesity and the Obesity Paradox in Heart Failure

Overweight and obesity, usually defined by high body mass index (BMI), have become a public health problem worldwide. Obesity is a major risk factor for cardiac remodeling and development of heart failure (HF). BMI usually correlates with HF risk in a dose-dependent fashion. A complex interaction between several mechanisms underlies the strong relationship between obesity and HF.

733-3 Successful Transplantation of Myoblasts into Adult Porcine Myocardium: A Potential Method to Repair a Failing Heart

The profound shortage of organ donors continues to fuel the search for other methods to refurbish a failing heart. The use of transgenic cells transplanted (Tx) in syngeneic rodents has shown modest success, but allogeneic and xenogeneic transplants have not been uniformly successful. To assess the feasibility of xenogeneic and allogeneic myoblast transplantation, six adult swine underwent transplantation of murine atrial tumor cells (Xenogeneic) and neonatal porcine myocytes (Allogeneic) into the left ventricular wall. Following general anesthesia, isolated cells were injected along the anterior and posterior wall ofthe porcine left ventricle (six sites per animal). All the animals were immunosuppressed with cyclosporine and prednisone and were followed for 1 month post-injection and then sacrificed. Results are as follows: In all 36 injected sites, the Tx cells proliferated within the host myocardium with no significant rejection. CPK MB did not increase after the procedure indicating that there was no damage to the host myocardium from the injection of cells. Moreover, Tx cells formed close associations with host myocytes that resembled intercalated discs on electron microscopy, and were composed of PAN cadherin on immunofluorescent staining. These cells also contained myofibrils and other cell architecture that resembled normal AT-l or neonatal myocytes. Additionally, these cells produced angiogenic factors resulting in a proliferation of the surrounding microvasculature. In conclusion, these findings indicate successful xenogeneic and allogeneic myocyte cell transplantation in a large animal model. These experiments set the stage for future studies testing the ability of these cells to form a syncitium, contract, and thereby “repair” a damaged heart.