Blood Pressure in De Novo Heart Transplant Recipients Treated With Everolimus Compared With a Cyclosporine-based Regimen: Results From the Randomized SCHEDULE Trial.

BACKGROUND: Systemic hypertension is prevalent in heart transplant recipients and has been partially attributed to treatment with calcineurin inhibitors (CNIs). SCandinavian HEart transplant De-novo stUdy with earLy calcineurin inhibitors avoidancE trial was the first randomized trial to study early withdrawal of CNIs in de novo heart transplant recipients, comparing an everolimus-based immunosuppressive regimen with conventional CNI-based treatment. As a prespecified secondary endpoint, blood pressure was repeatedly compared across treatment arms. METHODS: The The SCandinavian HEart transplant De-novo stUdy with earLy calcineurin inhibitors avoidancE trial was a prospective, multicenter, randomized, controlled, parallel-group, open-label trial in de novo adult heart transplant recipients, undertaken at transplant centers in Scandinavia. Blood pressure was assessed with 24-hour ambulatory blood pressure monitoring up to 3 years after heart transplantation (HTx) in 83 patients. RESULTS: Overall, systolic blood pressure fell with time, from 138 ± 15 mm Hg 2 weeks after HTx to 134 ± 11 mm Hg after 12 months and 132 ± 14 mm Hg after 36 months (P = 0.003). Diastolic blood pressure did not change over time. After 12 months, there was a numerically larger fall in systolic blood pressure in the everolimus arm (between-group difference 8 mm Hg; P = 0.053), and after 36 months, there was a significant between group difference of 13 mm Hg (P = 0.02) in favor of everolimus. CONCLUSIONS: In this first, randomized trial with early CNI avoidance in de novo HTx recipients, we observed a modest fall in systolic blood pressure over the first 1 to 3 years after transplantation. The fall in systolic blood pressure was more pronounced in patients allocated to everolimus.

Exercise capacity and peak oxygen consumption in asymptomatic patients with chronic aortic regurgitation.

BACKGROUND: In patients with chronic, hemodynamically significant aortic regurgitation (AR), a long period of left ventricular remodeling usually occurs prior to the development of symptoms or left ventricular dysfunction. The value of cardiopulmonary exercise testing in patients with asymptomatic AR is not established. MATERIAL AND METHODS: Sixty-six asymptomatic patients aged 44±14 years with hemodynamically significant, chronic AR and no indication for aortic valve replacement were evaluated by echocardiography, cardiac magnetic resonance imaging and exercise testing with measurement of peak oxygen consumption. RESULTS: The average left ventricular end diastolic volume was 244±62ml and the aortic regurgitant fraction 34±13%. At an average of 35.8±8.9ml/kg/min, peak oxygen consumption was well preserved. As in healthy individuals, a high peak oxygen consumption was associated with a relatively large LV end diastolic volume (r=0.51; p<0.001) and a low resting heart rate (r=-0.37; p=0.002). The aortic regurgitant fraction was not predictive of maximum oxygen consumption. Higher levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) were independently associated with poorer exercise capacity and oxygen uptake (adjusted ß -0.35; p=0.003). CONCLUSION: Our results suggest that in asymptomatic patients with moderate to severe AR and moderately dilated left ventricles, remodeling is primarily adaptive. An increased level of NT-proBNP is associated with a reduced capacity for work and reduced oxygen consumption, possibly heralding the onset of adverse remodeling.

Controlled release metoprolol for aortic regurgitation: a randomised clinical trial.

OBJECTIVE: Chronic aortic regurgitation (AR) creates a volume load on the left ventricle, which induces adaptive responses. With time, excessive left ventricular (LV) dilatation may precipitate heart failure. ß-adrenergic receptor antagonists (ß-blockers) are beneficial in patients with heart failure, but their effect in AR is unclear. This trial was designed to evaluate the effect of controlled release metoprolol on LV remodelling in patients with AR. METHODS: In this double blind trial, 75 asymptomatic patients aged 44±14 years, 89% males, fulfilling at least two echocardiographic criteria for moderate or severe chronic AR, were randomised to receive metoprolol CR/XL up-titrated to 200 mg/day, or matching placebo. The primary endpoint was LV end diastolic volume, measured by MRI after 6 months of treatment. RESULTS: After 6 months, the difference in the baseline-adjusted LV end diastolic volume between patients allocated to metoprolol and those allocated to placebo was 8 (95% CI -8 to 25) mL (p=0.32). The adjusted LV ejection fraction was 2.7 (95% CI 0.1 to 5.3) percentage points higher in the metoprolol group than in the placebo group (p=0.04). The exercise capacity and peak oxygen consumption did not differ between treatment arms. Serum concentrations of N-terminal pro-B-type natriuretic peptide were 138 (95% CI 71 to 205) pg/mL higher in the metoprolol group (p<0.001). There were no serious adverse events in either treatment arm. CONCLUSIONS: Treatment with metoprolol of adults with chronic, moderate to severe AR had no effect on LV volumes. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT01157572-results.

Soluble ST2 reflects hemodynamic stress in non-ischemic heart failure.

BACKGROUND: Elevated levels of soluble ST2 (sST2) are associated with adverse outcome in heart failure. A change in sST2 levels has also been shown to presage outcome. In vitro, ST2 expression is induced by myocardial stress and pro-inflammatory stimuli. The determinants of sST2 levels in vivo, and how they vary with clinical status over time, have not been well described. In a cohort of patients with non-ischemic heart failure, we aimed to assess the association between sST2-levels and hemodynamic parameters reflecting right and left ventricular pre- and afterload, and how these vary with time and clinical status. METHODS: We prospectively recruited 102 patients with a left ventricular ejection fraction of 26 ± 10% and a diagnosis of idiopathic dilated cardiomyopathy based on patient history, clinical examination, echocardiography and coronary angiography. Patients went through extensive baseline work-up and were re-examined after one year. Subsequently, heart transplantations and deaths were recorded. Determinants of sST2 were analyzed at baseline and after one year. Soluble ST2 was measured with a highly sensitive immunoassay. RESULTS: Soluble ST2 levels were associated with hemodynamic parameters, but these associations were attenuated with clinical improvement. Soluble ST2 was elevated in patients with severe symptoms, but did not vary with etiology, viral presence or the amount of myocardial fibrosis. Heart rate and right atrial pressure remained independent predictors of sST2 on multiple regression analysis. CONCLUSIONS: Our results imply that in non-ischemic heart failure, sST2 reflects hemodynamic stress rather than pathogenic processes in the myocardium.

The effect of rosuvastatin on inflammation, matrix turnover and left ventricular remodeling in dilated cardiomyopathy: a randomized, controlled trial.

BACKGROUND: Dilated cardiomyopathy is characterized by left ventricular dilatation and dysfunction. Inflammation and adverse remodeling of the extracellular matrix may be involved in the pathogenesis. Statins reduce levels of low density lipoprotein cholesterol, but may also attenuate inflammation and affect matrix remodeling. We hypothesized that treatment with rosuvastatin would reduce or even reverse left ventricular remodeling in dilated cardiomyopathy. MATERIALS AND METHODS: In this multicenter, randomized, double blind, placebo-controlled study, 71 patients were randomized to 10 mg of rosuvastatin or matching placebo. Physical examination, blood sampling, echocardiography and cardiac magnetic resonance imaging were performed at baseline and at six months' follow-up. The pre-specified primary end point was the change in left ventricular ejection fraction from baseline to six months. RESULTS: Over all, left ventricular ejection fraction improved 5 percentage points over the duration of the study, but there was no difference in the change in left ventricular ejection fraction between patients allocated to rosuvastatin and those allocated to placebo. Whereas serum low density lipoprotein cholesterol concentration fell significantly in the treatment arm, rosuvastatin did not affect plasma or serum levels of a wide range of inflammatory variables, including C-reactive protein. The effect on markers of extracellular matrix remodeling was modest. CONCLUSION: Treatment with rosuvastatin does not improve left ventricular ejection fraction in patients with dilated cardiomyopathy. TRIAL REGISTRATION: ClinicalTrials.gov NCT00505154.