Lidia Staszewsky

Valsartan for Prevention of Recurrent Atrial Fibrillation

BACKGROUND Atrial fibrillation is the most common cardiac arrhythmia, and no current therapy is ideal for control of this condition. Experimental studies suggest that angiotensin II-receptor blockers (ARBs) can influence atrial remodeling, and some clinical studies suggest that they may prevent atrial fibrillation. METHODS We conducted a large, randomized, prospective, placebo-controlled, multicenter trial to test whether the ARB valsartan could reduce the recurrence of atrial fibrillation. We enrolled patients who were in sinus rhythm but had had either two or more documented episodes of atrial fibrillation in the previous 6 months or successful cardioversion for atrial fibrillation in the previous 2 weeks. To be eligible, patients also had to have underlying cardiovascular disease, diabetes, or left atrial enlargement. Patients were randomly assigned to receive valsartan or placebo. The two primary end points were the time to a first recurrence of atrial fibrillation and the proportion of patients who had more than one recurrence of atrial fibrillation over the course of 1 year. RESULTS A total of 1442 patients were enrolled in the study. Atrial fibrillation recurred in 371 of the 722 patients (51.4%) in the valsartan group, as compared with 375 of 720 (52.1%) in the placebo group (adjusted hazard ratio, 0.97; 96% confidence interval [CI], 0.83 to 1.14; P=0.73). More than one episode of atrial fibrillation occurred in 194 of 722 patients (26.9%) in the valsartan group and in 201 of 720 (27.9%) in the placebo group (adjusted odds ratio, 0.89; 99% CI, 0.64 to 1.23; P=0.34). The results were similar in all predefined subgroups of patients, including those who were not receiving angiotensin-converting-enzyme inhibitors. CONCLUSIONS Treatment with valsartan was not associated with a reduction in the incidence of recurrent atrial fibrillation. (ClinicalTrials.gov number, NCT00376272.)

Prevalence and prognostic significance of ventricular arrhythmias after acute myocardial infarction in the fibrinolytic era. GISSI-2 results.

Backgound. Several studies performed before the advent of thrombolysis have shown that the presence of ventricular arrhythmias is an independent risk factor for subsequent mortality in patients recovering from acute myocardial infarction. Since fibrinolysis affects the natural history of infarction and may alter the clinical relevance of different risk factors, the aim of the present study was to establish the prevalence and prognostic value of ventricular arrhythmias in post-myocardial infarction patients treated with fibrinolytic agents during the acute phase. Methods and ResultsTwenty-four-hour Holter recordings obtained before discharge from the hospital in 8,676 post-myocardial infarction patients of the GISSI-2 study were analyzed for the presence of ventricular arrhythmias. Patients were followed for 6 months from the acute event; total and sudden cardiovascular mortality rates were computed, and relative risks in univariate and multivariate analyses were calculated. Ventricular arrhythmias were present in 64.1% of the patients, more than 10 premature ventricular beats per hour were recorded in 19.7% of the patients, and nonsustained ventricular tachycardia was present in 6.8% of the patients. Ventricular arrhythmias were more frequent when signs or symptoms of left ventricular damage were present. During follow-up, there was a total of 256 deaths (3.0%o of patients), 84 of which (32.8% of total deaths) were cardiac sudden deaths. Mortality rates were 2.01% in patients without ventricular arrhythmias, 2.7% in patients with one to 10 premature ventricular beats per hour, 5.5% in those with more than 10 premature ventricular beats per hour, and 4.8% in those with complex premature ventricular beats. Even after adjusting for several risk factors, the presence of frequent (more than 10 premature ventricular beats per hour) ventricular arrhythmias remained a significant predictor of total (RRc1, 1.62; 95% confidence interval, 1.16-2.26) and sudden mortality (RRc., 2.24; 95% confidence interval, 1.22-4.08). On the other hand, the presence of nonsustained ventricular tachycardia was not associated with a worsening of the prognosis in the adjusted analysis (RRc., 1.20; 95% confidence interval, 0.80-1.79). ConclusionThis study shows that approximately 36% of patients recovering from acute myocardial infarction presented with less than one premature ventricular beat per hour in Holter recordings obtained before discharge from the hospital, whereas almost 20%o of patients showed frequent (more than 10 premature ventricular beats per hour) ventricular arrhythmias. Due to the large size of the population of this study, these figures may be used as a reliable estimate of the prevalence of arrhythmias in postinfarction patients treated with fibrinolytic agents during the acute phase. Frequent premature ventricular beats are confirmed as independent risk factors of total and sudden death in the first 6 months following the acute event; the significance of nonsustained ventricular tachycardia in this population appears more controversial.

Valsartan Benefits Left Ventricular Structure and Function in Heart Failure: Val-HeFT Echocardiographic Study

OBJECTIVES The objective of the study was to evaluate the effect of an angiotensin receptor blocker on left ventricular (LV) structure and function when added to prescribed heart failure therapy. BACKGROUND The clinical benefit derived from heart failure therapy is attributed to the regression of LV remodeling. METHODS At 302 multinational sites, 5,010 patients in New York Heart Association (NYHA) classification II to IV heart failure taking angiotensin-converting enzyme inhibitor (ACEI) and/or beta-blocker (BB) were randomized into valsartan and placebo groups and followed for a mean of 22.4 months. Serial echocardiographic measurements of left ventricular internal diastolic diameter (LVIDd) and ejection fraction (EF) were recorded. Total study reproducibility calculated to 90% power at 5% significance defined detectable differences of 0.09 cm for LVIDd and 0.86% for EF. RESULTS Baseline LVIDd and EF for valsartan and placebo groups were similar: 3.6 +/- 0.5 versus 3.7 +/- 0.5 (cm/m(2)) and 26.6 +/- 7.3 versus 26.9 +/- 7.0 (%). Mean group changes from baseline over time were compared. Significant decrease in LVIDd and increase in EF began by four months, reached plateau by one year, and persisted to two years in valsartan compared with placebo patients, irrespective of age, gender, race, etiology, NYHA classification, and co-treatment therapy. Changes at 18 months were -0.12 +/- 0.4 versus -0.05 +/- 0.4 (cm/m(2)), p < 0.00001 for LVIDd, and +4.5 +/- 8.9 versus +3.2 +/- 8.6 (%), p < 0.00001 for EF. The exception occurred in patients taking both ACEI and BB as co-treatment, in whom the decrease in LVIDd and increase in EF were no different between valsartan and placebo groups. CONCLUSIONS The Val-HeFT echocardiographic substudy of 5,010 patients with moderate heart failure demonstrated that valsartan therapy taken with either ACEI or BB reversed LV remodeling.

Intermittent 6-month low-dose dobutamine infusion in severe heart failure : DICE Multicenter Trial

BACKGROUND Patients with end-stage heart failure are often refractory to maximal oral therapy, and they have high mortality rates, poor quality of life, and frequent hospitalizations with elevated health care costs. Intermittent dobutamine therapy has been suggested as an additional option in this clinical setting. METHODS AND RESULTS Thirty-eight patients clinically stable for at least 48 hours with standard treatment, New York Heart Association (NYHA) functional class III or IV, cardiac index </=2.2 L/min/m(2), and left ventricular ejection fraction </=30% were randomly assigned to ambulatory intermittent dobutamine or optimal standard treatment. Dobutamine was infused at 2.5 microgram/kg/min with a portable pump 48 hours/week for 6 months. The primary study end point was the reduction of hospitalizations for worsening of congestive heart failure (CHF); changes in NYHA functional class, 6-minute walking test, and mortality rates were secondary end points. During the 6-month follow-up, all patients in dobutamine and control groups underwent weekly clinical visits with serum sodium and potassium measurement. Baseline characteristics were age 65 +/- 2 years, NYHA class III/IV 17/21, ejection fraction 22% +/- 1%, and cardiac index 1.89 +/- 0.1 L/min/m(2), without differences between treatment groups. Hospitalizations for all causes over a 6-month period were 17 and 11 in control and dobutamine groups; 11 of 17 and 7 of 11 were for worsening CHF. Four control patients but none in the dobutamine group had 2 or more hospitalizations for worsening of CHF. There were no significant differences in NYHA functional class and in 6-minute walking test. Three patients in the control group died and 5 in the dobutamine group died. Two patients in the dobutamine group underwent heart transplantation. Protocol was discontinued in the dobutamine group for severe ventricular arrhythmias (1 patient), infusion system failure (1 patient), and consent withdrawal (1 patient). In 3 patients in the dobutamine group, drug dose was increased to 5 microgram/kg/min because of CHF. CONCLUSIONS Six-month intermittent low-dose dobutamine administration was well tolerated by patients with severe CHF; it did not improve the functional status and did not significantly increase the mortality rate as found with higher dobutamine doses in other studies. Hospitalizations for all causes and for worsening of CHF tended to be fewer in the dobutamine group.

Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I phenotype in the mouse model

Type I mucopolysaccharidosis (MPS I) is a lysosomal storage disorder caused by the deficiency of α-L-iduronidase, which results in glycosaminoglycan accumulation in tissues. Clinical manifestations include skeletal dysplasia, joint stiffness, visual and auditory defects, cardiac insufficiency, hepatosplenomegaly, and mental retardation (the last being present exclusively in the severe Hurler variant). The available treatments, enzyme-replacement therapy and hematopoietic stem cell (HSC) transplantation, can ameliorate most disease manifestations, but their outcome on skeletal and brain disease could be further improved. We demonstrate here that HSC gene therapy, based on lentiviral vectors, completely corrects disease manifestations in the mouse model. Of note, the therapeutic benefit provided by gene therapy on critical MPS I manifestations, such as neurologic and skeletal disease, greatly exceeds that exerted by HSC transplantation, the standard of care treatment for Hurler patients. Interestingly, therapeutic efficacy of HSC gene therapy is strictly dependent on the achievement of supranormal enzyme activity in the hematopoietic system of transplanted mice, which allows enzyme delivery to the brain and skeleton for disease correction. Overall, our data provide evidence of an efficacious treatment for MPS I Hurler patients, warranting future development toward clinical testing.

Mesoangioblasts, Vessel-Associated Multipotent Stem Cells, Repair the Infarcted Heart by Multiple Cellular Mechanisms A Comparison With Bone Marrow Progenitors, Fibroblasts, and Endothelial Cells

Objective—To test the potential of mesoangioblasts (Mabs) in reducing postischemic injury in comparison with bone marrow progenitor cells (BMPCs), fibroblasts (Fbs), and embryonic stem cell–derived endothelial cells (ECs), and to identify putative cellular protective mechanisms. Methods and Results—Cells were injected percutaneously in the left ventricular (LV) chamber of C57BL/6 mice, 3 to 6 hours after coronary ligation, and detected in the hearts 2 days and 6 weeks later. Echocardiographic examinations were performed at 6 weeks. LV dilation was reduced and LV shortening fraction was improved with Mabs and BMPCs but not with ECs and Fbs. Donor cell colonization of the host myocardium was modest and predominantly in the smooth muscle layer of vessels. Capillary density was higher in the peripheral infarct area and apoptotic cardiomyocytes were fewer with Mabs and BMPCs. Mabs and BMPCs, but not Fbs or ECs, promoted survival of cultured cardiocytes under low-oxygen in culture. This activity was present in Mab-conditioned medium and could be replaced by a combination of basic fibroblast growth factor (bFGF), insulin-like growth factor (IGF)-1, and hepatocyte growth factor (HGF), all of which are produced by these cells. Conditioned medium from Mabs, but not from Fbs, stimulated proliferation of smooth muscle cells in vitro. Conclusions—Mabs appear as effective as BMPCs in reducing postinfarction LV dysfunction, likely through production of antiapoptotic and angiogenic factors.

Cardiac mesoangioblasts are committed, self-renewable progenitors, associated with small vessels of juvenile mouse ventricle

Different cardiac stem/progenitor cells have been recently identified in the post-natal heart. We describe here the identification, clonal expansion and characterization of self-renewing progenitors that differ from those previously described for high spontaneous cardiac differentiation. Unique coexpression of endothelial and pericyte markers identify these cells as cardiac mesoangioblasts and allow prospective isolation and clonal expansion from the juvenile mouse ventricle. Cardiac mesoangioblasts express many cardiac transcription factors and spontaneously differentiate into beating cardiomyocytes that assemble mature sarcomeres and express typical cardiac ion channels. Cells similarly isolated from the atrium do not spontaneously differentiate. When injected into the ventricle after coronary artery ligation, cardiac mesoangioblasts efficiently generate new myocardium in the peripheral area of the necrotic zone, as they do when grafted in the embryonic chick heart. These data identify cardiac mesoangioblasts as committed progenitors, downstream of earlier stem/progenitor cells and suitable for the cell therapy of a subset of juvenile cardiac diseases.

Rationale and design of the GISSI-Atrial Fibrillation Trial: a randomized, prospective, multicentre study on the use of valsartan, an angiotensin II AT1-receptor blocker, in the prevention of atrial fibrillation recurrence.

Background The possibility of preventing atrial fibrillation recurrence with anti-arrhythmic agents is very limited, given the discouraging results obtained with current drugs in many patients. Data from experimental studies suggest that angiotensin II AT1-receptor blockers can influence atrial remodelling, a key factor in atrial fibrillation initiation and maintenance. Moreover, some preliminary clinical data show that angiotensin II AT1-receptor blockers can prevent atrial fibrillation episodes. The GISSI-Atrial Fibrillation (AF) trial is a randomized, prospective, parallel group, placebo-controlled, multicentre study designed to test whether angiotensin II AT1-receptor blockers can reduce atrial fibrillation recurrence. Objectives and Methods The primary objective of the study is to demonstrate that, in patients with a history of recent atrial fibrillation who are treated with the best recommended therapies, the addition of the angiotensin II AT1-receptor blocker valsartan (titrated up to 320 mg) is superior to placebo in reducing atrial fibrillation recurrence. A substudy will analyse the effect of valsartan on left atrial dimensions and on neurohormones. The study population consists of patients with symptomatic atrial fibrillation (at least two electrocardiogram documented atrial fibrillation episodes in the previous 6 months or successful cardioversion in the last 2 weeks) with underlying cardiovascular diseases or comorbidities. With approximately 100 centres participating in Italy, a total of 1402 patients are randomized in a 1: 1 ratio to receive valsartan or placebo. The enrolment period will last 12 months and the patients will be followed for 12 months from study entry. Conclusions The GISSI-AF is the largest trial aimed at assessing the role of angiotensin receptor blockade in reducing the recurrence of atrial fibrillation and its possible mechanisms of action in terms of its effects on atrium remodelling and neurohormones.

Human cardiac mesoangioblasts isolated from hypertrophic cardiomyopathies are greatly reduced in proliferation and differentiation potency

AIMS Our objective was to test whether progenitor cell proliferation and differentiation potential may vary depending upon the disease of the donor. METHODS AND RESULTS Human cardiac mesoangioblasts were isolated from cardiac muscle biopsies of patients undergoing open heart surgery for correction of mitral regurgitation following an acute myocardial infarction (MR-MI) or correction of mitral and aortic regurgitation with ensuing left ventricular hypertrophy (MAR-LVH). The cells express surface markers and cardiac genes similar to mouse cardiac mesoangioblasts; they have limited self-renewing and clonogenic activity and are committed mainly to cardiogenesis. Although cardiac differentiation can be induced by 5-azacytidine or by co-culture with rat neonatal cardiomyocytes, human cells do not contract spontaneously like their mouse counterparts. When locally injected in the infarcted myocardium of immunodeficient mice, cardiac mesoangioblasts generate a chimeric heart that contains human myocytes and some capillaries; likewise, they colonize chick embryo hearts when transplanted in ovo. At variance with cells from patients with MR-MI, when isolation was performed on biopsies from MAR-LVH, cells could be isolated in much lower numbers, proliferated less extensively and failed to differentiate. CONCLUSION Cardiac mesoangioblasts are present in the human heart but this endogenous progenitor population is progressively exhausted, possibly by continuous and inefficient regeneration attempts.

Predicting atrial fibrillation recurrence with circulating inflammatory markers in patients in sinus rhythm at high risk for atrial fibrillation: data from the GISSI atrial fibrillation trial

Background Inflammation may play a significant role in the pathogenesis of atrial fibrillation (AF). Objectives To examine the roles of three systemic inflammatory markers in predicting recurrent AF. Methods The association between the plasma concentrations of high-sensitivity C reactive protein (hsCRP), interleukin-6 (IL-6) and pentraxin-3 (PTX3) with echocardiographic parameters and with the time to first recurrence of AF was tested in 382 patients with a history of AF but in sinus rhythm at randomisation, enrolled in the GISSI-AF biohumoral study. Results Baseline PTX3 was related to left atrial, but not to left ventricular chamber volume. During one year of follow-up, 204 patients (53.1%) had a recurrent AF. There were no significant differences in baseline median [Q1–Q3] plasma concentrations of IL-6, hsCRP and PTX3 among patients with (2.11 [1.47–3.74] pg/ml, 3.30 [1.40–6.80] mg/l and 4.66 [3.27–6.97] ng/ml, respectively) or without recurrent AF (2.09 [1.37–2.90] pg/ml, p=0.182; 3.00 [1.10–6.20] mg/l, p=0.333; 5.09 [3.22–7.98] ng/ml, p=0.637). At 6 and 12 months follow-up, AF patients had significantly higher concentrations of IL-6 and PTX3 than those in sinus rhythm, and those with most recent episodes of AF had higher hsCRP. Baseline levels of IL-6, hsCRP or PTX3 were not significantly associated with a higher risk of recurrence of AF. Conclusion In patients with a history of AF, but without significant left ventricular dysfunction or heart failure, inflammatory biomarkers may be raised but are, at best, weak predictors of the risk for first recurrence of AF.