Characterization of the Cardiac Structure and Function of Conscious D2.B10-Dmdmdx/J (D2-mdx) mice from 16-17 to 24-25 Weeks of Age.

Duchenne muscular dystrophy (DMD) is the most common form of muscle degenerative hereditary disease. Muscular replacement by fibrosis and calcification are the principal causes of progressive and severe musculoskeletal, respiratory, and cardiac dysfunction. To date, the D2.B10-Dmdmdx/J (D2-mdx) model is proposed as the closest to DMD, but the results are controversial. In this study, the cardiac structure and function was characterized in D2-mdx mice from 16-17 up to 24-25 weeks of age. Echocardiographic assessment in conscious mice, gross pathology, and histological and cardiac biomarker analyses were performed. At 16-17 weeks of age, D2-mdx mice presented mild left ventricular function impairment and increased pulmonary vascular resistance. Cardiac fibrosis was more extended in the right ventricle, principally on the epicardium. In 24-25-week-old D2-mdx mice, functional and structural alterations increased but with large individual variation. High-sensitivity cardiac Troponin T, but not N-terminal pro-atrial natriuretic peptide, plasma levels were increased. In conclusion, left ventricle remodeling was mild to moderate in both young and adult mice. We confirmed that right ventricle epicardial fibrosis is the most outstanding finding in D2-mdx mice. Further long-term studies are needed to evaluate whether this mouse model can also be considered a model of DMD cardiomyopathy.

Searching for Preclinical Models of Acute Decompensated Heart Failure: a Concise Narrative Overview and a Novel Swine Model.

PURPOSE: Available animal models of acute heart failure (AHF) and their limitations are discussed herein. A novel and preclinically relevant porcine model of decompensated AHF (ADHF) is then presented. METHODS: Myocardial infarction (MI) was induced by occlusion of left anterior descending coronary artery in 17 male pigs (34 ± 4 kg). Two weeks later, ADHF was induced in the survived animals (n = 15) by occlusion of the circumflex coronary artery, associated with acute volume overload and increases in arterial blood pressure by vasoconstrictor infusion. After onset of ADHF, animals received 48-h iv infusion of either serelaxin (n = 9) or placebo (n = 6). The pathophysiology and progression of ADHF were described by combining evaluation of hemodynamics, echocardiography, bioimpedance, blood gasses, circulating biomarkers, and histology. RESULTS: During ADHF, animals showed reduced left ventricle (LV) ejection fraction < 30%, increased thoracic fluid content > 35%, pulmonary edema, and high pulmonary capillary wedge pressure ~ 30 mmHg (p < 0.01 vs. baseline). Other ADHF-induced alterations in hemodynamics, i.e., increased central venous and pulmonary arterial pressures; respiratory gas exchanges, i.e., respiratory acidosis with low arterial PO2 and high PCO2; and LV dysfunction, i.e., increased LV end-diastolic/systolic volumes, were observed (p < 0.01 vs. baseline). Representative increases in circulating cardiac biomarkers, i.e., troponin T, natriuretic peptide, and bio-adrenomedullin, occurred (p < 0.01 vs. baseline). Finally, elevated renal and liver biomarkers were observed 48 h after onset of ADHF. Mortality was ~ 50%. Serelaxin showed beneficial effects on congestion, but none on mortality. CONCLUSION: This new model, resulting from a combination of chronic and acute MI, and volume and pressure overload, was able to reproduce all the typical clinical signs occurring during ADHF in a consistent and reproducible manner.

Scientific and ethical issues in add-on designs for antidiabetic drugs.

This editorial describes the clinical trials related to antidiabetic drugs, most of them following an "add-on" design of where the new drug is added to metformin and the comparative arm is metformin plus placebo. Many drugs are already approved for therapy following this design; the authors believe that it is unethical to continue this trend because it makes it impossible to stratify the many antidiabetic drugs according to their efficacy and toxicity.

LIPCAR Is Increased in Chronic Symptomatic HF Patients. A Sub-Study of the GISSI-HF Trial.

BACKGROUND: The long noncoding RNA LIPCAR (Long Intergenic noncoding RNA Predicting CARdiac remodeling) has emerged as a promising biomarker in cardiac disease and cardiac remodeling. To determine whether LIPCAR levels help for a molecular phenotyping of chronic heart failure (HF) patients, this study assessed the association of LIPCAR with severity of the disease and its progression, and with risk of death or hospitalization in HF patients. METHODS: LIPCAR was measured in plasma of 967 HF patients with symptomatic heart failure participating in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca - Heart Failure (GISSI-HF) biohumoral sub-study. RESULTS: Plasma levels of LIPCAR were significantly associated with functional impairment as assessed by the New York Heart Association (NYHA) class, kidney function as reflected by estimated glomerular filtration rate, and creatinine, hemoglobin and mitral insufficiency. In females, these associations were more marked as compared to males. LIPCAR plasma levels were significantly related to the two cardiac markers, N-terminal pro-B type natriuretic peptide and high-sensitivity cardiac troponin T, but not to inflammatory markers such as high sensitivity C-reactive protein and pentraxin-3, nor to patient reported outcomes such as depression and quality of life. HF patients with high LIPCAR levels univariately showed significantly higher incidence of cardiovascular hospitalizations but not of death; after adjusting for covariates, no significant effects of LIPCAR were found for cardiovascular hospitalizations. CONCLUSION: The circulating long noncoding RNA LIPCAR was increased in HF patients with higher NYHA class, impaired kidney function, and lower hemoglobin, which are indicators of patients' overall state.

Total NT-proBNP, a novel biomarker related to recurrent atrial fibrillation.

BACKGROUND: Novel circulating biomarkers may help in understanding the underlying mechanisms of atrial fibrillation (AF), a challenge for AF management and prevention of cardiovascular (CV) events. Whether glycosylation affects the prognostic value of N-terminal pro-B type natriuretic peptide (NT-proBNP) in AF is still unknown. OBJECTIVES: To test how deglycosylated total NT-proBNP, NT-proBNP and a panel of biomarkers are associated with: (1) recurrent AF, (2) first hospitalization for CV reasons. METHODS: A total of 382 patients of the GISSI-AF trial in sinus rhythm with a history of AF, echocardiographic variables, total NT-proBNP, NT-proBNP and nine additional biomarkers [Total N-terminal pro-B type natriuretic peptide (Total NT proBNP), N-terminal pro-B type natriuretic peptide (NTproBNP), Angiopoietin 2 (Ang2), Bone morphogenic protein-10 (BMP10), Dickkopf-related protein-3 (DKK3), Endothelial cell specific molecule-1 (ESM1), Fatty acid-binding protein 3 (FABP3), Fibroblast growth factor 23 (FGF23), Growth differentiation factor-15 (GDF15), Insulin-like growth factor-binding protein-7 (IGFBP7) and Myosin binding protein C3 (MYPBC3)]. were assayed at baseline, 6 and 12 months under blind conditions in a laboratory at Roche Diagnostics, Penzberg, Germany. The associations between circulating biomarkers and AF at the 6- and 12-month visits, and their predictive value, were assessed in multivariable models with logistic regression analysis and Cox proportional hazards regression analysis. Biomarkers associations were modelled for 1SD increase in their level. RESULTS: Over a median follow-up of 365 days, 203/382 patients (53.1%) had at least one recurrence of AF and 16.3% were hospitalized for CV reasons. Total NT-proBNP, NT-proBNP, Ang2 and BMP10 showed the strongest associations with ongoing AF. Natriuretic peptides also predicted recurrent AF (total NT-proBNP: HR:1.19[1.04-1.36], p = 0.026; NT-proBNP: HR:1.19[1.06-1.35], p = 0.016; Ang2: HR:1.07[0.95-1.20], p = 0.283; BMP10: HR:1.09[0.96-1.25], p = 0.249) and CV hospitalization (total NT-proBNP: HR:1.57[1.29-1.90], p < 0.001 1.63], p = 0.097). CONCLUSIONS: The association of total NT-proBNP with the risk of AF first recurrence was similar to that of NT-proBNP, suggesting no influence of glycosylation. Analogous results were obtained for the risk of first hospitalization for CV reasons. Natriuretic peptides, Ang2 and BMP10 were associated with ongoing AF. Findings from the last two biomarkers point to a pathogenic role of cardiac extracellular matrix and cardiomyocyte growth in the myocardium of the right atrium and ventricle.

IGFBP7 and GDF-15, but not P1NP, are associated with cardiac alterations and 10-year outcome in an elderly community-based study.

BACKGROUND: Little is known about the clinical value of Insulin-like growth factor-binding protein-7 (IGFBP7), a cellular senescence marker, in an elderly general population with multiple co-morbidities and high prevalence of asymptomatic cardiovascular ventricular dysfunction. Inflammation and fibrosis are hallmarks of cardiac aging and remodelling. Therefore, we assessed the clinical performance of IGFBP7 and two other biomarkers reflecting these pathogenic pathways, the growth differentiation factor-15 (GFD-15) and amino-terminal propeptide of type I procollagen (P1NP), for their association with cardiac phenotypes and outcomes in the PREDICTOR study. METHODS: 2001 community-dwelling subjects aged 65-84 years who had undergone centrally-read echocardiography, were selected through administrative registries. Atrial fibrillation (AF) and 4 echocardiographic patterns were assessed: E/e' (> 8), enlarged left atrial area, left ventricular hypertrophy (LVH) and reduced midwall circumference shortening (MFS). All-cause and cardiovascular mortality and hospitalization were recorded over a median follow-up of 10.6 years. RESULTS: IGFBP7 and GDF-15, but not P1NP, were independently associated with prevalent AF and echocardiographic variables after adjusting for age and sex. After adjustment for clinical risk factors and cardiac patterns or NT-proBNP and hsTnT, both IGFBP7 and GDF-15 independently predicted all-cause mortality, hazard ratios 2.13[1.08-4.22] and 2.03[1.62-2.56] per unit increase of Ln-transformed markers, respectively. CONCLUSIONS: In a community-based elderly cohort, IGFBP7 and GDF-15 appear associated to cardiac alterations as well as to 10-year risk of all-cause mortality.

Cardiovascular mortality and morbidity burden in successive and age pre-stratified case-control cohorts of breast cancer women. A population-based study.

AIMS: To assess the existence, components and clinical relevance of cardiac causes of death and cardiovascular (CV) hospitalizations in a population-wide database of patients with breast cancer (BC). METHODS AND RESULTS: A population-wide database of the Puglia Region, Italy was analyzed, with a prospective comparative design. Three successive closely matched case/control cohorts representing current care in the period 2007-2014 were also stratified according to age to focus specifically on the potential interaction of treatment-related cardiac toxicity and the expected different baseline CV risk profiles. RESULTS: At 3-year follow-up, in the successive cohorts the incidence of BC-related (7.7, 7.0, 6.5%) and cardiac causes of death, specifically attributed to heart failure (HF, 1.3, 0.5, 0.5%), decreased. Significant mortality hazard ratio (HR) for HF was found in the total population (1.47, 95% CI 1.14-1.90), in particular in the 2007-2009 cohort (1.71, 95% CI 1.19-2.46) and in the 50-69 age group (7.96, 95% CI 2.81-22.55). Results at 5 years confirm the mortality findings, and a significant HR for hospitalizations for HF, non-atrial arrhythmias and ischemic heart disease in the younger than 50 subpopulation pointed to a late expression of toxicity in the youngest BC population. CONCLUSIONS: The incidence of CV causes of death 3 and 5 years after BC diagnosis was very low, even if an excess in risk of death for HF as compared with the control cohort was observed. While younger patients seems to tolerate BC and BC therapy better in the short term, HF mortality and morbidity resulted significantly increased at 5-year follow-up. As the risk for hospitalization for CV reasons increased at 5-year follow-up in particular in women aged less than 50 years, CV monitoring in this subgroup of patients seems mandatory.

Prevalence and Prognostic Impact of Chronic Obstructive Pulmonary Disease in Patients with Chronic Heart Failure: Data from the GISSI-HF Trial.

OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is a common comorbidity in patients with heart failure (HF). We aimed to assess its prevalence, characterization and long-term prognostic impact in the GISSI-HF population. METHODS: The study randomized 6,975 ambulatory HF patients to either n-3 polyunsaturated fatty acids or placebo. We performed a retrospective analysis of clinical characteristics and outcomes of the 1,533 patients diagnosed with COPD (22%). RESULTS: COPD was associated with a worse clinical presentation and an increased burden of comorbidities. At a median follow-up of 3.9 years, COPD was found to be an independent predictor of both predefined primary study end points, including all-cause mortality (HR 1.28, 95% CI 1.15-1.43, p < 0.0001) and all-cause mortality or hospitalization for cardiovascular reasons (HR 1.19, 95% CI 1.10-1.30, p < 0.0001). Both cardiovascular (HR 1.20, 95% CI 1.05-1.36, p = 0.007) and noncardiovascular mortality (HR 1.56, 95% CI 1.26-1.94, p < 0.0001) were significantly increased in COPD-HF patients, as well as hospitalizations for any reason (HR 1.23, 95% CI 1.14-1.34, p < 0.0001), for cardiovascular reasons (HR 1.16, 95% CI 1.06-1.27, p = 0.002) and for HF (HR 1.27, 95% CI 1.14-1.43, p < 0.0001). CONCLUSIONS: COPD is an independent predictor of mortality and hospitalizations in ambulatory HF patients. Increased awareness and improved management of COPD may reduce the burden of this morbidity to patients with HF.

Cardiac Remodeling, Circulating Biomarkers and Clinical Events in Patients with a History of Atrial Fibrillation. Data from the GISSI-AF Trial.

PURPOSE: Atrial fibrillation (AF) is the most common arrhythmia and has an increasing impact on public health because of its morbidity and mortality. Clinical and diagnostic tests to predict the recurrence of arrhythmia and clinical events before AF becomes permanent are still an open issue. METHODS: 307 out of 1442 patients in sinus rhythm, at high risk of recurrence of AF enrolled in the GISSI-AF study, participated in a substudy with echocardiographic and biohumoral evaluation at baseline and at 12-month follow-up. The relations between biomarker concentrations and echocardiographic parameters with study endpoints in 1 year, were analysed by a stepwise multivariable Cox model (entry criteria p < 0.5 and stay criteria p < 0.2). RESULTS: The echocardiographic variables, cardiac markers and clinical variables considered in the statistical model indicated a higher concentration of NT-proBNP at baseline as the strongest factor related to time of first AF recurrence (HR 1.42; 95 %CI 1.23-1.46), first CV hospitalization (HR 1.58; 95 %CI 1.31-1.92) and increasing duration of recurrent AF (OR 2.16; 95 %CI 1.52-3.08). Valsartan treatment was not related to clinical events. CONCLUSIONS: In patients in sinus rhythm with a history of AF a higher concentration of NT-proBNP at baseline was the strongest independent risk factor for first AF recurrence and its duration, and for the first hospital admission for cardiovascular reasons.

Relationship between post-cardiac arrest myocardial oxidative stress and myocardial dysfunction in the rat.

BACKGROUND: Reperfusion after resuscitation from cardiac arrest (CA) is an event that increases reactive oxygen species production leading to oxidative stress. More specifically, myocardial oxidative stress may play a role in the severity of post-CA myocardial dysfunction. This study investigated the relationship between myocardial oxidative stress and post-CA myocardial injury and dysfunction in a rat model of CA and cardiopulmonary resuscitation (CPR). Ventricular fibrillation was induced in 26 rats and was untreated for 6 min. CPR, including mechanical chest compression, ventilation, and epinephrine, was then initiated and continued for additional 6 min prior to defibrillations. Resuscitated animals were sacrificed at two h (n = 9), 4 h (n = 6) and 72 h (n = 8) following resuscitation, and plasma collected for assessment of: high sensitivity cardiac troponin T (hs-cTnT), as marker of myocardial injury; isoprostanes (IsoP), as marker of lipid peroxidation; and 8-hydroxyguanosine (8-OHG), as marker of DNA oxidative damage. Hearts were also harvested for measurement of tissue IsoP and 8-OHG. Myocardial function was assessed by echocardiography at the corresponding time points. Additional 8 rats were not subjected to CA and served as baseline controls. RESULTS: Compared to baseline, left ventricular ejection fraction (LVEF) was reduced at 2 and 4 h following resuscitation (p < 0.01), while it was similar at 72 h. Inversely, plasma hs-cTnT increased, compared to baseline, at 2 and 4 h post-CA (p < 0.01), and then recovered at 72 h. Similarly, plasma and myocardial tissue IsoP and 8-OHG levels increased at 2 and 4 h post-resuscitation (p < 0.01 vs. baseline), while returned to baseline 72 h later. Myocardial IsoP were directly related to hs-cTnT levels (r = 0.760, p < 0.01) and inversely related to LVEF (r = -0.770, p < 0.01). Myocardial 8-OHG were also directly related to hs-cTnT levels (r = 0.409, p < 0.05) and inversely related to LVEF (r = -0.548, p < 0.01). CONCLUSIONS: The present study provides evidence that lipid peroxidation and DNA oxidative damage in myocardial tissue are closely related to myocardial injury and LV dysfunction during the initial hours following CA.

Incremental value of left ventricular systolic and diastolic function to determine outcome in patients with acute ST-segment elevation myocardial infarction: the echocardiographic substudy of the OASIS-6 trial.

BACKGROUND: The echocardiographic substudy of the OASIS-6 trial evaluated the prognostic implications of left ventricle (LV) systolic and diastolic dysfunction early postacute ST-segment elevation myocardial infarction (STEMI) in patients treated with fondaparinux versus usual care. METHODS: Comprehensive echocardiograms were performed a median of 6 days after the index STEMI in 528 patients, 258 randomized to fondaparinux and 270 to usual care (unfractionated heparin or placebo), to assess LV systolic and diastolic function, LV mass, and LV end-systolic and end-diastolic volumes. A total of 245 (46.4%) patients were followed up for 3 months and 283 (53.6%) for 6 months. Major cardiac events (MACE) were defined as the composite of death, reinfarction, heart failure, or cardiogenic shock and resuscitated cardiac arrest. RESULTS: Patients with LV ejection fraction (LVEF) ≤ 45% and restrictive diastolic function (RDF) were at greatly increased risk of MACE (hazard ratio [HR] = 8.85, 95% CI, 4.21­18.60) compared to patients with LVEF ≥ 45% and without RDF. RDF remained a strong predictor for MACE in patients with LVEF ≥ 45% (HR = 4.38, 95% CI, 1.52­12.60) and in multivariate models adjusted for LVEF, LV end-systolic volume, and clinical variables. CONCLUSION: In this large international trial, LV systolic and diastolic function, as determined by echocardiography early following STEMI, are incremental predictors of MACE. In addition, RDF is a strong independent predictor of MACE after STEMI across a broad range of LVEF.

Incidence of atrial fibrillation in a population with impaired glucose tolerance: the contribution of glucose metabolism and other risk factors. A post hoc analysis of the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research trial.

BACKGROUND: The role of dysglycemia as an additional risk factor for atrial fibrillation (AF) is controversial. Therefore, it was of interest to assess risk factors for incident AF in a large, representative population of patients with cardiovascular risk factors and impaired glucose tolerance but not overt diabetes in NAVIGATOR. METHODS: Predictors of incident AF were analyzed in 8,943 patients without AF at baseline by Cox proportional hazards regression. Study treatments (valsartan vs no valsartan and nateglinide vs no nateglinide) and the time-dependent covariate for progression to type 2 diabetes mellitus were added separately to the model. RESULTS: The median age of the 8,943 patients included in the present analysis of the NAVIGATOR trial was 63 years. Half of those patients were men, 6,922 (77.4%) had a history of hypertension, and 255 (2.9%) had heart failure. The median glycated hemoglobin was 6%. During the study, 613 of the 8,943 patients without AF at baseline presented with at least 1 episode of AF (6.9% 5-year incidence). Besides established predictors of incident AF, a 1 mmol/L increment of baseline fasting glucose, but not progression to diabetes, was found to be associated with a 33% increased risk of incident AF. Neither valsartan nor nateglinide affected AF incidence. CONCLUSIONS: In a trial population with impaired glucose tolerance, fasting plasma glucose and well-known risk factors (age, hypertension, and elevated body weight), but not progression to diabetes, predict risk of AF.

Ibuprofen plus isosorbide dinitrate treatment in the mdx mice ameliorates dystrophic heart structure.

BACKGROUND: Co-administration of ibuprofen (IBU) and isosorbide dinitrate (ISDN) provides synergistic beneficial effects on dystrophic skeletal muscle. Whether this treatment has also cardioprotective effects in this disease was still unknown. AIMS: To evaluate the effects of co-administration of IBU and ISDN (a) on left ventricular (LV) structure and function, and (b) on cardiac inflammatory response and fibrosis in mdx mice. METHODS: Three groups of mice were studied: mdx mice treated with IBU (50 mg kg⁻¹)+ISDN (30 mg kg⁻¹) administered daily in the diet, mdx mice that received standard diet without drugs and wild type aged-matched mice. Animals were analysed after 10-11 months of treatment. Structural and functional parameters were evaluated by echocardiography while histological analyses were performed to evaluate inflammatory response, collagen deposition, cardiomyocyte number and area. RESULTS: Treatment for 10-11 months with IBU+ISDN preserved LV wall thickness and LV mass. Drug treatment also preserved the total number of cardiomyocytes in the LV and attenuated the increase in cardiomyocyte size, when compared to untreated mdx mice. Moreover, a trend towards a decreased number of inflammatory cells, a reduced LV myocardial interstitial fibrosis and an enhanced global LV function response to stress was observed in treated mdx mice. CONCLUSIONS: Treatment for 10-11 months with IBU+ISDN is effective in preventing the alterations in LV morphology of mdx mice while not reaching statistical significance on LV function and cardiac inflammation.

Thromboembolic event rate in paroxysmal and persistent atrial fibrillation: data from the GISSI-AF trial.

BACKGROUND: Few data on the thromboembolic (TE) risk of paroxysmal and persistent atrial fibrillation (AF) are available. This study aimed to assess the incidence of TE events in paroxysmal and persistent AF. METHODS: We performed a subset post hoc analysis of 771 patients with paroxysmal and 463 with persistent AF enrolled in the multicenter, prospective, randomized, double-blind, placebo-controlled GISSI-AF trial - comparing the efficacy of valsartan versus placebo in preventing AF recurrences - where the choice of antithrombotic treatment was left to the judgment of the referring physician. TE and major outcome events were centrally validated. AF recurrences were detected by frequent clinic visits and a transtelephonic monitoring device with weekly and symptomatic transmissions. RESULTS: Eighty-five percent of patients had a history of hypertension, and the 7.7% had heart failure, left ventricular dysfunction, or both. The mean CHADS2 score was 1.41±0.84. TE and major bleeding events were observed at a low incidence among the overall population at 1-year follow-up (0.97% and 0.81%, respectively). The univariate and multivariable analyses revealed no statistically significant differences in the incidence of TE, major bleeding events or mortality in paroxysmal and persistent AF patients. TE events were more common among women than men (p=0.02). The follow-up examination showed under- or overtreatment with warfarin in many patients, according to guideline suggestions. Warfarin was more frequently prescribed to patients with persistent AF (p<0.0001) and patients with AF recurrences (p<0.0001). AF recurrences were noninvasively detected in 632 (51.2%) patients. In patients without AF recurrences, the TE event rate was 0.5% versus 1.74%, 1.28%, and 1.18% for those with only symptomatic, only asymptomatic or both symptomatic and asymptomatic AF recurrences, respectively, but the difference was not statistically significant, even after adjusting for warfarin treatment and the CHADS2 score (HR 2.93; CI 95%; 0.8-10.9; p=0.11). CONCLUSIONS: TE and major bleeding events showed a very low incidence in the GISSI-AF trial population, despite under- or overtreatment with warfarin in many patients. TE events had a similar rate in paroxysmal and persistent AF. TRIAL REGISTRATION NUMBER: NCT00376272.

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.)

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.

Systematic review and meta-analysis: renin-Angiotensin system inhibitors in the prevention of atrial fibrillation recurrences: an unfulfilled hope.

PURPOSE: To analyze the published data on the role of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II-receptor blockers (ARBs) in secondary prevention of AF. Some post-hoc analyses from trials in different clinical scenarios suggested the efficacy of ACEIs and ARBs in the prevention of new onset atrial fibrillation (AF), while their efficacy in preventing AF recurrences is notably controversial. METHODS: The authors reviewed all published prospective, randomized vs. placebo or no-treatment studies, concerning the effect of ACEIs and ARBs in the prevention of AF recurrences. Four ACEIs studies accounting for a total of 355 patients and six ARBs studies comprising 4.040 patients were analyzed. RESULTS: The pooled ACEIs data showed a statistical significant effect in preventing AF recurrences. However, the studies did not have a robust follow-up algorithm to recognize AF episodes, and were individually very small. On the contrary, pooled ARBs data did not show any effect in preventing AF recurrences (RR 0.90; 95% CI, 0.75-1.08; p = 0.24). The ARBs analyzed population was much larger in three large prospective, randomized, double-blind, placebo-control trials with transtelephoning monitoring of AF recurrences and neutral results. The meta-analysis of ACEIs and ARBs trials together could suggest a publication bias that may result in an overestimation of the treatment effect. CONCLUSIONS: Currently there is no role for ARBs in secondary prevention of AF. With regard to ACEIs, the data are not strong enough for a conclusion, although the efficacy is expected to be the same as that of ARBs.

Effects of Candesartan on Left Ventricular Function, Aldosterone and BNP in Chronic Heart Failure.

PURPOSE: Heart failure (HF) is characterized by activation of neurohormonal systems such as aldosterone and natriuretic peptides. In the absence of published data, CandHeart trial was designed to assess the effects on left ventricular (LV) function, aldosterone and brain natriuretic peptide (BNP) of candesartan in patients with HF and preserved (LVEF ≥ 40%) or depressed (LVEF <40%) LV systolic function. METHODS: A total of 514 patients with stable symptomatic NYHA II-IV HF and any left ventricular ejection fraction (LVEF)were randomized to candesartan (target dose 32 mg once daily) as add-on therapy or standard medical therapy alone. Standardized echocardiographic exams were performed locally under central quality control, whereas biomarkers were assayed in a core laboratory. RESULTS: The majority of patients (73.3%) were NYHA II and on ACE inhibitors (91.8%) and beta-blockers (85.4%). Mean age was 66 ± 11 years. Mean LVEF was 36.2 ± 9.7% and 24.9% of patients had LVEF ≥ 40%. LVEF increased significantly more in the candesartan group (p = 0.09 at 12 weeks and p = 0.01 at 48 weeks) and left ventricular end-diastolic diameter decreased in candesartan group (p = 0.05 at 12 weeks). Candesartan significantly reduced aldosterone at 48 weeks (p = 0.009). BNP was reduced similarly over time in both study groups (p = 0.35 and p = 0.98 at 12 and 48 weeks, respectively). There were 6.6% of discontinuations of candesartan for adverse events. CONCLUSIONS: In CandHeart, the addition of candesartan to standard medical treatment did not reduce circulating BNP more than standard therapy (primary endpoint), but it significantly improved LV function and produced a marked decrease in aldosterone levels at study end.

[Beta-blockers after myocardial infarction with preserved systolic function: useful or redundant?] / I betabloccanti nel post-infarto con funzione sistolica conservata: utili o ridondanti?

Given the lack of adequately sized randomized clinical trials (RCTs) testing the value of maintenance beta-blockers for post-myocardial infarction (MI) patients without reduced left ventricular ejection fraction and treated according to current standards, several observational studies have tried to address this highly relevant issue. However, results from observational studies have yielded opposite conclusions, with some suggesting that beta-blockers are associated with clinical benefit and others suggesting that they have no benefit. Due to the observational nature of these studies, the risk of bias is very high. In particular the existence of a confounding by indication factor is present when the prescription of the therapy is not random and is instead based on patients' clinical characteristics. Some randomness is needed to ensure that individuals with identical characteristics can be observed in both states (with or without beta-blockers). The only chance, therefore, to solve the question of benefits of beta-blockers is the execution of adequately sized RCTs. Currently, four large RCTs are ongoing in Europe, and, among them, the REBOOT-CNIC trial is already beyond three quarters of the expected cohort to be enrolled (6000/8648 revascularized MI patients without left ventricular dysfunction). An Italian cohort (1800 patients) will be included, enrolled by the Italian REBOOT Network. Enrollment is expected to be complete by the end of 2022, and the first results will become available by the end of 2025.