. Latini R, Masson S, Pirelli S, Barlera S, Pulitano G, Carbonieri E, Gulizia M, Vago T, Favero C, Zdunek D, Struck J, Staszewsky L, Maggioni AP, Franzosi MG, Disertori M on the behalf of the ...GISSI‐AF Investigators (Istituto di Ricerche Farmacologiche “Mario Negri”, Milan; Istituti Ospitalieri, Cremona; POL Madonna della Consolazione, Reggio Calabria; Ospedale Nuovo Girolimo Fracastoro, San Bonifacio; Ospedale Garibaldi‐Nesima, Catania; Ospedale Luigi Sacco, Milan, Italy; Roche Diagnostics, Rotkreuz, Switzerland; B.R.A.H.M.S. AG, Henningsdorf, Germany; ANMCO Research Center, Florence; and Ospedale Santa Chiara, Trento, Italy). Circulating cardiovascular biomarkers in recurrent atrial fibrillation: data from the GISSI‐Atrial Fibrillation Trial. J Intern Med 2011; 269: 160–171.
Objective. We evaluated the prognostic role of circulating cardiovascular biomarkers in patients with a history of recent atrial fibrillation (AF).
Background. Predicting long‐term maintenance of sinus rhythm in patients with AF is difficult.
Methods. Plasma concentrations of three specific cardiac markers high‐sensitivity troponin T (hsTnT), N‐terminal probrain natriuretic peptide (NT‐proBNP) and mid‐regional proatrial natriuretic peptide (MR‐proANP) and three stable fragments of vasoactive peptides mid‐regional proadrenomedullin (MR‐proADM), copeptin (CT‐proAVP) and CT‐proendothelin‐1 (CT‐proET‐1) were measured at baseline and after 6 and 12 months in 382 patients enrolled in the GISSI‐AF study, a prospective randomized trial to determine the effect of valsartan to reduce the recurrence of AF. The association between these markers, clinical characteristics and recurrence of AF was tested by univariate and multivariate Cox models.
Results. Mean patient age was 68 ± 9 years (37.2% females). A total of 84.8% of patients had a history of hypertension. In total, 59.7% qualified for history of AF because of successful cardioversion, 11.8% because of two or more episodes of AF in the 6 months preceding randomization and 28.5% because of both. Patients in AF at 6 or 12 months (203 (53.1%) with first recurrence) had significantly higher concentrations of most biomarkers. Despite low baseline levels, higher concentrations of hsTnT {adjusted hazard ratio (HR) 95% confidence intervals (CIs) for 1 SD increment (1.15 1.04–1.28, P = 0.007), MR‐proANP (1.15 1.01–1.30, P = 0.04), NT‐proBNP (1.24 1.11–1.39, P = 0.0001) and CT‐proET‐1 (1.16 1.01–1.33, P = 0.03) independently predicted higher risk of a first recurrence of AF. Changes over time of MR‐proANP tended to predict subsequent recurrence (adjusted HR 95%CI) (1.53 0.98–2.37, P = 0.06).
Conclusion. Circulating markers of cardiomyocyte injury/strain and endothelin are related to recurrence of AF in patients in sinus rhythm with a history of recent AF.
•Incretin-based drugs have been suggested to increase the risk of hospitalization for heart failure in clinical trials.•Incretin-based drugs are not associated with an increased risk of ...hospitalization for HF in real-world data from Italy.•These data support the cardiovascular safety of incretin-based drugs in the clinical practice.
There are concerns that incretin-based antidiabetic drugs – including dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists – increase the risk of hospitalization for heart failure (HF). To further analyse this issue, we conducted a nested case-control study within a cohort of antidiabetic users in a real world setting.
Within a cohort of 133,639 subjects with a first prescription of an antidiabetic drug (new-users) between 2010 and 2016 in Lombardy, Italy, and were followed-up to 2016, we identified 4057 subjects with a first hospitalization for HF and 80,450 controls matched on sex, age, and date of cohort-entry.
The multivariate odds ratios (ORs) of HF in relation to current use of incretin-based drugs as compared to current use of two or more oral antidiabetics was 1.06 (95% confidence interval, CI, 0.83–1.35), with no evidence of a trend in risk with increasing duration of use. The corresponding ORs were 1.10 (95% CI 0.85–1.41) for DPP-4 inhibitors and 0.84 (95% CI 0.48–1.47) for GLP-1 receptor agonists. Estimates were consistent in various sensitivity analyses.
This study indicates that incretin-based drugs are not associated with an increased risk of hospitalization for HF, thus providing further reassurance on the cardiovascular safety of these antidiabetic drugs in the clinical practice.
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.
Diabetes and oxidative stress concur to cardiac myocyte death in various experimental settings. We assessed whether
N-acetyl-
l-cysteine (NAC), an antioxidant and glutathione precursor, has a ...protective role in a rat model of streptozotocin (STZ)-induced diabetes and in isolated myocytes exposed to high glucose (HG). Diabetic rats were treated with NAC (0.5 g/kg per day) or vehicle for 3 months. At sacrifice left ventricle (LV) myocyte number and size, collagen deposition and reactive oxygen species (ROS) were measured by quantitative histological methods. Diabetes reduced LV myocyte number by 29% and increased myocyte volume by 20% compared to non-diabetic controls. NAC protected from myocyte loss (+25% vs. untreated diabetics,
P < 0.05) and reduced reactive hypertrophy (–16% vs. untreated diabetics,
P < 0.05). Perivascular fibrosis was high in diabetic rats (+88% vs. control,
P < 0.001) but prevented by NAC. ROS production and fraction of ROS-positive cardiomyocyte nuclei were drastically raised in diabetic rats (2.4- and 5.1-fold vs. control,
P < 0.001) and normalized by NAC. In separate experiments, isolated adult rat ventricular myocytes were incubated in a medium containing high concentrations of glucose (HG, 25 mM) ± 0.01 mM NAC; myocyte survival (Trypan blue exclusion and apoptosis by TUNEL) and glutathione content were evaluated. The number of dead and apoptotic myocytes increased five and 6.7-fold in HG and glutathione decreased by 48% (
P < 0.05). NAC normalized cell death and apoptosis and prevented glutathione loss. NAC effectively protects from hyperglycemia-induced myocyte cell death and compensatory hypertrophy through direct scavenging of ROS and replenishment of the intracellular glutathione content.
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.
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 μg/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 μg/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. (Am Heart J 1999;138:247-53.)
Aims
Up to one‐third of patients with diabetes mellitus and heart failure (HF) are treated with insulin. As insulin causes sodium retention and hypoglycaemia, its use might be associated with worse ...outcomes.
Methods and results
We examined two datasets: 24 012 patients with HF from four large randomized trials and an administrative database of 4 million individuals, 103 857 of whom with HF. In the former, survival was examined using Cox proportional hazards models adjusted for baseline variables and separately for propensity scores. Fine–Gray competing risk regression models were used to assess the risk of hospitalization for HF. For the latter, a case–control nested within a population‐based cohort study was conducted with propensity score. Prevalence of diabetes mellitus at study entry ranged from 25.5% to 29.5% across trials. Insulin alone or in combination with oral hypoglycaemic drugs was prescribed at randomization to 24.4% to 34.5% of the patients with diabetes. The rates of death from any cause and hospitalization for HF were higher in patients with vs. without diabetes, and highest of all in patients prescribed insulin propensity score pooled hazard ratio for all‐cause mortality 1.27 (1.16–1.38), for HF hospitalization 1.23 (1.13–1.33). In the administrative registry, insulin prescription was associated with a higher risk of all‐cause death odds ratio (OR) 2.02, 95% confidence interval (CI) 1.87–2.19 and rehospitalization for HF (OR 1.42, 95% CI 1.32–1.53).
Conclusions
Whether insulin use is associated with poor outcomes in HF should be investigated further with controlled trials, as should the possibility that there may be safer alternative glucose‐lowering treatments for patients with HF and type 2 diabetes mellitus.
Troponin changes over time have been suggested to allow for an early diagnosis of cardiac injury ensuing cancer chemotherapy; cancer patients with troponin elevation may benefit of therapy with ...enalapril. It is unknown whether a preventive treatment with enalapril may further increase the benefit.
The International CardioOncology Society-one trial (ICOS-ONE) was a controlled, open-label trial conducted in 21 Italian hospitals. Patients were randomly assigned to two strategies: enalapril in all patients started before chemotherapy (CT; ‘prevention’ arm), and enalapril started only in patients with an increase in troponin during or after CT (‘troponin-triggered’ arm). Troponin was assayed locally in 2596 blood samples, before and after each anthracycline-containing CT cycle and at each study visit; electrocardiogram and echocardiogram were done at baseline, and at 1, 3, 6 and 12-month follow-up. Primary outcome was the incidence of troponin elevation above the threshold.
Of the 273 patients, 88% were women, mean age 51 ± 12 years. The majority (76%) had breast cancer, 3% had a history of hypertension and 4% were diabetic. Epirubicin and doxorubicin were most commonly prescribed, with median cumulative doses of 360 270–360 and 240 240–240 mg/m2, respectively. The incidence of troponin elevation was 23% in the prevention and 26% in the troponin-triggered group (p = 0.50). Three patients (1.1%) -two in the prevention, one in the troponin-triggered group-developed cardiotoxicity, defined as 10% point reduction of LV ejection fraction, with values lower than 50%.
Low cumulative doses of anthracyclines in adult patients with low cardiovascular risk can raise troponins, without differences between the two strategies of giving enalapril. Considering a benefit of enalapril in the prevention of LV dysfunction, a troponin-triggered strategy may be more convenient.
•No differences were observed between preventiveor troponin-triggered enalapril-based.•1-year incidence of cardiovascular events was very low in patients without heart disease and low doses of anthracyclines.•Considering a benefit of enalapril in theprevention of LV dysfunction, a troponin-triggered strategy may be more convenient.
Aims
Insulin causes sodium retention and hypoglycaemia and its use is associated with worse outcomes in heart failure (HF) with reduced ejection fraction. We have investigated whether this is also ...the case in HF with preserved ejection fraction (HFpEF).
Methods and results
We examined the association between diabetes/diabetes treatments and the risk of the primary composite of cardiovascular death or HF hospitalization, as well as other outcomes in adjusted analyses in CHARM‐Preserved (left ventricular ejection fraction ≥ 45%), I‐Preserve and TOPCAT (Americas) pooled. Of 8466 patients, 2653 (31%) had diabetes, including 979 (37%) receiving insulin. Patients receiving insulin were younger, had a higher body mass index, prevalence of ischaemic aetiology, N‐terminal pro‐B‐type natriuretic peptide and use of diuretics, worse New York Heart Association class and signs and symptoms, and worse quality of life and renal function, compared to patients with diabetes not on insulin. Among the 1398 patients with echocardiographic data, insulin use was associated with higher left ventricular end‐diastolic pressure and more diastolic dysfunction than in other participants. The primary outcome occurred at a rate of 6.3 per 100 patient‐years in patients without diabetes, and 10.2 and 17.1 per 100 patient‐years in diabetes patients without and with insulin use, respectively fully adjusted hazard ratio (aHR) insulin‐treated diabetes vs. other diabetes: 1.41, 95% confidence interval (CI) 1.23–1.63, P < 0.001. The adjusted HR is 1.67 (95% CI 1.20–2.32, p = 0.002) for sudden death (insulin‐treated diabetes vs. other diabetes).
Conclusions
Insulin use is associated with poor outcomes in HFpEF. Although we cannot conclude a causal association, the safety of insulin and alternative glucose‐lowering treatments in HF needs to be evaluated in clinical trials.
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