Although active-controlled trials with renin–angiotensin inhibitors are ethically mandated in heart failure with reduced ejection fraction, clinicians and regulators often want to know how the ...experimental therapy would perform compared with placebo. The angiotensin receptor-neprilysin inhibitor LCZ696 was compared with enalapril in PARADIGM-HF. We made indirect comparisons of the effects of LCZ696 with putative placebos.
We used the treatment-arm of the Studies Of Left Ventricular Dysfunction (SOLVD-T) as the reference trial for comparison of an ACE inhibitor to placebo and the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity-Alternative trial (CHARM-Alternative) as the reference trial for comparison of an ARB to placebo. The hazard ratio of LCZ696 vs. a putative placebo was estimated through the product of the hazard ratio of LCZ696 vs. enalapril (active-control) and that of the historical active-control (enalapril or candesartan) vs. placebo. For the primary composite outcome of cardiovascular death or heart failure hospitalization in PARADIGM-HF, the relative risk reduction with LCZ696 vs. a putative placebo from SOLVD-T was 43% (95%CI 34–50%; P < 0.0001) with similarly large effects on cardiovascular death (34%, 21–44%; P < 0.0001) and heart failure hospitalization (49%, 39–58%; P < 0.0001). For all-cause mortality, the reduction compared with a putative placebo was 28% (95%CI 15–39%; P < 0.0001). Putative placebo analyses based on CHARM-Alternative gave relative risk reductions of 39% (95%CI 27–48%; P < 0.0001) for the composite outcome of cardiovascular death or heart failure hospitalization, 32% (95%CI 16–45%; P < 0.0001) for cardiovascular death, 46% (33–56%; P < 0.0001) for heart failure hospitalization, and 26% (95%CI 11–39%; P < 0.0001) for all-cause mortality.
These indirect comparisons of LCZ696 with a putative placebo show that the strategy of combined angiotensin receptor blockade and neprilysin inhibition led to striking reductions in cardiovascular and all-cause mortality, as well as heart failure hospitalization. These benefits were obtained even though LCZ696 was added to comprehensive background beta-blocker and mineralocorticoid receptor antagonist therapy.
Transplantation (Tx) of skeletal myoblasts (SM) within an infarcted myocardium improves global left ventricular (LV) function, although a direct systolic effect remains controversial.
Global and ...regional LV functions were studied in a sheep model (n=16) of infarction before (baseline), and 4 (M4), and 12 (M12) months after in-scar injections of autologous SM or culture medium (CM). LV end-diastolic volume (EDV), ejection fraction (EF), wall motion score (WMS), and systolic myocardial velocity gradient (MVG) across the scar were measured by echocardiography with tissue Doppler imaging. Parameters were similar at baseline between groups. At M4, Tx of SM reduced the postinfarction increase in EDV (72+/-8 versus 105+/-13 mL in the CM group, P<0.05) and the decrease in EF (48+/-5 versus 33+/-3% in the CM group, P=0.006) although it improved WMS (5.4+/-1.2 versus 13+/-2.2 in the CM group, P<0.01) and SMVG (0.60+/-0.13 versus -0.04+/-.13 seconds(-1) in the CM group, P<0.05). Results were similar at M12. In-scar accumulation of myotubes and SM were detected in all Tx animals up to M12, with co-expression of fast and slow isoforms of the myosin heavy chain (MHC) (30% of the fibers versus 0% in the normal skeletal muscle) and decreased collagen density (30+/-2% versus 73+/-3%, P<0.0001).
For up to 1 year, Tx of SM limits postinfarction EF deterioration and improves systolic scar function through colonization of fibrosis by skeletal muscle cells with expression of both MHC isoforms, which may confer to the graft the ability to withstand a cardiac-type workload.
Rheumatic heart disease (RHD) remains a major public health problem worldwide. Although early diagnosis by echocardiography may potentially play a key role in developing active surveillance, ...systematic evaluation of simple approaches in resource poor settings are needed.
We prospectively compared focused cardiac ultrasound (FCU) to a reference approach for RHD screening in a school children population. FCU included (1) the use of a pocket-sized echocardiography machine, (2) nonexpert staff (2 nurses with specific training), and (3) a simplified set of echocardiographic criteria. The reference approach used standardized echocardiographic examination, reviewed by an expert cardiologist, according to 2012 World Heart Federation criteria. Among the 6 different echocardiographic criteria, first tested in a preliminary phase, mitral regurgitation jet length≥2 cm or any aortic regurgitation was considered best suited to be FCU criteria. Of the 1217 subjects enrolled (mean, 9.6±1 years; 49.6% male), 49 (4%) were diagnosed with RHD by the reference approach. The sensitivity of FCU for the detection of RHD was 83.7% (95% confidence interval, 73.3-94.0) for nurse A and 77.6% (95% confidence interval, 65.9-89.2) for nurse B. FCU yielded a specificity of 90.9% (95% confidence interval, 89.3-92.6) and 92.0% (95% confidence interval, 90.4-93.5) according to users. Percentage of agreement among nurses was 91.4%.
FCU by nonexperts using pocket devices seems feasible and yields acceptable sensitivity and specificity for RHD detection when compared with the state-of-the-art approach, thereby opening new perspectives for mass screening for RHD in low-resource settings.
Few studies have assessed the effects of cell therapy in non-ischaemic cardiomyopathies which, however, contribute to a large number of cardiac failures. Assuming that such conditions are best suited ...for a global delivery of cells, we assessed the effects of epicardially delivered adipose tissue-derived stroma cell (ADSC) sheets in a mouse model of dilated cardiomyopathy based on cardiac-specific and tamoxifen-inducible invalidation of serum response factor.
Three weeks after tamoxifen administration, the function of the left ventricle (LV) was assessed by echocardiography. Twenty-nine mice were then allocated to control (n = 9, non-transgenic), sham (n = 10, transgenic non-treated), and treated (n = 10, transgenic) groups. In the treated group, 3 × 10(6) allogeneic ADSCs were cultured for 2 days onto temperature-responsive polymers and the generated sheets were then transplanted over the surface of the heart. In 10 additional mice, the sheet was made of green fluorescent protein (GFP)-labelled ADSCs to track cell fate. Function, engraftment, and fibrosis were blindly assessed after 3 weeks. In the non-treated group, fractional shortening declined compared with baseline, whereas the sheet application resulted in its stabilization. This correlated with a lesser degree of LV remodelling, as LV end-diastolic and end-systolic diameters did not differ from baseline values. Many GFP(+) cells were identified in the epicardial graft and in the myocardium. Treated animals also displayed a reduced expression of the stress-induced atrial natriuretic factor and beta-myosin heavy chain genes. These protective effects were also accompanied by a reduction of myocardial fibrosis.
These results strongly suggest the functional relevance of epicardially delivered cell-seeded biomaterials to non-ischaemic heart failure.
Summary Background Routine management of hypertensive adults is based on assessment of risk factors for coronary artery disease; risk factors for heart failure (HF) remain poorly investigated despite ...the key role of hypertension in HF development. Aim To assess the components of HF risk in hypertensive adults in primary care, compare physicians’ estimations of HF and global cardiovascular risks with established calculation algorithms, and assess the concordance of these algorithms. Methods O-PREDICT was a transverse, observational, multicentre French survey conducted in 2006 among general practitioners who included the first hypertensive, non-HF patient seen in each of three age classes (< 60, 60–70, > 70 years). Estimations of HF and global cardiovascular risks (at 4 and 10 years, respectively) were performed subjectively during the consultation and calculated a posteriori according to algorithms from the Framingham cohort and the European SCORE database, respectively. For each of these methods, patients were stratified into four risk categories (i.e., no, low, moderate, high). Results One thousand five hundred and thirty seven physicians recruited 4523 patients (61% men; 64.5 ± 10.9 years; systolic blood pressure 149.9 ± 15.4 mmHg); most (67.2%) patients had one or two cardiovascular/HF risk factors (dyslipidaemia 48.8%, left ventricular hypertrophy 25.3%, diabetes 18.8%, coronary artery disease 8.8%, valvulopathy 6.1%); the number increased with advancing age and in men versus women. According to the Framingham algorithm, the risk of HF (mean 5.4 ± 8.5%; 13.4% of patients at high risk) increased with advancing age ( p < 0.001), nearly doubling for each decade increase. According to the European SCORE system, global cardiovascular risk (mean 5.4 ± 4.3%) was moderate or elevated in 48.1% of patients. Concordance between physicians’ estimations and theoretical calculations for HF and global risks was poor, as was concordance between algorithms ( κ w = 0.28, 0.12, 0.11, respectively). Conclusion More than one in 10 hypertensive patients seen in primary care is at high risk of HF at 4 years according to the Framingham model; this algorithm appears to offer additional information to that provided by the SCORE system. Physicians’ estimations of risks correlated poorly with algorithm calculations, suggesting that the use of these tools in general practice should be encouraged.
Beneficial hemodynamic effects after dynamic cardiomyoplasty have been inconsistently demonstrated, and the effects seen may be due to the wrap itself, to flap stimulation, or both. The aim of this ...study was to determine whether flap stimulation per se acts as a systolic active process after cardiomyoplasty.
Catheterizations were performed in 13 patients 14.4 +/- 7 months after cardiomyoplasty. New York Heart Association functional class decreased from 3.3 to 2.1 after the procedure (P = .0005). Hemodynamic evaluations were first performed with the stimulator on in the 2:1 mode and then after the stimulator had been off for at least 24 hours. Left ventricular (LV) ejection fraction increased from 25.1 +/- 6% before surgery to 28.2 +/- 6.7% with the stimulator on after cardiomyoplasty (P = .04). When stimulation was stopped, there was no change (P > .05) in indexes of systolic or diastolic LV function (peak systolic LV pressure, LV ejection fraction, peak positive dP/dt, peak negative dP/dt, or tau). Pulmonary capillary wedge pressure and cardiac index were unchanged when stimulated and nonstimulated settings were compared (P > .05). However, a remarkable heterogeneity of individual responses was observed. Ejection fraction and cardiac index decreased with the stimulator off in 3 patients, but peak positive dP/dt decreased in 6 patients; diastolic function deteriorated in 2 patients, but a slight improvement was noted in 3 patients. Cardiothoracic ratio, echocardiographic LV end-diastolic dimension, and fractional shortening remained unchanged between immediate (< 1 month) and long-term (36.7 +/- 25.9 months) postoperative evaluations.
In the majority of our patients, there was no short-term hemodynamic benefit of flap stimulation; therefore, we conclude that the efficacy of cardiomyoplasty may be a consequence of a passive "girdling effect," which limits the progression of ventricular enlargement and further deterioration of ejection fraction.
La maladie de Fabry est une des causes souvent méconnue d’hypertrophie du ventricule gauche chez les hommes atteints de cardiomyopathie hypertrophique à début tardif. Une revue des études faites dans ...la littérature pour rechercher la prévalence de la maladie de Fabry chez les sujets atteints de cardiomyopathie est présentée. Les femmes hétérozygotes peuvent aussi présenter une hypertrophie myocardique à début Tardif.
Fabry disease has been recognized as a cause of left ventricular hypertrophy in men with late-onset hypertrophic cardiomyopathy. A review of the literature is made to establish the prevalence of Fabry disease in subjects with hypertrophic cardiomyopathy. Although Fabry disease is considered as a recessive X-linked disorder, affected women are reported.
Mitral valve prolapse (MVP) by Barlow disease is recognized a genetic disease. Fibro-elastic deficiency (FED)-MVP is considered a pure degenerative condition. FLNA, the first gene involved in MVP, ...encodes for Filamin-A, a cytoskeleton associated protein. It interacts with a protein named Filgap, encoded by ARHGAP24 (Chr. 4), in the mechanical transduction. We hypothesized that ARHGAP24 mutations could elicit MVP with same pathway.
Four probands with ARHGAP24 mutations were identified among 96 MVP. By a familial echocardiographic screening we enrolled 19 adults of whom 13 had an ARHGAP24 mutation. The mutated group was matched with a control group of 39 healthy adults. Anterior (AML) and posterior (PML) mitral leaflets length and thickness were measured. The coaptation point position was the ratio of coaptation height on the systolic annulus diameter. MVP (displacement>2mm above the annulus line), minimal systolic displacement (MSD, displacement<2mm) and abnormal antero-posterior coaptation position (AAC, ratio<60%) were assessed.
The conjunction of MSD and AAC defines a MVP prodromal form (MVP-prod).
There was no difference between the two groups on baseline characteristics. Leaflets were thin in the mutated group (PML: 2.7±1 vs 2.2±0.5mm in control, P=0.21, AML: 2.5±0.9 vs 2.1±0.4mm, P=0.25), as reported in FEDMVP. Only the PML was elongated (8.2±1.6 vs 6.0±1.2mm/m 2, P=0.0003) in the mutated group, leading to an anterior displacement of the coaptation point (51±11 vs 66±7%, P=0.0003). Abnormal mitral phenotype (70% of MVP, 23% of MVP prod) and mitral regurgitation (93 vs 38%, P=0.0007) were frequent in the mutated group. Two probands were operated for severe MR related to chordal rupture; histological examination confirmed the leaflets thinness.
ARHGAP24 is the first gene for autosomal dominant inherited MVP. Our limited series of patients exhibit typical features of FED-MVP. Our results could change the paradigm of a pure degenerative disease for FED-MVP.
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