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The level to which systolic blood pressure should be controlled in hypertensive patients without diabetes remains unknown. We tested the hypothesis that tight control compared with usual control of systolic blood pressure would be beneficial in such patients. In this randomised open-label trial undertaken in 44 centres in Italy, 1111 non-diabetic patients with systolic blood pressure 150 mm Hg or greater were randomly assigned to a target systolic blood pressure of less than 140 mm Hg (usual control; n=553) or less than 130 mm Hg (tight control; n=558). After stratification by centre, we used a computerised random function to allocate patients to either group. Observers who were unaware of randomisation read electrocardiograms and adjudicated events. Open-label agents were used to reach the randomised targets. The primary endpoint was the rate of electrocardiographic left ventricular hypertrophy 2 years after randomisation. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00421863. Over a median follow-up of 2·0 years (IQR 1·93–2·03), systolic and diastolic blood pressure were reduced by a mean of 23·5/8·9 mm Hg (SD 10·6/7·0) in the usual-control group and by 27·3/10·4 mm Hg (11·0/7·5) in the tight-control group (between-group difference 3·8 mm Hg systolic [95% CI 2·4–5·2], p<0·0001; and 1·5 mm Hg diastolic [0·6–2·4]; p=0·041). The primary endpoint occurred in 82 of 483 patients (17·0%) in the usual-control group and in 55 of 484 patients (11·4%) of the tight-control group (odds ratio 0·63; 95% CI 0·43–0·91; p=0·013). A composite cardiovascular endpoint occurred in 52 (9·4%) patients in the usual-control group and in 27 (4·8%) in the tight-control group (hazard ratio 0·50, 95% CI 0·31–0·79; p=0·003). Side-effects were rare and did not differ significantly between the two groups. Our findings lend support to a lower blood pressure goal than is recommended at present in non-diabetic patients with hypertension. Boehringer-Ingelheim, Sanofi-Aventis, Pfizer.

Prior small studies have shown multiple benefits of frequent nocturnal hemodialysis compared to conventional three times per week treatments. To study this further, we randomized 87 patients to three times per week conventional hemodialysis or to nocturnal hemodialysis six times per week, all with single-use high-flux dialyzers. The 45 patients in the frequent nocturnal arm had a 1.82-fold higher mean weekly stdKt/Vurea, a 1.74-fold higher average number of treatments per week, and a 2.45-fold higher average weekly treatment time than the 42 patients in the conventional arm. We did not find a significant effect of nocturnal hemodialysis for either of the two coprimary outcomes (death or left ventricular mass (measured by MRI) with a hazard ratio of 0.68, or of death or RAND Physical Health Composite with a hazard ratio of 0.91). Possible explanations for the left ventricular mass result include limited sample size and patient characteristics. Secondary outcomes included cognitive performance, self-reported depression, laboratory markers of nutrition, mineral metabolism and anemia, blood pressure and rates of hospitalization, and vascular access interventions. Patients in the nocturnal arm had improved control of hyperphosphatemia and hypertension, but no significant benefit among the other main secondary outcomes. There was a trend for increased vascular access events in the nocturnal arm. Thus, we were unable to demonstrate a definitive benefit of more frequent nocturnal hemodialysis for either coprimary outcome.

The optimal timing of aortic valve replacement in asymptomatic patients with aortic stenosis is uncertain. Replacement fibrosis, as assessed by midwall (nonischemic) late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging, is an irreversible marker of left ventricular decompensation in aortic stenosis. Once established, it progresses rapidly and is associated with poor long-term prognosis in a dose-dependent manner. The objective of this multicenter prospective randomized controlled trial is to determine whether early aortic valve replacement in asymptomatic patients with severe aortic stenosis can improve the adverse prognosis associated with midwall LGE. Patients will be screened for likelihood of having LGE with electrocardiography or high-sensitivity troponin I. Those at high risk will proceed to CMR imaging. Approximately 400 patients with midwall LGE will be randomized 1:1 to early valve replacement or routine care. Those who do not exhibit midwall LGE will continue with routine care and be randomized to a study registry or no further follow-up. Follow-up will be annual for approximately 3 years until the number of required outcome events is achieved. The primary endpoint is a composite of all-cause mortality and unplanned aortic stenosis–related hospitalization. The expected event rate is 25.0% in the routine care arm and 13.4% in the early intervention arm over the first 2 years; 88 observed primary outcome events will give 90% power at 5% significance level. Key secondary endpoints include all-cause mortality, sudden cardiac death, stroke, and symptomatic status. The EVOLVED trial is the first multicenter randomized controlled trial to compare early aortic valve replacement to routine care in asymptomatic patients with severe aortic stenosis and midwall LGE.

•High intensity and long duration aerobic exercise training increases the risk for left atrial enlargement, an important risk factor for the development of atrial fibrillation.•The effects of chronic aerobic exercise upon left atrial size are amplified in patients with left ventricular hypertrophy and increased LV stiffness.•The effects of these changes on atrial electromechanical properties and atrial fibrosis need further investigation.•Further work is also needed to understand long term effects of habitual aerobic exercise and risk for atrial fibrillation in patients with left ventricular hypertrophy. Habitual aerobic exercise is associated with left atrial (LA) enlargement which may increase risk of atrial fibrillation. Patients with LVH and increased LV stiffness may be more predisposed to LA remodeling due to higher LA pressures during exercise. We tested the hypothesis 1 year of aerobic exercise training would increase LA size to a greater extent in patients with LVH than controls. Adults with LVH (n = 53) enriched for increased cardiac risk and LV stiffness and control (CON) subjects (n = 58) were randomized to 1 year of high intensity aerobic exercise (ex) or yoga control. LA and LV volumes were measured using 3D echo. Of 111 participants, 83 had complete data available (LVH: 18 exercisers, 10 yoga; CON: 29 exercisers, 26 yoga). Baseline LA volume indices were similar between groups (LVH: 19.8 ± 4.4 mL/m2 vs CON: 18.8 ± 4.1 mL/m2; p = 0.33). After 1 year, the effects of exercise (p = 0.003) and LVH (p = 0.001) were each associated with increased LA volume index. More subjects in the LVH/exercise group (33.3%) increased LA size >5 mL/m2 and LA/LV volume ratios >0.1 compared to the other groups (10% LVH/yoga, 3.4% CON/ex, 3.8% CON/yoga; Chi square p = 0.006). In conclusion, 1 year of aerobic training resulted in higher LA volumes in subjects with LVH and LV stiffness compared to healthy subjects. The increase in LA size was greater than changes in LV size suggesting chronic aerobic training in may preferentially affect LA remodeling in subjects with LVH and LV stiffness.

Migalastat stabilizes mutant α-galactosidase in Fabry's disease, reducing globotriaosylceramide deposition. In this study, the percentage of patients with a decrease of 50% or more in kidney interstitial capillary deposition at 6 months was similar in the migalastat and placebo groups. Fabry’s disease is a rare, progressive, and devastating X-linked disorder caused by the functional deficiency of lysosomal α-galactosidase. 1 The resultant accumulation of glycosphingolipids, predominantly globotriaosylceramide (GL-3), can lead to multisystem disease and early death. 2 Binding of the pharmacologic chaperone migalastat to the active site of α-galactosidase stabilizes certain mutant enzymes, thus facilitating proper trafficking to lysosomes, where dissociation of migalastat allows α-galactosidase to catabolize accumulated substrates. 3 – 7 In patients with mutant enzymes that are identified with the validated assay, orally administered migalastat may be an alternative treatment option for addressing certain unmet medical needs associated with enzyme-replacement therapy — for . . .

Aims Left ventricular hypertrophy (LVH) has been associated with an increased risk of cardiovascular (CV) disease and linked to increased morbidity and mortality. In patients with chronic kidney disease (CKD) and type 2 diabetes (T2D), hypertension is common, and patients with these co‐morbidities additionally have a high prevalence of LVH. This analysis of the prespecified pooled FIDELITY analysis comprising the randomized, double‐blind, placebo‐controlled, multicentre FIDELIO‐DKD and FIGARO‐DKD phase III studies aimed to explore the CV and kidney effects of finerenone, a nonsteroidal mineralocorticoid receptor antagonist, in patients with CKD and T2D stratified by a diagnosis of LVH at baseline. Methods and results A diagnosis of LVH in the FIDELITY patient population was determined at baseline using investigator‐reported electrocardiogram (ECG) findings. The two efficacy outcomes, assessed by baseline LVH, were the composite CV outcome of time to CV death, non‐fatal myocardial infarction, non‐fatal stroke, or hospitalization for heart failure (HHF), and a composite kidney outcome of time to onset of kidney failure, a sustained decrease in estimated glomerular filtration rate (eGFR) ≥57% from baseline over ≥4 weeks, or kidney‐related death. Safety outcomes by baseline LVH were reported as treatment‐emergent adverse events. At baseline out of 13 026 patients in FIDELITY, 96.5% had hypertension and 9.6% had investigator‐reported LVH. The relative risk reduction for the composite CV and kidney outcomes with finerenone versus placebo was lower in the LVH subgroup; however, the treatment effect of finerenone was not modified by baseline LVH for either outcome (Pinteraction = 0.1075 for composite CV outcome and Pinteraction = 0.1782 for composite kidney outcome). Analysis of the composite CV outcome components showed a greater reduction in the risk of HHF versus placebo for patients with baseline LVH compared with those without (Pinteraction = 0.0024). Overall safety events were comparable between the LVH subgroups and treatment arms. Treatment‐emergent hyperkalaemia was observed more frequently with finerenone versus placebo, but discontinuation rates were low in both treatment arms and between LVH subgroups. Conclusions In conclusion, the overall CV and kidney benefits of finerenone versus placebo were not modified by the presence of LVH at baseline, with overall safety findings being similar between LVH subgroups. A greater benefit was observed for HHF in patients with versus without LVH, suggesting that LVH may be a predictor of the treatment effect of finerenone on HHF.

Background and Aims Sodium-glucose co-transporter 2 (SGLT2) inhibitors have beneficial effects in heart failure (HF), including reverse remodelling, but the mechanisms by which these benefits are conferred are unclear. Inflammation is implicated in the pathophysiology of heart failure (HF) and there are some pre-clinical data suggesting that SGLT2 inhibitors may reduce inflammation. There is however a lack of clinical data. The aim of our study was to investigate whether improvements in cardiac remodelling caused by dapagliflozin in individuals with type 2 diabetes (T2D) and left ventricular hypertrophy (LVH) were associated with its effects on inflammation. Methods We measured C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), interleukin 6 (IL-6), and interleukin 10 (IL-10) and neutrophil-to-lymphocyte ratio (NLR) in plasma samples of 60 patients with T2D and left ventricular hypertrophy (LVH) but without symptomatic HF from the DAPA-LVH trial in which participants were randomised dapagliflozin 10 mg daily or placebo for 12 months and underwent cardiac magnetic resonance imaging (CMR) at baseline and end of treatment. The primary analysis was to investigate the effect of dapagliflozin on inflammation and to assess the relationships between changes in inflammatory markers and LV mass and global longitudinal strain (GLS) and whether the effect of dapagliflozin on LV mass and GLS was modulated by baseline levels of inflammation. Results Following 12 months of treatment dapagliflozin significantly reduced CRP compared to placebo (mean difference of -1.96; 95% CI -3.68 to -0.24, p  = 0.026). There were no significant statistical changes in other inflammatory markers. There were modest correlations between improvements in GLS and reduced inflammation (NLR ( r  = 0.311), IL-1β ( r  = 0.246), TNF-α ( r  = 0.230)) at 12 months. Conclusions Dapagliflozin caused a significant reduction in CRP compared to placebo. There were correlations between reductions in inflammatory markers including IL-1β and improvements in global longitudinal strain (but not reduced LV mass). Reductions in systemic inflammation might play a contributory role in the cardiovascular benefits of dapagliflozin. Trial registration Clinicaltrials.gov NCT02956811 (06/11/2016).

Background Cardiovascular magnetic resonance (CMR) is part of the diagnostic work-up for cardiac amyloidosis (CA). Deep learning (DL) is an application of artificial intelligence that may allow to automatically analyze CMR findings and establish the likelihood of CA. Methods 1.5 T CMR was performed in 206 subjects with suspected CA (n = 100, 49% with unexplained left ventricular (LV) hypertrophy; n = 106, 51% with blood dyscrasia and suspected light-chain amyloidosis). Patients were randomly assigned to the training (n = 134, 65%), validation (n = 30, 15%), and testing subgroups (n = 42, 20%). Short axis, 2-chamber, 4-chamber late gadolinium enhancement (LGE) images were evaluated by 3 networks (DL algorithms). The tags “amyloidosis present” or “absent” were attributed when the average probability of CA from the 3 networks was ≥ 50% or < 50%, respectively. The DL strategy was compared to a machine learning (ML) algorithm considering all manually extracted features (LV volumes, mass and function, LGE pattern, early blood-pool darkening, pericardial and pleural effusion, etc.), to reproduce exam reading by an experienced operator. Results The DL strategy displayed good diagnostic accuracy (88%), with an area under the curve (AUC) of 0.982. The precision (positive predictive value), recall score (sensitivity), and F1 score (a measure of test accuracy) were 83%, 95%, and 89% respectively. A ML algorithm considering all CMR features had a similar diagnostic yield to DL strategy (AUC 0.952 vs. 0.982; p = 0.39). Conclusions A DL approach evaluating LGE acquisitions displayed a similar diagnostic performance for CA to a ML-based approach, which simulates CMR reading by experienced operators.

AimsHypertrophic cardiomyopathy (HCM) is characterised by left ventricular hypertrophy (LVH), myocardial fibrosis, enhanced oxidative stress and energy depletion. Unbound/loosely bound tissue copper II ions are powerful catalysts of oxidative stress and inhibitors of antioxidants. Trientine is a highly selective copper II chelator. In preclinical and clinical studies in diabetes, trientine is associated with reduced LVH and fibrosis, and improved mitochondrial function and energy metabolism. Trientine was associated with improvements in cardiac structure and function in an open-label study in patients with HCM.MethodsThe Efficacy and Mechanism of Trientine in Patients with Hypertrophic Cardiomyopathy (TEMPEST) trial is a multicentre, double-blind, parallel group, 1:1 randomised, placebo-controlled phase II trial designed to evaluate the efficacy and mechanism of action of trientine in patients with HCM. Patients with a diagnosis of HCM according to the European Society of Cardiology Guidelines and in New York Heart Association classes I–III are randomised to trientine or matching placebo for 52 weeks. Primary outcome is change in left ventricular (LV) mass indexed to body surface area, measured using cardiovascular magnetic resonance. Secondary efficacy objectives will determine whether trientine improves exercise capacity, reduces arrhythmia burden, reduces cardiomyocyte injury, improves LV and atrial function, and reduces LV outflow tract gradient. Mechanistic objectives will determine whether the effects are mediated by cellular or extracellular mass regression and improved myocardial energetics.ConclusionTEMPEST will determine the efficacy and mechanism of action of trientine in patients with HCM.Trial registration numbersNCT04706429 and ISRCTN57145331.

Childhood obesity continues to escalate worldwide and may affect left ventricular (LV) geometry and function. The aim of this study was to investigate the impact of obesity on prevalence of left ventricular hypertrophy (LVH) and diastolic dysfunction in children. In this analysis of prospectively collected cross-sectional data of children between 5 and 16 years of age from randomly selected schools in Peru, parameters of LV geometry and function were compared according to presence or absence of obesity (body mass index z-score > 2). LVH was based on left ventricular mass index (LVMI) adjusted for age and sex and defined by a z-score of > 2. LV diastolic function was assessed using mitral inflow early-to-late diastolic flow (E/A) ratio, peak early diastolic tissue velocities of the lateral mitral annulus (E′), early diastolic transmitral flow velocity to tissue Doppler mitral annular early diastolic velocity (E/E′) ratio, and left atrial volume index (LAVI). Among 1023 children, 681 children (mean age 12.2 ± 3.1 years, 341 male (50.1%)) were available for the present analysis, of which 150 (22.0%) were obese. LVH was found in 21 (14.0%) obese and in 19 (3.6%) non-obese children (p adjusted  < 0.001). LVMI was greater in obese than that in non-obese children (36.1 ± 8.6 versus 28.7 ± 6.9 g/m 2.7 , p < 0.001). The mean mitral E/E′ ratio and LAVI were significantly higher in obese than those in non-obese individuals (E/E′: 5.2 ± 1.1 versus 4.9 ± 0.8, p adjusted  = 0.043; LAVI 11.0 ± 3.2 versus 9.6 ± 2.9, p adjusted  = 0.001), whereas E′ and E/A ratio were comparable. Childhood obesity was associated with left ventricular hypertrophy and determinants of diastolic dysfunction. ClinicalTrials.gov Identifier: NCT02353663.