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BACKGROUND: Atrial fibrillation (AF) is promoted by various stimuli like angiotensin II, endothelin-1, epinephrine/norepinephrine, vagal activation, or mechanical stress, all of which activate receptors coupled to G-proteins of the Ga(q)/Ga(11)-family (G(q)). Besides pro-fibrotic and pro-inflammatory effects, G(q)-mediated signaling induces inositol trisphosphate receptor (IP(3)R)-mediated intracellular Ca(2+) mobilization related to delayed after-depolarisations and AF. However, direct evidence of arrhythmogenic G(q)-mediated signaling is absent. METHODS AND RESULTS: To define the role of G(q) in AF, transgenic mice with tamoxifen-inducible, cardiomyocyte-specific Ga(q)/Ga(11)-deficiency (G(q)-KO) were created and exposed to intracardiac electrophysiological studies. Baseline electrophysiological properties, including heart rate, sinus node recovery time, and atrial as well as AV nodal effective refractory periods, were comparable in G(q)-KO and control mice. However, inducibility and mean duration of AF episodes were significantly reduced in G(q)-KO mice-both before and after vagal stimulation. To explore underlying mechanisms, left atrial cardiomyocytes were isolated from G(q)-KO and control mice and electrically stimulated to study Ca(2+)-mobilization during excitation-contraction coupling using confocal microscopy. Spontaneous arrhythmogenic Ca(2+) waves and sarcoplasmic reticulum content-corrected Ca(2+) sparks were less frequent in G(q)-KO mice. Interestingly, nuclear but not cytosolic Ca(2+) transient amplitudes were significantly decreased in G(q)-KO mice. CONCLUSION: G(q)-signaling promotes arrhythmogenic atrial Ca(2+)-release and AF in mice. Targeting this pathway, ideally using G(q)-selective, biased receptor ligands, may be a promising approach for the treatment and prevention of AF. Importantly, the atrial-specific expression of the G(q)-effector IP(3)R confers atrial selectivity mitigating the risk of life-threatening ventricular pro-arrhythmic effects.

Aims Although the effect of the angiotensin receptor blocker neprilysin inhibitor (ARNI) sacubitril/valsartan on heart failure (HF) hospitalizations and cardiovascular death has been evaluated, its effects on functional capacity in patients with HF and ejection fraction (EF) >40% has yet to be determined. In addition, no prior studies have compared sacubitril/valsartan with angiotensin‐converting enzyme inhibitor therapy. We sought to compare the effect of ARNI to background‐medication‐based individualized comparators (BMICs) on N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), functional capacity [6 min walk distance (6MWD)], symptoms, and quality of life [Kansas City Cardiomyopathy Questionnaire (KCCQ)] in patients with HF and EF >40% in a randomized clinical trial. Methods PARALLAX is a prospective, randomized, controlled, double‐blind multicentre clinical trial in patients with chronic symptomatic HF with EF >40%, New York Heart Association (NYHA) class II–IV symptoms, elevated natriuretic peptides, and evidence of structural heart disease. Eligible patients are randomized to sacubitril/valsartan vs. BMIC for cardiovascular and related co‐morbidities. BMIC includes (i) enalapril, (ii) valsartan, and (iii) placebo depending on the type of medical therapy prior to enrolment. The primary endpoints are the change in plasma NT‐proBNP concentration from baseline to 12 weeks and the change from baseline in 6MWD distance at 24 weeks. The secondary endpoints assess quality of life and symptom burden. Conclusions PARALLAX will determine if sacubitril/valsartan compared with standard medical therapy for co‐morbidities improves NT‐proBNP levels, exercise capacity, quality of life, and symptom burden in HF patients with EF >40%.

BACKGROUND: Implementation of four-dimensional flow magnetic resonance (4D Flow MR) in clinical routine requires awareness of confounders. PURPOSE: To investigate inter-vendor comparability of 4D Flow MR derived aortic hemodynamic parameters, assess scan-rescan repeatability, and intra- and interobserver reproducibility. STUDY TYPE: Prospective multicenter study. POPULATION: Fifteen healthy volunteers (age 24.5 ± 5.3 years, 8 females). FIELD STRENGTH/SEQUENCE: 3 T, vendor-provided and clinically used 4D Flow MR sequences of each site. ASSESSMENT: Forward flow volume, peak velocity, average, and maximum wall shear stress (WSS) were assessed via nine planes (P1-P9) throughout the thoracic aorta by a single observer (AD, 2 years of experience). Inter-vendor comparability as well as scan-rescan, intra- and interobserver reproducibility were examined. STATISTICAL TESTS: Equivalence was tested setting the 95% confidence interval of intraobserver and scan-rescan difference as the limit of clinical acceptable disagreement. Intraclass correlation coefficient (ICC) and Bland-Altman plots were used for scan-rescan reproducibility and intra- and interobserver agreement. A P-value 0.9: excellent, 0.75-0.9: good). RESULTS: Ten volunteers finished the complete study successfully. 4D flow derived hemodynamic parameters between scanners of three different vendors are not equivalent exceeding the equivalence range. P3-P9 differed significantly between all three scanners for forward flow (59.1 ± 13.1 mL vs. 68.1 ± 12.0 mL vs. 55.4 ± 13.1 mL), maximum WSS (1842.0 ± 190.5 mPa vs. 1969.5 ± 398.7 mPa vs. 1500.6 ± 247.2 mPa), average WSS (1400.0 ± 149.3 mPa vs. 1322.6 ± 211.8 mPa vs. 1142.0 ± 198.5 mPa), and peak velocity between scanners I vs. III (114.7 ± 12.6 cm/s vs. 101.3 ± 15.6 cm/s). Overall, the plane location at the sinotubular junction (P1) presented most inter-vendor stability (forward: 78.5 ± 15.1 mL vs. 80.3 ± 15.4 mL vs. 79.5 ± 19.9 mL [P = 0.368]; peak: 126.4 ± 16.7 cm/s vs. 119.7 ± 13.6 cm/s vs. 111.2 ± 22.6 cm/s [P = 0.097]). Scan-rescan reproducibility and intra- and interobserver variability were good to excellent (ICC ≥ 0.8) with best agreement for forward flow (ICC ≥ 0.98). DATA CONCLUSION: The clinical protocol used at three different sites led to differences in hemodynamic parameters assessed by 4D flow. LEVEL OF EVIDENCE: 2. TECHNICAL EFFICACY STAGE: 2.

Objectives: This study examined the relationship among high-sensitivity troponin-T (hs-TnT), outcomes, and treatment with sacubitril/valsartan in patients with heart failure (HF) and preserved ejection fraction (HFpEF). Background: hs-TnT is a marker of myocardial injury in HF. Methods: The PARAGON-HF trial randomized 4,796 patients with HFpEF to sacubitril/valsartan or valsartan. We compared the risk of the composite outcome of cardiovascular death (CVD) and total HF hospitalization (HHF) according to hs-TnT. We also assessed the effect of allocated treatment on hs-TnT. Results: hs-TnT was available in 1,141 patients (24%) at run-in (median value: 17 ng/L) and 1,260 (26%) at randomization, with 58.3% having hs-TnT >14 ng/L (upper limit of normal). During a median follow-up of 34 months, there were 393 outcome events (82 CVD, 311 HHF). Adjusting for demographics, comorbidities, left ventricular ejection fraction (LVEF), and N-terminal pro B-type natriuretic peptide (NT-proBNP), log-hs-TnT at randomization was an independent predictor of the composite outcome (HR: 1.38; 95% CI: 1.19-1.59; P < 0.001). Compared with valsartan, sacubitril/valsartan significantly reduced hs-TnT by 9% at week 16 (P < 0.001). Patients whose hs-TnT decreased from randomization to 16 weeks to at or below the median value of 17 ng/L subsequently had a lower risk of CVD/HHF compared with those with persistently elevated hs-TnT (P = 0.046). Patients with higher baseline hs-TnT (>17 ng/L) appeared to have a greater benefit from sacubitril/valsartan treatment when accounting for other potential effect modifiers (P interaction = 0.07). Conclusions: Higher baseline hs-TnT was associated with increased risk of CVD/HHF, whereas hs-TnT decrease at 16 weeks led to lower subsequent risk of CVD/HHF compared with those who had persistently elevated values. Sacubitril/valsartan significantly reduced hs-TnT compared with valsartan. hs-TnT may be helpful in identifying patients with HFpEF who are more likely to benefit from sacubitril/valsartan.

Lipids represent a valuable target for metabolomic studies since altered lipid metabolism is known to drive the pathological changes in cardiovascular disease (CVD). Metabolomic technologies give us the ability to measure thousands of metabolites providing us with a metabolic fingerprint of individual patients. Metabolomic studies in humans have supported previous findings into the pathomechanisms of CVD, namely atherosclerosis, apoptosis, inflammation, oxidative stress, and insulin resistance. The most widely studied classes of lipid metabolite biomarkers in CVD are phospholipids, sphingolipids/ceramides, glycolipids, cholesterol esters, fatty acids, and acylcarnitines. Technological advancements have enabled novel strategies to discover individual biomarkers or panels that may aid in the diagnosis and prognosis of CVD, with sphingolipids/ceramides as the most promising class of biomarkers thus far. In this review, application of metabolomic profiling for biomarker discovery to aid in the diagnosis and prognosis of CVD as well as metabolic abnormalities in CVD will be discussed with particular emphasis on lipid metabolites.