Thioredoxin 1 (TRX1) Overexpression Cancels the Slow Force Response (SFR) Development

The stretch of cardiac muscle increases developed force in two phases. The first phase occurs immediately after stretch and is the expression of the Frank–Starling mechanism, while the second one or slow force response (SFR) occurs gradually and is due to an increase in the calcium transient amplitude. An important step in the chain of events leading to the SFR generation is the increased production of reactive oxygen species (ROS) leading to redox sensitive ERK1/2, p90RSK, and NHE1 phosphorylation/activation. Conversely, suppression of ROS production blunts the SFR. The purpose of this study was to explore whether overexpression of the ubiquitously expressed antioxidant molecule thioredoxin-1 (TRX1) affects the SFR development and NHE1 phosphorylation. We did not detect any change in basal phopho-ERK1/2, phopho-p90RSK, and NHE1 expression in mice with TRX1 overexpression compared to wild type (WT). Isolated papillary muscles from WT or TRX1-overexpressing mice were stretched from 92 to 98% of its maximal length. A prominent SFR was observed in WT mice that was completely canceled in TRX1 animals. Interestingly, myocardial stretch induced a significant increase in NHE1 phosphorylation in WT mice that was not detected in TRX1-overexpressing mice. These novel results suggest that magnification of cardiac antioxidant defense power by overexpression of TRX1 precludes NHE1 phosphorylation/activation after stretch, consequently blunting the SFR development.

Cardiac Mineralocorticoid Receptor and the Na+/H+ Exchanger: Spilling the Beans

Current evidence reveals that cardiac mineralocorticoid receptor (MR) activation following myocardial stretch plays an important physiological role in adapting developed force to sudden changes in hemodynamic conditions. Its underlying mechanism involves a previously unknown nongenomic effect of the MR that triggers redox-mediated Na+/H+ exchanger (NHE1) activation, intracellular Na+ accumulation, and a consequent increase in Ca2+ transient amplitude through reverse Na+/Ca2+ exchange. However, clinical evidence assigns a detrimental role to MR activation in the pathogenesis of severe cardiac diseases such as congestive heart failure. This mini review is meant to present and briefly discuss some recent discoveries about locally triggered cardiac MR signals with the objective of shedding some light on its physiological but potentially pathological consequences in the heart.

N-Terminal Pro-B-Type Natriuretic Peptide and Longitudinal Risk of Hypertension

Background Hypertension is a common condition that increases risk for future cardiovascular disease. N-terminal B-type natriuretic peptide (NT-proBNP) is higher in individuals with hypertension, but studies of its association with hypertension risk have been mixed. Methods The REasons for Geographic And Racial Differences in Stroke (REGARDS) study enrolled 30,239 Black or White adults aged ≥45 years from 2003-2007. A subcohort included 4,400 participants who completed a second assessment in 2013-2016. NT-proBNP was measured by immunoassay in 1,323 participants without baseline hypertension, defined as blood pressure ≥140/90 or self-reported antihypertensive prescriptions. Two robust Poisson regression models assessed hypertension risk, yielding incidence rate ratios (IRRs): Model 1 included behavioral & demographic covariates and Model 2 added risk factors. A sensitivity analysis using a less conservative definition of hypertension (blood pressure ≥130/80 or self-reported antihypertensive prescriptions) was conducted. Results 466 participants developed hypertension after mean follow-up of 9.4 years. NT-proBNP was not associated with hypertension (Model 2 IRR per SD log NT-proBNP 1.01, 95% CI 0.92-1.12), with no differences by sex, BMI, age, or race. Similar findings were seen in lower-threshold sensitivity analysis. Conclusions NT-proBNP was not associated with incident hypertension; this did not differ by race or sex. Cross-sectional associations of natriuretic peptides with hypertension are likely due to myocardial stretch due to increased afterload.

P3492Carvedilol and its analogue VK-II-86 attenuate stretch-induced manifestations of mechanoelectric feedback

Background Mechanical stretch modifies Ca2+ handling and myocardial electrophysiology, favoring arrhythmogenesis. The store-overload-induced Ca2+ release (SOICR) through the ryanodine receptor (RyR2) seems to be implicated in this deleterious effect. Carvedilol and its analogue VK-II-86 (which does not have significant beta-blocking effects) suppress SOCIR by directly reducing the open duration of the cardiac RyR2, and could modulate calcium-related changes produced by myocardial stretch. Purpose The aim of this study was to investigate, by the ventricular fibrillation (VF) spectral analysis, whether carvedilol and VK-II-86 prevents stretch-induced arrhythmogenic effects. Methods The VF modifications induced by acute stretch were studied in Langendorff-perfused rabbit hearts using epicardial multiple electrodes under control conditions (n=10), during carvedilol infusion (0.1 and 1 μM) (n=10) and during VK-II-86 infusion (0.1 and 1 μM) (n=10). Spectral techniques were used to establish the baseline and stretch characteristics in the three series above mentioned: VF dominant frequency (DF) and VF spectral concentration (SpC) were determined. A two-factor ANOVA test was used and significance was reached when p<0.05. Results Myocardial stretch significantly increased DF with respect to pre-stretch values in control conditions (13.3±1.2 vs. 16.1±3.0 Hz, p<0.05) and during the perfusion of 0.1μM carvedilol (11.6±1.5 vs. 13.6±2.9 Hz, p<0.05) and 0.1μM VK-II-86 (13.2±2.2 vs. 16.2±4.1 Hz, p<0.05). However, the maximum concentration of both drugs (1μM) abolished this stretch-induced VF acceleration (carvedilol: 6.9±2.2 vs. 7.3±2.6 Hz, ns; VK-II-86: 7.0±1.4 vs. 7.1±0.6 Hz, ns). The significant stretch-induced decrease in SpC in control conditions (31.4±8.6 vs. 23.2±6.4%, p<0.01) was attenuated under 0.1μM carvedilol (0.1μM: 27.6±8.4 vs. 23.5±6.1%, ns) and 0.1μM VK-II-86 (24.7±5.4 vs. 21.2±3.9%, ns), but not under 1μM of both drugs (carvedilol: 41.3±11.3 vs. 30.3±5.7%, p<0.05; VK-II-86: 34.7±7.2 vs. 28.3±3.9%, p<0.01). Nevertheless, during stretch, arrhythmia regularity and organization was greater (higher SpC) under the highest concentration of carvedilol (p<0.01) and VK-II-86 (p<0.05) than in control conditions (control: 23.2±6.4%, carvedilol 1μM: 30.3±5.7%, VK-II-86 1μM: 28.3±3.9%). Conclusion Carvedilol and its analogue VK-II-86 abolished the changes in VF activation frequency produced by myocardial stretch at the highest studied concentration, and also attenuated the stretch-induced activation heterogeneity at the lowest concentration. The similarity in the effects of both drugs on the stretch-induced alterations would imply that its protective effect is due to its ability to inhibit store-overload-induced calcium release.

P1602Basic electrophysiological modifications induced by carvedilol in unstrectched and stretched ventricular myocardium

Background Acute regional ventricular stretch (ARVS) is a pathophysiologic event that may occur in certain situations, originating arrhythmogenic effects through the mechanoelectrical feedback. Mechanical effects of stretch originate calcium-related changes as sarcoplasmic recticulum Ca2+ overload that can trigger Ca2+ diastolic leaks (store-overload-induced Ca2+ release, SOICR), mediated by the cardiac ryanodine receptor (RyR2). SOICR seems to be implicated in the mechanisms underlying stretch-induced arrhythmias. Carvedilol can inhibit the overload of Ca2+ through blocking of beta-adrenergic receptors, and also suppress the release of Ca2+ induced by the SOICR. Purpose The aim of this investigation was to study the effects of carvedilol on the changes in ventricular refractoriness produced by AVRS, directly related with reentrant phenomenon and life-threatening arrhythmias. Methods Eleven adult male New Zealand White rabbits (3–3.5 kg) were heparinized (2500 IU) and euthanized by intravenous injection of sodium thiopental (100 mg/kg), according to European Ethic Guidelines. The hearts were excised, isolated and perfused in a Langendorff system. A pacing electrode and a recording multielectrode (121 electrodes) were placed on the left ventricle epicardium. The ARVS was produced by an “ad hoc” device introduced into the left ventricle. The ventricular effective and functional refractory periods (VERP, VFRP) were determined by the ventricular extrastimulus test with a basic cycle length of 250 ms, previously and at the third minute of ARVS, in control conditions and under Carvedilol (1 μM) infusion. The pacing threshold was determined for each situation and the stimulus amplitude was twice the diastolic threshold. A Student's t-test was used. Significance was reached when p<0.05. Results Myocardial stretch reduced VERP and VFRP with respect to pre-stretch values under control conditions (VERP: 110±13 vs 99±16 ms, VFRP: 119±13 vs 113±13 ms, p<0.05; n=10). No stretch-induced modifications of refractoriness were observed under carvedilol action (VERP: 139±18 vs 140±17 ms, VFRP: 161±29 vs 157±15 ms, ns; n=8). Before stretching, there were differences between control and carvedilol conditions (VERP: 110±13 vs 139±18 ms, VFRP: 119±13 vs 161±29 ms, p<0.001), and during stretch VERP and VFRP were significantly higher under carvedilol perfusion than in control conditions (VERP: 99±16 vs 140±17 ms, VFRP: 113±13 vs 157±15 ms, p<0.001). Conclusion The beta-adrenergic blocker and ryanodine receptor antagonist, carvedilol, attenuates the intrinsic electrophysiological modifications on refractoriness produced by myocardial acute local stretch.

Natriuretic Peptides in Heart Failure with Preserved Left Ventricular Ejection Fraction: From Molecular Evidences to Clinical Implications

The incidence of heart failure with preserved ejection fraction (HFpEF) is increasing and its challenging diagnosis and management combines clinical, imagistic and biological data. Natriuretic peptides (NPs) are hormones secreted in response to myocardial stretch that, by increasing cyclic guanosine monophosphate (cGMP), counteract myocardial fibrosis and hypertrophy, increase natriuresis and determine vasodilatation. While their role in HFpEF is controversial, most authors focused on b-type natriuretic peptides (BNPs) and agreed that patients may show lower levels. In this setting, newer molecules with an increased specificity, such as middle-region pro-atrial natriuretic peptide (MR-proANP), emerged as promising markers. Augmenting NP levels, either by NP analogs or breakdown inhibition, could offer a new therapeutic target in HFpEF (already approved in their reduced EF counterparts) by increasing the deficient cGMP levels found in patients. Importantly, these peptides also retain their prognostic value. This narrative review focuses on NPs’ physiology, diagnosis, therapeutic and prognostic implication in HFpEF.