Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website.Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre -including this research content -immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

Background Right ventricular (RV) failure from increased pulmonary vascular loading is a major cause of morbidity and mortality, yet its modulation by disease remains poorly understood. We tested the hypotheses that, unlike the systemic circulation, pulmonary vascular resistance (RPA) and compliance (CPA) are consistently and inversely related regardless of age, pulmonary hypertension (PH), or interstitial fibrosis, and that this relation may be changed by elevated pulmonary capillary wedge pressure (PCWP), augmenting RV pulsatile load. Methods and Results Several large clinical databases with right heart/pulmonary catheterization data were analyzed to determine the RPA-CPA relationship with PH, pulmonary fibrosis, patient age, and varying PCWP. Patients with suspected or documented PH (n=1009) and normal PCWP displayed a consistent RPA-CPA hyperbolic (inverse) dependence; CPA=0.564/(0.047+RPA), with a near constant resistance-compliance product (RC) (0.48±0.17 seconds). In the same patients, the systemic RC was highly variable. Severe pulmonary fibrosis (n=89) did not change the RPA-CPA relation. Increasing patient age led to a very small though statistically significant change in the relation. However, elevation of the PCWP (n=8142) had a larger impact, significantly lowering CPA for any RPA, and negatively correlating RC (p<0.0001). Conclusions PH and pulmonary fibrosis do not significantly change the hyperbolic dependence between RPA and CPA, while patient age has only minimal affects. This fixed relationship helps explain the difficulty of reducing total RV afterload by therapies that have modest impact on mean RPA. Higher PCWP appears to enhance net RV afterload by elevating pulsatile, relative to resistive load, and may contribute to RV dysfunction.

8. Wirtz H, Hasenclever D, Schwabe K, et al. ACE inhibitor for lung protection during mechanical ventilation for acute lung injury-results of the double-blind, placebo controlled, randomised ACEmeVENT pilot study.

Objective The aim of this study is to determine if activation of β3-adrenoceptor (β3-AR) and downstream signaling of NOS isoforms protects the heart from failure and hypertrophy induced by pressure overload. Background β3-AR and its downstream signaling pathways are recognized as novel modulators of heart function. Unlike _1- and _2-ARs, _3-ARs are stimulated at high catecholamine concentrations and induce negative inotropic effects, serving as a “brake” to protect the heart from catecholamine overstimulation. Methods C57BL/6J and nNOS knock-out mice were assigned to receive transverse aortic constriction (TAC), BRL37344 (β3-agonist, BRL0.1 mg/kg/hour), or both. Results Three weeks of BRL treatment in wild type mice attenuated left ventricular dilation and systolic dysfunction, and partially reduced cardiac hypertrophy induced by TAC. This effect was associated with increased nitric oxide (NO) production and superoxide suppression. TAC decreased endothelial NO synthase (eNOS) dimerization, indicating eNOS uncoupling, which was not reversed by BRL treatment. However, nNOS protein expression was up-regulated 2-fold by BRL, and the suppressive effect of BRL on superoxide generation was abrogated by acute neuronal NO synthase (nNOS) inhibition. Furthermore, BRL cardioprotective effects were actually detrimental in nNOS−/− mice. Conclusion These results are the first to show in vivo cardioprotective effects of β3-AR specific agonism in pressure overload hypertrophy and heart failure, and support nNOS as the primary downstream NOS isoform in maintaining NO and reactive oxygen species (ROS) balance in the failing heart.

Abstract-Inflammation may play an important role in the pathogenesis of cardiac fibrosis in heart failure (HF) after myocardial infarction (MI). N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally occurring antifibrotic peptide whose plasma concentration is increased 4-to 5-fold by angiotensin-converting enzyme inhibitors. We tested the hypothesis that in rats with HF after MI, Ac-SDKP acts as an anti-inflammatory cytokine, preventing and also reversing cardiac fibrosis in the noninfarcted area (reactive fibrosis), and thus affording functional improvement. We found that Ac-SDKP significantly decreased total collagen content in the prevention group from 23.7Ϯ0.9 to 15.0Ϯ0.7 g/mg and in the reversal group from 22.6Ϯ2. , PϽ0.01 (reversal). Ac-SDKP did not alter either blood pressure or left ventricular hypertrophy (LVH); however, it depressed systolic cardiac function in the prevention study while having no significant effect in the reversal group. We concluded that Ac-SDKP has an anti-inflammatory effect in HF that may contribute to its antifibrotic effect; however, this decrease in fibrosis without changes in LVH was not accompanied by an improvement in cardiac function. Key Words: rat Ⅲ myocardial infarction Ⅲ cardiac function Ⅲ collagen Ⅲ macrophages Ⅲ transforming growth factor-␤ N -acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally occurring antifibrotic peptide whose plasma concentration is increased 4-to 5-fold by angiotensin-converting enzyme inhibitors. Ac-SDKP is released from its precursor thymosin-␤ 4 , which is present in most cells. 1 It inhibits pluripotent hematopoietic stem cell and hepatocyte proliferation by halting entry into the S phase of the cell cycle, maintaining cells in the G 0 /G 1 phase and thereby helping control their proliferation. [2][3][4] We have shown that in vitro Ac-SDKP inhibited cardiac fibroblast proliferation and collagen synthesis, 5 while in vivo it prevented collagen deposition in the left ventricle (LV) and kidneys in rats with aldosterone-salt hypertension and renovascular hypertension. 5,6 This decrease in collagen deposition was associated with a reduced number of proliferating cell nuclear antigen (PCNA)-positive cells, a marker of cell proliferation. These effects of Ac-SDKP occurred without changes in blood pressure or cardiomyocyte hypertrophy. Our studies suggest that one of the mechanisms by which Ac-SDKP prevents fibrosis is by inhibiting fibroblast proliferation and collagen synthesis. It is also known that inflammation plays a central role in the pathogenesis of interstitial and perivascular cardiac fibrosis in heart failure (HF) post-myocardial infarction (MI). Fibrosis is often co-localized with macrophages, which release cytokines such as transforming growth factor-␤ (TGF-␤) that play a crucial role in myocardial fibrosis. 7 There is evidence that Ac-SDKP inhibits TGF-␤ signal transduction through suppression of Smad2 phosphorylation. 8,9 However, it is not known whether it also inhibits the expression of TGF-␤.In the present study,...

Abstract-Hypertensive heart disease is characterized by early development of hypertrophy and fibrosis that leads to heart failure (HF). HF develops in spontaneously hypertensive rats (SHR) after 18 months; however, it is not clear whether hypertrophy leads to altered cardiac performance at an earlier age in these rats. We studied cardiac performance in 10-to 11-month-old SHR and age-matched Wistar-Kyoto rats (WKY), using presssure-volume (PV) conductance catheter system to evaluate systolic and diastolic function in vivo at different preloads, including preload recruitable stroke work (PRSW), ϩdP/dt, and its relation to end-diastolic volume (ϩdP/dt-EDV) and preload-adjusted maximal power (PWR max -EDV 2 ) as well as the time constant of left ventricular pressure decay, tau (), as an index of relaxation. The slope of the end-diastolic pressure-volume relation (EDPVR) and the ex vivo PV relation, both indexes of stiffness, were also calculated for each heart, and the Doppler E/A ratio was determined. In addition, plasma samples were obtained to assess B-type natriuretic peptide levels (BNP). We found that PRSW was higher in SHR than in WKY (174.5Ϯ15.6 versus 92.6Ϯ18.9 mm Hg; PϽ0.01). ϩdP/dt and ϩdP/dt-EDV were also enhanced in SHR versus WKY (9125Ϯ662 versus 6633Ϯ392 mm Hg/sec, PϽ0.01, and 28.14Ϯ4.35 versus 12.7Ϯ2.8 mm Hg/s per L, PϽ0.02). In addition, PWR-EDV 2 was elevated in SHR (7.3Ϯ1.5 versus 3.1Ϯ0.6 mW/L 2 ). was prolonged in SHR (14.5Ϯ1 ms versus 10.8Ϯ0.8 for WKY, PϽ0.02) and EDPVR was significantly greater in SHR than in WKY (0.01Ϯ0.005 versus 0.004Ϯ0.001, PϽ0.05). The ex vivo pressure-volume relation was also steeper for SHR and the E/A ratio was 2.53Ϯ0.15 for SHR versus 1.67Ϯ0.08 for WKY (PϽ0.02). BNP was 45Ϯ2.5 pg/mL for SHR and 33.3Ϯ1.8 pg/mL for WKY (PϽ0.02). Taken together, these data suggest that at 10 to 11 months of age, before HF develops, SHR have increased systolic performance accompanied by delayed relaxation and increased diastolic stiffness.

Myocardial stretch elicits a rapid increase in developed force, which is mainly caused by an increase in myofilament calcium sensitivity (Frank-Starling mechanism). Over the ensuing 10-15 min, a second gradual increase in force takes place. This slow force response to stretch is known to be the result of an increase in the calcium transient amplitude and constitutes the in vitro equivalent of the Anrep effect described 100 years ago in the intact heart. In the present review, we will update and discuss what is known about the Anrep effect as the mechanical counterpart of autocrine/paracrine mechanisms involved in its genesis. The chain of events triggered by myocardial stretch comprises 1) release of angiotensin II, 2) release of endothelin, 3) activation of the mineralocorticoid receptor, 4) transactivation of the epidermal growth factor receptor, 5) increased formation of mitochondria reactive oxygen species, 6) activation of redox-sensitive kinases upstream myocardial Na(+)/H(+) exchanger (NHE1), 7) NHE1 activation, 8) increase in intracellular Na(+) concentration, and 9) increase in Ca(2+) transient amplitude through the Na(+)/Ca(2+) exchanger. We will present the experimental evidence supporting each of the signaling steps leading to the Anrep effect and its blunting by silencing NHE1 expression with a specific small hairpin interference RNA injected into the ventricular wall.

Rationale The heart is exquisitely sensitive to mechanical stimuli in order to rapidly adapt to physiological demands. In muscle lacking dystrophin, such as Duchenne muscular dystrophy (DMD), increased load during contraction triggers pathological responses thought to worsen the disease. The relevant mechano-transducers and therapies to target them remain unclear. Objectives We tested the role of transient receptor potential canonical channels TRPC3 and TRPC6 and their modulation by protein kinase G in controlling cardiac systolic mechano-sensing, and determined their pathophysiological relevance in an experimental model of DMD. Methods and Results Contracting isolated papillary muscles and/or cardiomyocytes from controls and mice genetically lacking either TRPC3 or TRPC6 were subjected to auxotonic load to induce stress-stimulated contractility (SSC, gradual rise in force and intracellular Ca2+). Incubation with cGMP (PKG activator) markedly blunted SSC in controls and Trpc3−/−; whereas in Trpc6−/−, the resting SSC response was diminished and cGMP had no impact. In DMD myocytes (mdx/utrophin deficient), the SSC was excessive and arrhythmogenic. Gene deletion or selective drug blockade of TRPC6, or cGMP/PKG activation, all reversed this phenotype. Chronic PDE5A inhibition also normalized abnormal mechano-sensing while blunting progressive chamber hypertrophy in DMD mice. Conclusion PKG is a potent negative-modulator of cardiac systolic mechano-signaling that requires TRPC6 as the target effector. In dystrophic hearts, excess SSC and arrhythmia are coupled to TRPC6 and are ameliorated by its targeted suppression or PKG activation. These results highlight novel therapeutic targets for this disease.