Background: Psoriasis is a chronic inflammatory skin disease with increased obesity, non-calcified coronary artery burden (NCB), and incident myocardial infarction. We sought to assess the relationship between inflammation, visceral adipose tissue (VAT), and NCB. Furthermore, we evaluated whether improvement in VAT would be associated with reduction in NCB over time in psoriasis. Methods: Consecutive psoriasis patients (PSO) underwent coronary computed-tomography angiography to quantify NCB and abdominal computed tomography to calculate VAT, at baseline (n=237), one year (n=176), and four-years (n=50). Results: Patients with high hs-CRP had significantly greater visceral adiposity (17952.9±849.2 vs 13370.7±806.8 cc3, p<0.001) and non-calcified coronary burden (1.26±0.03 vs 1.07±0.02 mm2) than those with low hs-CRP. Those with higher VAT had more systemic inflammation [hs-CRP: 2.5 (1.0-5.3) vs 1.2 (0.6-2.9) mg/L] with ~50% higher NCB (1.42±0.6 vs 0.91±0.2 mm2 , p<0.001). VAT associated with NCB in fully adjusted models (β=0.47, p<0.001). At one-year follow up, patients who had worsening hs-CRP had an increase in VAT (14748.7±878.1 to 15158.7±881.5 cc3; p=0.03), whereas those who improved hs-CRP improved their VAT (16876.1±915.2 to 16310.4±889.6 cc3; p=0.04). At one-year, in those who decreased VAT, there was 10.3% reduction in NCB (β=0.26, p<0.0001), which persisted in a subset at four-years (β=0.39, p=0.003). Conclusions: Inflammation drives development of VAT, increased cardiometabolic risk, and NCB in psoriasis. Reduction of inflammation associated with reduction in VAT, and associated with longitudinal improvement in NCB. These findings demonstrate the important role of inflammation in the development of VAT in humans and its impact on early atherogenesis.
Aparna Sajja, Khaled M. Abdelrahman, Aarthi S. Reddy, Amit K. Dey, Domingo E. Uceda, Sundus S. Lateef, Alexander V. Sorokin, Heather L. Teague, Jonathan H. Chung, Joshua P. Rivers, Aditya A. Joshi, Youssef A. Elnabawi, Aditya Goyal, Justin Rodante, Andrew Keel, Julie A. Erb-Alvarez, Benjamin Lockshin, Ronald Prussick, Evan L. Siegel, Martin P. Playford, Marcus Y. Chen, David A. Bluemke, Joel M. Gelfand, Nehal N. Mehta
Heart failure is often accompanied by titin-dependent myocardial stiffness. Phosphorylation of titin by cGMP-dependent protein kinase (PKG)I increases cardiomyocyte distensibility. The upstream pathways stimulating PKGI-mediated titin phosphorylation are unclear. We studied whether C-type natriuretic peptide (CNP), via its guanylyl cyclase-B (GC-B) receptor and cGMP/PKGI signalling, modulates titin-based ventricular compliance. To dissect GC-B-mediated effects of endogenous CNP in cardiomyocytes, we generated mice with cardiomyocyte (CM)-restricted GC-B deletion. The impact on heart morphology and function, myocyte passive tension and titin isoform expression and phosphorylation was studied at baseline and after increased afterload induced by transverse aortic constriction (TAC).Pressure-overload increased left ventricular, especially endothelial CNP expression, with an early peak after 3 days. Concomitantly, titin phosphorylation at Ser4080, the site phosphorylated by PKGI, was augmented. Notably, in CM GC-B KO mice this titin response was abolished. TAC-induced hypertrophy and fibrosis were not different between genotypes. However, the KO mice presented mild systolic and diastolic dysfunction together with myocyte stiffness, which were not observed in control littermates. In vitro, recombinant PKGI rescued reduced Titin-Ser4080 phosphorylation and reverted passive stiffness of GC-B-deficient cardiomyocytes. CNP-induced activation of GC-B/cGMP/PKGI signalling in cardiomyocytes provides a protecting regulatory circuit preventing titin-based myocyte stiffening during early phases of pressure-overload.
Konstanze Michel, Melissa Herwig, Franziska Werner, Katarina Špiranec Spes, Marco Abeßer, Kai Schuh, Swati Dabral, Andreas Mügge, Hideo A. Baba, Boris V. Skryabin, Nazha Hamdani, Michaela Kuhn
The spontaneously hypertensive rat (SHR) is a genetic model of primary hypertension with an etiology that includes sympathetic overdrive. To elucidate the neurogenic mechanisms underlying the pathophysiology of this model, we analyzed the dynamic baroreflex response to spontaneous fluctuations in arterial pressure in conscious SHRs, as well as in the Wistar-Kyoto (WKY), the Dahl salt-sensitive, the Dahl salt-resistant, and the Sprague-Dawley rat. Observations revealed the existence of long intermittent periods (lasting up to several minutes) of engagement and disengagement of baroreflex control of heart rate. Analysis of these intermittent periods revealed a predictive relationship between increased mean arterial pressure and progressive baroreflex disengagement that was present in the SHR and WKY strains but absent in others. This relationship yielded the hypothesis that a lower proportion of engagement versus disengagement of the baroreflex in SHR compared with WKY contributes to the hypertension (or increased blood pressure) in SHR compared with WKY. Results of experiments using sinoaortic baroreceptor denervation were consistent with the hypothesis that dysfunction of the baroreflex contributes to the etiology of hypertension in the SHR. Thus, this study provides experimental evidence for the roles of the baroreflex in long-term arterial pressure regulation and in the etiology of primary hypertension in this animal model.
Feng Gu, E. Benjamin Randall, Steven Whitesall, Kimber Converso-Baran, Brian E. Carlson, Gregory D. Fink, Daniel E. Michele, Daniel A. Beard
Dilated cardiomyopathy (DCM) is often associated with sarcomere protein mutations that confer reduced myofilament tension-generating capacity. We demonstrate that cardiac twitch tension-time integrals can be targeted and tuned to prevent DCM remodeling in hearts with contractile dysfunction. We employ a transgenic murine model of DCM caused by the D230N tropomyosin (Tm) mutation and design a sarcomere-based intervention specifically targeting the twitch tension-time integral of D230N-Tm hearts using multiscale computational models of intra- and inter-molecular interactions in the thin filament and cell-level contractile simulations. Our models predict that increasing the calcium-sensitivity of thin filament activation using the cardiac troponin C (cTnC) variant L48Q can sufficiently augment twitch tension-time integrals of D230N-Tm hearts. Indeed, cardiac muscle isolated from double-transgenic (DTG) hearts expressing D230N Tm and L48Q cTnC have increased calcium-sensitivity of tension development and increased twitch tension-time integrals compared to preparations from hearts with D230N Tm alone. Longitudinal echocardiographic measurements revealed that DTG hearts retain normal cardiac morphology and function, while D230N-Tm hearts develop progressive DCM. We present a computational and experimental framework for targeting molecular mechanisms governing the twitch tension of cardiomyopathic hearts to counteract putative mechanical drivers of adverse remodeling, and open new possibilities for tension-based treatments of genetic cardiomyopathies.
Joseph D. Powers, Kristina B. Kooiker, Allison B. Mason, Abigail E. Teitgen, Galina V. Flint, Jil C. Tardiff, Steven D. Schwartz, Andrew D. McCulloch, Michael Regnier, Jennifer Davis, Farid Moussavi-Harami
Background: Left atrial (LA) and left ventricular (LV) remodeling are associated with atrial fibrillation (AF). The prospective associations of impairment in cardiac mechanical function, as assessed by speckle-tracking echocardiography, with incident AF are less clear. Methods: In the Cardiovascular Health Study, a community-based cohort of older adults, participants free of AF with echocardiograms of adequate quality for speckle-tracking were included. We evaluated the associations of indices of cardiac mechanics (LA reservoir strain, LV longitudinal strain, and LV early diastolic strain rate) with incident AF. Results: Of 4,341 participants with strain imaging, participants with lower LA reservoir strain were older, had more cardiometabolic risk factors, and had lower renal function at baseline. Over median follow-up of 10 years, 497 (11.4%) participants developed AF. Compared with the highest quartile of LA reservoir strain, the lowest quartile of LA reservoir strain was associated with higher risk of AF after covariate adjustment, including LA volume and LV longitudinal strain (HR: 1.80, 95% CI: 1.31-2.45, P <0.001). The association of LA reservoir strain and AF was stronger in subgroups with higher blood pressure, NT-proBNP, and LA volumes. There were no associations of LV longitudinal strain and LV early diastolic strain rate with incident AF after adjustment for LA reservoir strain. Conclusion: Lower LA reservoir strain was associated with incident AF, independent of LV mechanics, and with stronger associations in high-risk subgroups. These findings suggest that mechanical dysfunction of the LA precedes the development of AF. Therapies targeting LA mechanical dysfunction may prevent progression to AF.
Ravi B. Patel, Joseph A. Delaney, Mo Hu, Harnish Patel, Jeanette Y. Cheng, John Gottdiener, Jorge R. Kizer, Gregory M. Marcus, Mintu P. Turakhia, Rajat Deo, Susan R. Heckbert, Bruce M. Psaty, Sanjiv J. Shah
Diabetes is a risk factor for myocardial infarction, and outcomes after myocardial infarction are worse among diabetics compared with nondiabetics. Diabetes is associated with impaired Heme clearance. Here, we determined whether heme toxicity and impaired heme clearance contribute to diabetic myocardial infarction injury and assessed IL-10 as a therapeutic agent for diabetic myocardial infarction. Plasma-free hemoglobin was significantly elevated in diabetic mice compared with nondiabetic mice after myocardial infarction. Infarct size had strong correlation to the level of plasma-free hemoglobin. Hemoglobin and reactive iron deposition within the infarct zone were also demonstrated in diabetic MI. IL-10 significantly reduced infarct size and improved cardiac function in diabetic mice. Moreover, IL-10 improved capillary density, reduced apoptosis, and decreased inflammation in the border zone of the infarcted hearts, findings that were partially inhibited by Tin protoporphyrin (a heme oxygenase-1 inhibitor). IL-10 upregulated CD163, the hemoglobin:haptoglobin scavenger receptor, and heme oxygenase-1 in THP-1–derived and primary human CD14+ macrophages. IL-10 significantly protected against ischemic injury when HL-1 cardiomyocytes were cotreated with hemoglobin. Together, our findings indicate that IL-10 is cardioprotective in diabetic myocardial infarction via upregulation of heme clearance pathways. These findings implicate heme clearance as a potentially novel therapeutic direction for diabetic myocardial infarction.
Rajesh Gupta, Lijun Liu, Xiaolu Zhang, Xiaoming Fan, Prasanna Krishnamurthy, Suresh Verma, Jörn Tongers, Sol Misener, Nikita Ashcherkin, Hongliu Sun, Jiang Tian, Raj Kishore
Previous studies have shown an association between elevated atrial NADPH-dependent oxidative stress and decreased plasma apelin in patients with atrial fibrillation (AF), though the basis for this relationship is unclear. In the current study, RT-PCR and immunofluorescence studies of human right atrial appendages (RAAs) showed expression of the apelin receptor, APJ, and reduced apelin content in the atria, but not in plasma, of patients with AF versus normal sinus rhythm. Disruption of the apelin gene in mice increased (2.4-fold) NADPH-stimulated superoxide levels and slowed atrial conduction velocities in optical mapping of a Langendorff-perfused isolated heart model, suggesting that apelin levels may influence AF vulnerability. Indeed, in mice with increased AF vulnerability (induced by chronic intense exercise), apelin administration reduced the incidence and duration of induced atrial arrhythmias in association with prolonged atrial refractory periods. Moreover, apelin decreased AF induction in isolated atria from exercised mice while accelerating conduction velocity and increasing action potential durations. At the cellular level, these changes were associated with increased atrial cardiomyocyte sodium currents. These findings support the conclusion that reduced atrial apelin is maladaptive in fibrillating human atrial myocardium and that increasing apelin bioavailability may be a worthwhile therapeutic strategy for treating and preventing AF.
Young M. Kim, Robert Lakin, Hao Zhang, Jack Liu, Ayaaz Sachedina, Maneesh Singh, Emily Wilson, Marco Perez, Subodh Verma, Thomas Quertermous, Jeffrey Olgin, Peter H. Backx, Euan A. Ashley
Cardiac energetic dysfunction has been reported in patients with type 2 diabetes (T2D) and is an independent predictor of mortality. Identification of the mechanisms driving mitochondrial dysfunction, and therapeutic strategies to rescue these modifications, will improve myocardial energetics in T2D. We demonstrate using 31P-magnetic resonance spectroscopy (31P-MRS) that decreased cardiac ATP and phosphocreatine (PCr) concentrations occurred before contractile dysfunction or a reduction in PCr/ATP ratio in T2D. Real-time mitochondrial ATP synthesis rates and state 3 respiration rates were similarly depressed in T2D, implicating dysfunctional mitochondrial energy production. Driving this energetic dysfunction in T2D was an increase in mitochondrial protein acetylation, and increased ex vivo acetylation was shown to proportionally decrease mitochondrial respiration rates. Treating T2D rats in vivo with the mitochondrial deacetylase SIRT3 activator honokiol reversed the hyperacetylation of mitochondrial proteins and restored mitochondrial respiration rates to control levels. Using 13C-hyperpolarized MRS, respiration with different substrates, and enzyme assays, we localized this improvement to increased glutamate dehydrogenase activity. Finally, honokiol treatment increased ATP and PCr concentrations and increased total ATP synthesis flux in the T2D heart. In conclusion, hyperacetylation drives energetic dysfunction in T2D, and reversing acetylation with the SIRT3 activator honokiol rescued myocardial and mitochondrial energetics in T2D.
Matthew Kerr, Jack J. Miller, Dharendra Thapa, Sophie Stiewe, Kerstin N. Timm, Claudia N. Montes Aparicio, Iain Scott, Damian J. Tyler, Lisa C. Heather
The Ca2+-binding protein calmodulin has emerged as a pivotal player in tuning Na+ channel function, although its impact in vivo remains to be resolved. Here, we identify the role of calmodulin and the NaV1.5 interactome in regulating late Na+ current in cardiomyocytes. We created transgenic mice with cardiac-specific expression of human NaV1.5 channels with alanine-substitutions for the IQ motif (IQ/AA). The mutations rendered the channels incapable of binding calmodulin to the C-terminus. The IQ/AA transgenic mice exhibited normal ventricular repolarization without arrhythmias, and an absence of increased late Na+ current. In comparison, transgenic mice expressing a lidocaine-resistant (F1759A) human NaV1.5 demonstrated increased late Na+ current and prolonged repolarization in cardiomyocytes, with spontaneous arrhythmias. To determine regulatory factors that prevent late Na+ current for IQ/AA mutant, we considered fibroblast growth factor homologous factors (FHFs), which are within the NaV1.5 proteomic subdomain shown by proximity labeling in transgenic mice expressing NaV1.5 conjugated to ascorbate peroxidase. We find FGF13 diminishes late current of the IQ/AA but not F1759A mutant cardiomyocytes, suggesting that endogenous FHFs may serve to prevent late Na+ current in mouse cardiomyocytes. Leveraging endogenous mechanisms may furnish an alternative avenue for developing novel pharmacology that selectively blunts late Na+ current.
Jeffrey M. Abrams, Daniel Roybal, Nourdine Chakouri, Alex N. Katchman, Richard L. Weinberg, Lin Yang, Bi-Xing Chen, Sergey I. Zakharov, Jessica A. Hennessey, Uma Mahesh R. Avula, Johanna Diaz, Chaojian Wang, Elaine Y. Wan, Geoffrey S. Pitt, Manu Ben-Johny, Steven O. Marx
Arrhythmogenic cardiomyopathy (AC) is a heart disease often caused by mutations in genes coding for desmosomal proteins including desmoglein-2 (DSG2), plakoglobin (PG), and desmoplakin (DP). Therapy is symptomatic to limit arrhythmia since the mechanisms by which desmosomal components control cardiomyocyte function are largely unknown. A new paradigm would be to stabilize desmosomal cardiomyocyte adhesion and hyper-adhesion, which renders desmosomal adhesion independent from Ca2+. Here, we further characterized the mechanisms behind enhanced cardiomyocyte adhesion and hyper-adhesion. Dissociation assays performed in HL-1 cells and murine ventricular cardiac slice cultures allowed us to define a set of signaling pathways regulating cardiomyocyte adhesion under basal and hyper-adhesive conditions. Adrenergic signaling, activation of PKC and inhibition of p38MAPK enhanced cardiomyocyte adhesion, referred to as positive adhesiotropy, and induced hyper-adhesion. Activation of ERK1/2 paralleled positive adhesiotropy, whereas adrenergic signaling induced Pg phosphorylation at S665 under both basal and hyper-adhesive conditions. Adrenergic signaling and p38MAPK inhibition recruited DSG2 to cell junctions. In PG-deficient mice with an AC phenotype, only PKC activation and p38MAPK inhibition enhanced cardiomyocyte adhesion. Our results demonstrate that cardiomyocyte adhesion can be stabilized by different signaling mechanisms, which are in part off-set in PG-deficient AC.
Maria Shoykhet, Sebastian Trenz, Ellen Kempf, Tatjana Williams, Brenda Gerull, Camilla Schinner, Sunil Yeruva, Jens Waschke
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