Journal Of Clinical & Experimental Cardiology[JOURNAL]
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200 papers
Genetic Testing in High-risk Spontaneous Coronary Artery Dissection-Searching for Clinical Utility Among Background Genetic Noise.
Giudicessi JR, Tweet MS, Hayes SN
JAMA Cardiol · 2022 Oct · PMID 36103199 · Full text
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Sympathetic nerve innervation and metabolism in ischemic myocardium in response to remote ischemic perconditioning.
Kiss A, Wu P, Schlederer M … +14 more , Pilz PM, Szabo PL, Li J, Weber L, Vraka C, Pichler V, Mitterhauser M, Zhang X, Zins K, Abraham D, Li S, Podesser BK, Hacker M, Li X
Basic Res Cardiol · 2022 Aug · PMID 36008727 · Full text
Sympathetic nerve denervation after myocardial infarction (MI) predicts risk of sudden cardiac death. Therefore, therapeutic approaches limit infarct size, improving adverse remodeling and restores sympathetic innervatio...
Sympathetic nerve denervation after myocardial infarction (MI) predicts risk of sudden cardiac death. Therefore, therapeutic approaches limit infarct size, improving adverse remodeling and restores sympathetic innervation have a great clinical potential. Remote ischemic perconditioning (RIPerc) could markedly attenuate MI-reperfusion (MIR) injury. In this study, we aimed to assess its effects on cardiac sympathetic innervation and metabolism. Transient myocardial ischemia is induced by ligature of the left anterior descending coronary artery (LAD) in male Sprague-Dawley rats, and in vivo cardiac 2-[F]FDG and [C]mHED PET scans were performed at 14-15 days after ischemia. RIPerc was induced by three cycles of 5-min-long unilateral hind limb ischemia and intermittent 5 min of reperfusion during LAD occlusion period. The PET quantitative parameters were quantified in parametric polar maps. This standardized format facilitates the regional radioactive quantification in deficit regions to remote areas. The ex vivo radionuclide distribution was additionally identified using autoradiography. Myocardial neuron density (tyrosine hydroxylase positive staining) and chondroitin sulfate proteoglycans (CSPG, inhibiting neuron regeneration) expression were assessed by immunohistochemistry. There was no significant difference in the mean hypometabolism 2-[F]FDG uptake ratio (44.6 ± 4.8% vs. 45.4 ± 4.4%) between MIR rats and MIR + RIPerc rats (P > 0.05). However, the mean [C]mHED nervous activity of denervated myocardium was significantly elevated in MIR + RIPerc rats compared to the MIR rats (35.9 ± 7.1% vs. 28.9 ± 2.3%, P < 0.05), coupled with reduced denervated myocardium area (19.5 ± 5.3% vs. 27.8 ± 6.6%, P < 0.05), which were associated with preserved left-ventricular systolic function, a less reduction in neuron density, and a significant reduction in CSPG and CD68 expression in the myocardium. RIPerc presented a positive effect on cardiac sympathetic-nerve innervation following ischemia, but showed no significant effect on myocardial metabolism.
Endothelial progenitor cells overexpressing Grb2-associated binder 1 for in vitro-constructed tissue-engineered heart valves.
Zhang L, Zuo J, Huang S … +1 more , Chang Q
Kardiologiia · 2022 Jul · PMID 35989628 · Publisher ↗
Aim Endothelial progenitor cells (EPCs) play important roles in heart valve replacement surgery. Up-regulation of Grb2‑associated binder 1 (Gab1) promotes hepatocyte growth factor (HGF) - induced endothelial progenito...
Aim Endothelial progenitor cells (EPCs) play important roles in heart valve replacement surgery. Up-regulation of Grb2‑associated binder 1 (Gab1) promotes hepatocyte growth factor (HGF) - induced endothelial progenitor cell proliferation and migration. This study aimed to investigate the effects of up-regulation of Gab1 in hepatocyte growth factor-induced EPCs in tissue-engineered heart valves (TEHV).Material and methods Fresh porcine aortic valves were placed in 1 % Triton X-100 and trypsin buffer for decellularization. EPCs in the control group were cultured normally, whereas those in the experimental group were both HGF stimulated and transfected with adenovirus containing the Gab1 gene. Cells in the two groups were seeded onto the decellularized valve scaffolds and cultured for 3 or 7 days. TEHV were analyzed by HE and AB-PAS staining.Results By day 3, the experimental group had formed confluent endothelial monolayers on top of the decellularized valves, on the basis of by HE staining and AB-PAS staining. One week later, the control group showed a imperfect endothelial layer.Conclusion HGF-induced EPCs overexpressing Gab1 can endothelialize the decellularized matrix and create functional TEHV, which may then be preconditioned in a bioreactor before clinical implantation.
Clinical Outcomes Following Simple or Complex Stenting for Coronary Bifurcation Lesions: A Meta-Analysis.
Zhang Q, Huan H, Han Y … +4 more , Liu H, Sun S, Wang B, Wei S
Clin Med Insights Cardiol · 2022 · PMID 35982991 · Full text
BACKGROUND: Stent placement remains a challenge for coronary bifurcation lesions. While both simple and complex stenting strategies are available, it is unclear which one results in better clinical outcomes. This meta-an...
BACKGROUND: Stent placement remains a challenge for coronary bifurcation lesions. While both simple and complex stenting strategies are available, it is unclear which one results in better clinical outcomes. This meta-analysis aims to explore the long-term prognosis following treatment with the 2 stenting strategies. METHOD: Randomized controlled trials found from searches of the PubMed, EMBASE, and Cochrane Central Register of Controlled Trials were included in this meta-analysis. The complex stent placement strategy was identified as the control group, and the simple stent placement strategy was identified as the experimental group. Data were synthesized with a random effects model. The quality of the randomized controlled trials was assessed by Jadad scale scores. The clinical endpoints at 6 months, 1 year, and 5 years were analyzed. RESULTS: A total of 11 randomized controlled trials met the inclusion criteria. A total of 2494 patients were included in this meta-analysis. The odds ratio [OR] of the major adverse cardiac events (MACEs) at 6 months was 0.85 (95% confidence interval [CI] 0.53-1.35; = .49, = 0%). The OR of the MACEs at 1 year was 0.61 (95% CI 0.36-1.05; = .08, = 0%). The OR of the MACEs at 5 years was 0.69 (95% CI 0.51-0.92; = .01, = 0%). Compared with the complex strategy, the simple strategy was associated with a lower incidence of MACEs at 5 years. CONCLUSION: Compared to the complex stenting strategy, the simple stenting strategy can better reduce the occurrence of long-term MACEs for coronary bifurcation lesions.
Gut-derived low-grade endotoxaemia, atherothrombosis and cardiovascular disease.
Violi F, Cammisotto V, Bartimoccia S … +3 more , Pignatelli P, Carnevale R, Nocella C
Nat Rev Cardiol · 2023 Jan · PMID 35840742 · Full text
Systemic inflammation has been suggested to have a pivotal role in atherothrombosis, but the factors that trigger systemic inflammation have not been fully elucidated. Lipopolysaccharide (LPS) is a component of the membr...
Systemic inflammation has been suggested to have a pivotal role in atherothrombosis, but the factors that trigger systemic inflammation have not been fully elucidated. Lipopolysaccharide (LPS) is a component of the membrane of Gram-negative bacteria present in the gut that can translocate into the systemic circulation, causing non-septic, low-grade endotoxaemia. Gut dysbiosis is a major determinant of low-grade endotoxaemia via dysfunction of the intestinal barrier scaffold, which is a prerequisite for LPS translocation into the systemic circulation. Experimental studies have demonstrated that LPS is present in atherosclerotic arteries but not in normal arteries. In atherosclerotic plaques, LPS promotes a pro-inflammatory status that can lead to plaque instability and thrombus formation. Low-grade endotoxaemia affects several cell types, including leukocytes, platelets and endothelial cells, leading to inflammation and clot formation. Low-grade endotoxaemia has been described in patients at risk of or with overt cardiovascular disease, in whom low-grade endotoxaemia was associated with atherosclerotic burden and its clinical sequelae. In this Review, we describe the mechanisms favouring the development of low-grade endotoxaemia, focusing on gut dysbiosis and changes in gut permeability; the plausible biological mechanisms linking low-grade endotoxaemia and atherothrombosis; the clinical studies suggesting that low-grade endotoxaemia is a risk factor for cardiovascular events; and the potential therapeutic tools to improve gut permeability and eventually eliminate low-grade endotoxaemia.
Endothelial ACKR3 drives atherosclerosis by promoting immune cell adhesion to vascular endothelium.
Gencer S, Döring Y, Jansen Y … +13 more , Bayasgalan S, Yan Y, Bianchini M, Cimen I, Müller M, Peters LJF, Megens RTA, von Hundelshausen P, Duchene J, Lemnitzer P, Soehnlein O, Weber C, van der Vorst EPC
Basic Res Cardiol · 2022 Jun · PMID 35674847 · Full text
Atherosclerosis is the foundation of potentially fatal cardiovascular diseases and it is characterized by plaque formation in large arteries. Current treatments aimed at reducing atherosclerotic risk factors still allow...
Atherosclerosis is the foundation of potentially fatal cardiovascular diseases and it is characterized by plaque formation in large arteries. Current treatments aimed at reducing atherosclerotic risk factors still allow room for a large residual risk; therefore, novel therapeutic candidates targeting inflammation are needed. The endothelium is the starting point of vascular inflammation underlying atherosclerosis and we could previously demonstrate that the chemokine axis CXCL12-CXCR4 plays an important role in disease development. However, the role of ACKR3, the alternative and higher affinity receptor for CXCL12 remained to be elucidated. We studied the role of arterial ACKR3 in atherosclerosis using western diet-fed Apoe mice lacking Ackr3 in arterial endothelial as well as smooth muscle cells. We show for the first time that arterial endothelial deficiency of ACKR3 attenuates atherosclerosis as a result of diminished arterial adhesion as well as invasion of immune cells. ACKR3 silencing in inflamed human coronary artery endothelial cells decreased adhesion molecule expression, establishing an initial human validation of ACKR3's role in endothelial adhesion. Concomitantly, ACKR3 silencing downregulated key mediators in the MAPK pathway, such as ERK1/2, as well as the phosphorylation of the NF-kB p65 subunit. Endothelial cells in atherosclerotic lesions also revealed decreased phospho-NF-kB p65 expression in ACKR3-deficient mice. Lack of smooth muscle cell-specific as well as hematopoietic ACKR3 did not impact atherosclerosis in mice. Collectively, our findings indicate that arterial endothelial ACKR3 fuels atherosclerosis by mediating endothelium-immune cell adhesion, most likely through inflammatory MAPK and NF-kB pathways.
Multiparametric MRI identifies subtle adaptations for demarcation of disease transition in murine aortic valve stenosis.
Quast C, Kober F, Becker K … +17 more , Zweck E, Hoffe J, Jacoby C, Flocke V, Gyamfi-Poku I, Keyser F, Piayda K, Erkens R, Niepmann S, Adam M, Baldus S, Zimmer S, Nickenig G, Grandoch M, Bönner F, Kelm M, Flögel U
Basic Res Cardiol · 2022 May · PMID 35643805 · Full text
Aortic valve stenosis (AS) is the most frequent valve disease with relevant prognostic impact. Experimental model systems for AS are scarce and comprehensive imaging techniques to simultaneously quantify function and mor...
Aortic valve stenosis (AS) is the most frequent valve disease with relevant prognostic impact. Experimental model systems for AS are scarce and comprehensive imaging techniques to simultaneously quantify function and morphology in disease progression are lacking. Therefore, we refined an acute murine AS model to closely mimic human disease characteristics and developed a high-resolution magnetic resonance imaging (MRI) approach for simultaneous in-depth analysis of valvular, myocardial as well as aortic morphology/pathophysiology to identify early changes in tissue texture and critical transition points in the adaptive process to AS. AS was induced by wire injury of the aortic valve. Four weeks after surgery, cine loops, velocity, and relaxometry maps were acquired at 9.4 T to monitor structural/functional alterations in valve, aorta, and left ventricle (LV). In vivo MRI data were subsequently validated by histology and compared to echocardiography. AS mice exhibited impaired valve opening accompanied by significant valve thickening due to fibrotic remodelling. While control mice showed bell-shaped flow profiles, AS resulted not only in higher peak flow velocities, but also in fragmented turbulent flow patterns associated with enhanced circumferential strain and an increase in wall thickness of the aortic root. AS mice presented with a mild hypertrophy but unaffected global LV function. Cardiac MR relaxometry revealed reduced values for both T1 and T2 in AS reflecting subtle myocardial tissue remodelling with early alterations in mitochondrial function in response to the enhanced afterload. Concomitantly, incipient impairments of coronary flow reserve and myocardial tissue integrity get apparent accompanied by early troponin release. With this, we identified a premature transition point with still compensated cardiac function but beginning textural changes. This will allow interventional studies to explore early disease pathophysiology and novel therapeutic targets.
Repurposing drugs to treat cardiovascular disease in the era of precision medicine.
Abdelsayed M, Kort EJ, Jovinge S … +1 more , Mercola M
Nat Rev Cardiol · 2022 Nov · PMID 35606425 · Full text
Drug repurposing is the use of a given therapeutic agent for indications other than that for which it was originally designed or intended. The concept is appealing because of potentially lower development costs and short...
Drug repurposing is the use of a given therapeutic agent for indications other than that for which it was originally designed or intended. The concept is appealing because of potentially lower development costs and shorter timelines than are needed to produce a new drug. To date, drug repurposing for cardiovascular indications has been opportunistic and driven by knowledge of disease mechanisms or serendipitous observation rather than by systematic endeavours to match an existing drug to a new indication. Innovations in two areas of personalized medicine - computational approaches to associate drug effects with disease signatures and predictive model systems to screen drugs for disease-modifying activities - support efforts that together create an efficient pipeline to systematically repurpose drugs to treat cardiovascular disease. Furthermore, new experimental strategies that guide the medicinal chemistry re-engineering of drugs could improve repurposing efforts by tailoring a medicine to its new indication. In this Review, we summarize the historical approach to repurposing and discuss the technological advances that have created a new landscape of opportunities.
Rare and Common Genetic Variation Underlying the Risk of Hypertrophic Cardiomyopathy in a National Biobank.
Biddinger KJ, Jurgens SJ, Maamari D … +8 more , Gaziano L, Choi SH, Morrill VN, Halford JL, Khera AV, Lubitz SA, Ellinor PT, Aragam KG
JAMA Cardiol · 2022 Jul · PMID 35583889 · Full text
IMPORTANCE: Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death in young people. Although rare genetic variants are well-established contributors to HCM risk, common genetic variants have recentl...
IMPORTANCE: Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death in young people. Although rare genetic variants are well-established contributors to HCM risk, common genetic variants have recently been implicated in disease pathogenesis. OBJECTIVE: To assess the contributions of rare and common genetic variation to risk of HCM in the general population. DESIGN, SETTING, AND PARTICIPANTS: This cohort study of the UK Biobank (data from 2006-2010) and the Mass General Brigham Biobank (2010-2019) assessed the relative and joint contributions of rare genetic variants and a common variant (polygenic) score to risk of HCM. Both rare and common variant predictors were then evaluated in the context of relevant clinical risk factors. Data analysis was conducted from May 2021 to February 2022. EXPOSURES: Pathogenic rare variants, common-variant (polygenic) score, and clinical risk factors. MAIN OUTCOMES AND MEASURES: Risk of HCM. RESULTS: The primary study population comprised 184 511 individuals from the UK Biobank. Mean (SD) age was 56 (8) years, 83 690 (45%) of participants were men, and 204 (0.1%) participants had HCM. Of 51 genes included in clinical genetic testing panels for HCM, pathogenic or likely pathogenic variants in 14 core genes (designated by the American College of Medical Genetics and Genomics [ACMG]) were associated with 55-fold higher odds (95% CI, 35-83) of HCM, while those in the remaining 37 non-ACMG genes were not significantly associated with HCM (OR, 1.8; 95% CI, 0.6-4.0). ClinVar pathogenic or likely pathogenic mutations in MYBPC3 (OR, 72; 95% CI, 39-124) and MYH7 (OR, 61; 95% CI, 26-121) were strongly associated with HCM, as were loss-of-function variants in ALPK3 (OR, 13; 95% CI, 4.4-28). A polygenic score was strongly associated with HCM (OR per SD increase in score, 1.6; 95% CI, 1.4-1.8), with concordant results in the Mass General Brigham Biobank. Genetic factors enhanced clinical risk prediction for HCM: addition of rare variant carrier status and the polygenic score to clinical risk factors (obesity, hypertension, atrial fibrillation, and coronary artery disease) improved the area under the receiver operator characteristic curve from 0.71 (95% CI, 0.65-0.77) to 0.82 (95% CI, 0.77-0.87). CONCLUSIONS AND RELEVANCE: Both rare and common genetic variants contribute substantially to HCM susceptibility in the general population and improve HCM risk prediction beyond that achieved with clinical factors.
Cardioprotection by selective SGLT-2 inhibitors in a non-diabetic mouse model of myocardial ischemia/reperfusion injury: a class or a drug effect?
Nikolaou PE, Mylonas N, Makridakis M … +15 more , Makrecka-Kuka M, Iliou A, Zerikiotis S, Efentakis P, Kampoukos S, Kostomitsopoulos N, Vilskersts R, Ikonomidis I, Lambadiari V, Zuurbier CJ, Latosinska A, Vlahou A, Dimitriadis G, Iliodromitis EK, Andreadou I
Basic Res Cardiol · 2022 May · PMID 35581445 · Publisher ↗
Major clinical trials with sodium glucose co-transporter-2 inhibitors (SGLT-2i) exhibit protective effects against heart failure events, whereas inconsistencies regarding the cardiovascular death outcomes are observed. T...
Major clinical trials with sodium glucose co-transporter-2 inhibitors (SGLT-2i) exhibit protective effects against heart failure events, whereas inconsistencies regarding the cardiovascular death outcomes are observed. Therefore, we aimed to compare the selective SGLT-2i empagliflozin (EMPA), dapagliflozin (DAPA) and ertugliflozin (ERTU) in terms of infarct size (IS) reduction and to reveal the cardioprotective mechanism in healthy non-diabetic mice. C57BL/6 mice randomly received vehicle, EMPA (10 mg/kg/day) and DAPA or ERTU orally at the stoichiometrically equivalent dose (SED) for 7 days. 24 h-glucose urinary excretion was determined to verify SGLT-2 inhibition. IS of the region at risk was measured after 30 min ischemia (I), and 120 min reperfusion (R). In a second series, the ischemic myocardium was collected (10th min of R) for shotgun proteomics and evaluation of the cardioprotective signaling. In a third series, we evaluated the oxidative phosphorylation capacity (OXPHOS) and the mitochondrial fatty acid oxidation capacity by measuring the respiratory rates. Finally, Stattic, the STAT-3 inhibitor and wortmannin were administered in both EMPA and DAPA groups to establish causal relationships in the mechanism of protection. EMPA, DAPA and ERTU at the SED led to similar SGLT-2 inhibition as inferred by the significant increase in glucose excretion. EMPA and DAPA but not ERTU reduced IS. EMPA preserved mitochondrial functionality in complex I&II linked oxidative phosphorylation. EMPA and DAPA treatment led to NF-kB, RISK, STAT-3 activation and the downstream apoptosis reduction coinciding with IS reduction. Stattic and wortmannin attenuated the cardioprotection afforded by EMPA and DAPA. Among several upstream mediators, fibroblast growth factor-2 (FGF-2) and caveolin-3 were increased by EMPA and DAPA treatment. ERTU reduced IS only when given at the double dose of the SED (20 mg/kg/day). Short-term EMPA and DAPA, but not ERTU administration at the SED reduce IS in healthy non-diabetic mice. Cardioprotection is not correlated to SGLT-2 inhibition, is STAT-3 and PI3K dependent and associated with increased FGF-2 and Cav-3 expression.
Neonatal injury models: integral tools to decipher the molecular basis of cardiac regeneration.
Costa A, Cushman S, Haubner BJ … +3 more , Derda AA, Thum T, Bär C
Basic Res Cardiol · 2022 May · PMID 35503383 · Full text
Myocardial injury often leads to heart failure due to the loss and insufficient regeneration of resident cardiomyocytes. The low regenerative potential of the mammalian heart is one of the main drivers of heart failure p...
Myocardial injury often leads to heart failure due to the loss and insufficient regeneration of resident cardiomyocytes. The low regenerative potential of the mammalian heart is one of the main drivers of heart failure progression, especially after myocardial infarction accompanied by large contractile muscle loss. Preclinical therapies for cardiac regeneration are promising, but clinically still missing. Mammalian models represent an excellent translational in vivo platform to test drugs and treatments for the promotion of cardiac regeneration. Particularly, short-lived mice offer the possibility to monitor the outcome of such treatments throughout the life span. Importantly, there is a short period of time in newborn mice in which the heart retains full regenerative capacity after cardiac injury, which potentially also holds true for the neonatal human heart. Thus, in vivo neonatal mouse models of cardiac injury are crucial to gain insights into the molecular mechanisms underlying the cardiac regenerative processes and to devise novel therapeutic strategies for the treatment of diseased adult hearts. Here, we provide an overview of the established injury models to study cardiac regeneration. We summarize pioneering studies that demonstrate the potential of using neonatal cardiac injury models to identify factors that may stimulate heart regeneration by inducing endogenous cardiomyocyte proliferation in the adult heart. To conclude, we briefly summarize studies in large animal models and the insights gained in humans, which may pave the way toward the development of novel approaches in regenerative medicine.
Optogenetic manipulation of cardiac electrical dynamics using sub-threshold illumination: dissecting the role of cardiac alternans in terminating rapid rhythms.
Biasci V, Santini L, Marchal GA … +11 more , Hussaini S, Ferrantini C, Coppini R, Loew LM, Luther S, Campione M, Poggesi C, Pavone FS, Cerbai E, Bub G, Sacconi L
Basic Res Cardiol · 2022 Apr · PMID 35488105 · Full text
Cardiac action potential (AP) shape and propagation are regulated by several key dynamic factors such as ion channel recovery and intracellular Ca cycling. Experimental methods for manipulating AP electrical dynamics com...
Cardiac action potential (AP) shape and propagation are regulated by several key dynamic factors such as ion channel recovery and intracellular Ca cycling. Experimental methods for manipulating AP electrical dynamics commonly use ion channel inhibitors that lack spatial and temporal specificity. In this work, we propose an approach based on optogenetics to manipulate cardiac electrical activity employing a light-modulated depolarizing current with intensities that are too low to elicit APs (sub-threshold illumination), but are sufficient to fine-tune AP electrical dynamics. We investigated the effects of sub-threshold illumination in isolated cardiomyocytes and whole hearts by using transgenic mice constitutively expressing a light-gated ion channel (channelrhodopsin-2, ChR2). We find that ChR2-mediated depolarizing current prolongs APs and reduces conduction velocity (CV) in a space-selective and reversible manner. Sub-threshold manipulation also affects the dynamics of cardiac electrical activity, increasing the magnitude of cardiac alternans. We used an optical system that uses real-time feedback control to generate re-entrant circuits with user-defined cycle lengths to explore the role of cardiac alternans in spontaneous termination of ventricular tachycardias (VTs). We demonstrate that VT stability significantly decreases during sub-threshold illumination primarily due to an increase in the amplitude of electrical oscillations, which implies that cardiac alternans may be beneficial in the context of self-termination of VT.
[The role of thrombin in the pathogenesis of atherosclerosis and its complications].
Dukhin OA, Kalinsaya AI, Shpektor AV … +1 more , Vasilieva EY
Kardiologiia · 2022 Mar · PMID 35414364 · Publisher ↗
Thrombin is a key regulator of the homeostasis system. Also, it actively participates in progression of various systemic diseases, including atherosclerosis. There is a large amount of experimental and clinical data on t...
Thrombin is a key regulator of the homeostasis system. Also, it actively participates in progression of various systemic diseases, including atherosclerosis. There is a large amount of experimental and clinical data on the involvement of thrombin in the pathogenesis of ischemic heart disease (IHD). Thus, studying thrombin activity regulation is promising. Also, the question whether it is possible to use biomarkers of thrombin activity as predictors of cardiovascular complications in IHD patients is relevant. The present review focuses on major mechanisms of thrombin functioning, its role in development and progression of atherosclerosis, and available tests for evaluation of thrombin functional activity. Major clinical studies are discussed that evaluated the efficacy of thrombin inhibitors and protease-activated receptor antagonists.
Electron microscopy of cardiac 3D nanodynamics: form, function, future.
Kohl P, Greiner J, Rog-Zielinska EA
Nat Rev Cardiol · 2022 Sep · PMID 35396547 · Publisher ↗
The 3D nanostructure of the heart, its dynamic deformation during cycles of contraction and relaxation, and the effects of this deformation on cell function remain largely uncharted territory. Over the past decade, the f...
The 3D nanostructure of the heart, its dynamic deformation during cycles of contraction and relaxation, and the effects of this deformation on cell function remain largely uncharted territory. Over the past decade, the first inroads have been made towards 3D reconstruction of heart cells, with a native resolution of around 1 nm, and of individual molecules relevant to heart function at a near-atomic scale. These advances have provided access to a new generation of data and have driven the development of increasingly smart, artificial intelligence-based, deep-learning image-analysis algorithms. By high-pressure freezing of cardiomyocytes with millisecond accuracy after initiation of an action potential, pseudodynamic snapshots of contraction-induced deformation of intracellular organelles can now be captured. In combination with functional studies, such as fluorescence imaging, exciting insights into cardiac autoregulatory processes at nano-to-micro scales are starting to emerge. In this Review, we discuss the progress in this fascinating new field to highlight the fundamental scientific insight that has emerged, based on technological breakthroughs in biological sample preparation, 3D imaging and data analysis; to illustrate the potential clinical relevance of understanding 3D cardiac nanodynamics; and to predict further progress that we can reasonably expect to see over the next 10 years.
Regional analysis of inflammation and contractile function in reperfused acute myocardial infarction by in vivo F cardiovascular magnetic resonance in pigs.
Bönner F, Gastl M, Nienhaus F … +14 more , Rothe M, Jahn A, Pfeiler S, Gross U, Schultheiss HP, Ibanez B, Kozerke S, Szendroedi J, Roden M, Westenfeld R, Schrader J, Flögel U, Heusch G, Kelm M
Basic Res Cardiol · 2022 Apr · PMID 35389088 · Full text
Inflammatory cell infiltration is central to healing after acute myocardial infarction (AMI). The relation of regional inflammation to edema, infarct size (IS), microvascular obstruction (MVO), intramyocardial hemorrhage...
Inflammatory cell infiltration is central to healing after acute myocardial infarction (AMI). The relation of regional inflammation to edema, infarct size (IS), microvascular obstruction (MVO), intramyocardial hemorrhage (IMH), and regional and global LV function is not clear. Here we noninvasively characterized regional inflammation and contractile function in reperfused AMI in pigs using fluorine (F) cardiovascular magnetic resonance (CMR). Adult anesthetized pigs underwent left anterior descending coronary artery instrumentation with either 90 min occlusion (n = 17) or without occlusion (sham, n = 5). After 3 days, in surviving animals a perfluorooctyl bromide nanoemulsion was infused intravenously to label monocytes/macrophages. At day 6, in vivo H-CMR was performed with cine, T2 and T2* weighted imaging, T2 and T1 mapping, perfusion and late gadolinium enhancement followed by F-CMR. Pigs were sacrificed for subsequent ex vivo scans and histology. Edema extent was 35 ± 8% and IS was 22 ± 6% of LV mass. Six of ten surviving AMI animals displayed both MVO and IMH (3.3 ± 1.6% and 1.9 ± 0.8% of LV mass). The F signal, reflecting the presence and density of monocytes/macrophages, was consistently smaller than edema volume or IS and not apparent in remote areas. The F signal-to-noise ratio (SNR) > 8 in the infarct border zone was associated with impaired remote systolic wall thickening. A whole heart value of F integral (F SNR × milliliter) > 200 was related to initial LV remodeling independently of edema, IS, MVO, and IMH. Thus, F-CMR quantitatively characterizes regional inflammation after AMI and its relation to edema, IS, MVO, IMH and regional and global LV function and remodeling.
Uncovering the molecular identity of cardiosphere-derived cells (CDCs) by single-cell RNA sequencing.
Kogan PS, Wirth F, Tomar A … +24 more , Darr J, Teperino R, Lahm H, Dreßen M, Puluca N, Zhang Z, Neb I, Beck N, Luzius T, de la Osa de la Rosa L, Gärtner K, Hüls C, Zeidler R, Ramanujam D, Engelhardt S, Wenk C, Holdt LM, Mononen M, Sahara M, Cleuziou J, Hörer J, Lange R, Krane M, Doppler SA
Basic Res Cardiol · 2022 Mar · PMID 35258704 · Full text
Cardiosphere-derived cells (CDCs) generated from human cardiac biopsies have been shown to have disease-modifying bioactivity in clinical trials. Paradoxically, CDCs' cellular origin in the heart remains elusive. We stud...
Cardiosphere-derived cells (CDCs) generated from human cardiac biopsies have been shown to have disease-modifying bioactivity in clinical trials. Paradoxically, CDCs' cellular origin in the heart remains elusive. We studied the molecular identity of CDCs using single-cell RNA sequencing (sc-RNAseq) in comparison to cardiac non-myocyte and non-hematopoietic cells (cardiac fibroblasts/CFs, smooth muscle cells/SMCs and endothelial cells/ECs). We identified CDCs as a distinct and mitochondria-rich cell type that shared biological similarities with non-myocyte cells but not with cardiac progenitor cells derived from human-induced pluripotent stem cells. CXCL6 emerged as a new specific marker for CDCs. By analysis of sc-RNAseq data from human right atrial biopsies in comparison with CDCs we uncovered transcriptomic similarities between CDCs and CFs. By direct comparison of infant and adult CDC sc-RNAseq data, infant CDCs revealed GO-terms associated with cardiac development. To analyze the beneficial effects of CDCs (pro-angiogenic, anti-fibrotic, anti-apoptotic), we performed functional in vitro assays with CDC-derived extracellular vesicles (EVs). CDC EVs augmented in vitro angiogenesis and did not stimulate scarring. They also reduced the expression of pro-apoptotic Bax in NRCMs. In conclusion, CDCs were disclosed as mitochondria-rich cells with unique properties but also with similarities to right atrial CFs. CDCs displayed highly proliferative, secretory and immunomodulatory properties, characteristics that can also be found in activated or inflammatory cell types. By special culture conditions, CDCs earn some bioactivities, including angiogenic potential, which might modify disease in certain disorders.
RGS3L allows for an M muscarinic receptor-mediated RhoA-dependent inotropy in cardiomyocytes.
Levay MK, Krobert KA, Vogt A … +8 more , Ahmad A, Jungmann A, Neuber C, Pasch S, Hansen A, Müller OJ, Lutz S, Wieland T
Basic Res Cardiol · 2022 Mar · PMID 35230541 · Full text
The role and outcome of the muscarinic M acetylcholine receptor (MR) signaling in healthy and diseased cardiomyocytes is still a matter of debate. Here, we report that the long isoform of the regulator of G protein signa...
The role and outcome of the muscarinic M acetylcholine receptor (MR) signaling in healthy and diseased cardiomyocytes is still a matter of debate. Here, we report that the long isoform of the regulator of G protein signaling 3 (RGS3L) functions as a switch in the muscarinic signaling, most likely of the MR, in primary cardiomyocytes. High levels of RGS3L, as found in heart failure, redirect the G-mediated Rac1 activation into a G-mediated RhoA/ROCK activation. Functionally, this switch resulted in a reduced production of reactive oxygen species (- 50%) in cardiomyocytes and an inotropic response (+ 18%) in transduced engineered heart tissues. Importantly, we could show that an adeno-associated virus 9-mediated overexpression of RGS3L in rats in vivo, increased the contractility of ventricular strips by maximally about twofold. Mechanistically, we demonstrate that this switch is mediated by a complex formation of RGS3L with the GTPase-activating protein p190RhoGAP, which balances the activity of RhoA and Rac1 by altering its substrate preference in cardiomyocytes. Enhancement of this complex formation could open new possibilities in the regulation of the contractility of the diseased heart.
[The frequency and profile of drug treatment in subjects with dyslipidemias and cardimetabolic diseases in an urban russian population older then 55 years].
Malyutina SK, Mazdorova EV, Shapkina MY … +6 more , Avdeeva EM, Simonova GI, Hubacek JA, Bobak M, Nikitin YP, Ryabikov AN
Kardiologiia · 2021 Dec · PMID 35057721 · Publisher ↗
Aim To analyze frequency and profile of the lipid-lowering therapy (LLT) in patients with dyslipidemia (DLP) and cardiometabolic diseases (CMD) in a population sample aged 55-84 years at the current time (2015-2017)...
Aim To analyze frequency and profile of the lipid-lowering therapy (LLT) in patients with dyslipidemia (DLP) and cardiometabolic diseases (CMD) in a population sample aged 55-84 years at the current time (2015-2017).Material and methods Despite guidelines on DLP treatment and the availability of effective and safe lipid-lowering drugs, control of DPL in primary and secondary prevention of cardiovascular diseases (CVD) is insufficient. Knowledge of the level of pharmaceutical correction of DLP in the Russian population is limited; it requires an LLT assessment in various regions and in a wide age range, and a regular monitoring taking into account changing approaches to the correction of DLP. A random population of men and women aged 55-84 years (n=3 896) was evaluated in Novosibirsk in 2015-2017 (project HAPIEE). A joint DLP category was established as low-density lipoprotein cholesterol (LDL-C) ≥3.0 mmol/l, or total cholesterol (TC) ≥5.0 mmol/l, or triglycerides (TG) ≥1.7 mmol/l, or LLT. The combined group of DLP and CMD included ischemic heart disease (IHD), type 2 diabetes mellitus (DM2), and DLP. Regular LLD treatment for the recent 12 months, excluding the dosage of medicines, was assessed using the Anatomic Therapeutic Chemical (ATC) classification. The conditional control of serum lipids was taken as the achievement of LDL-C <3.0 mmol/l, TC <5.0 mmol/l, and TG <1.7 mmol/l.Results In the study sample, the total prevalence of DLP and CMD was 88 % (82.8 % for men and 91.3 % for women, p<0.001). 48.3% of patients in the IHD group, 35.0% in the DM2 group, 29.4% in the DLP group, and 32.8% in the CMD group took LLT. Control of serum lipids was achieved in 18.3% (37.9 % of patients on LLT) of patients with IHD; 9 % (25.6 % of patients on LLT) of patients with DM2; 7.3 % (24.8 % of patients on LLT) of patients with DLP; and 9.0 % (27.6 % of patients on LLTсреди) in the DLP and CMD group. Women with DM2 and DLP more frequently achieved lipid control than men (p<0.001). 98.7 % of study participants took statins as LLT.Conclusion In the sample of urban population aged 55-84 years in 2015-2017, 90 % of patients had DLP or CMD, and at least ¾ of them required blood lipid control. The lipid control was achieved in every fifth IHD patient and in approximately 40% of those who took LLT. For DM2 or DLP patients, the lipid control was achieved in every tenth patient and in approximately 25% of those receiving LLT. Frequency of lipid control in IHD patients was comparable for men and women; in DM2 and DLP, men less frequently achieved the lipid control than women. About 70% of patients in the combined DLP and CMD group and more than 50% of IHD patients did not take LLT, which considerably contributed to the insufficient lipid control in primary and secondary prevention of atherosclerotic CVDs in this population.
Myocardial Inflammation and Sudden Death in the Inherited Cardiomyopathies.
McKenna WJ, Caforio ALP
Can J Cardiol · 2022 Apr · PMID 35032619 · Publisher ↗
The best studied of the inherited cardiomyopathies-hypertrophic (HCM), dilated (DCM) and arrhythmogenic (ACM)-present overlapping clinical phenotypes with varying, often unrecognized, risk of sudden death. Risk assessmen...
The best studied of the inherited cardiomyopathies-hypertrophic (HCM), dilated (DCM) and arrhythmogenic (ACM)-present overlapping clinical phenotypes with varying, often unrecognized, risk of sudden death. Risk assessment is informed by patient sex and by the specific disease-causing variant. HCM and arrhythmogenic right ventricular cardiomyopathy (ARVC) remain important causes of sudden death. A phenotype mimicking DCM in patients with inherited ACM is associated with premature sudden death in families with overlapping DCM and ACM phenotypes. The role of inflammation as a determinant of disease development and progression and sudden death is poorly understood but potentially important. Sudden death registries report myocarditis as the cause in 5% to 13%; examination of 30 hearts from victims of ARVC sudden death found focal myocarditis in areas of myocyte necrosis in 20 (67%). The link to specific disease-causing variants remains to be explored, including genetic determinants of the immune response. Clinical and experimental studies support immune- and autoimmune-mediated disease in DCM and ACM. Immunosuppression in biopsy-proven noninfectious myocarditis and inflammatory DCM is a treatment option. Recognition of ACM requires greater focus on distinguishing ACM from DCM. The potential to recognize disease before adverse events and to characterize patients who may benefit from immunosuppression or device therapy highlights the importance of more comprehensive genetic and immunologic characterization of patients with myocarditis and in those with a family history or clinical presentation of an inherited cardiomyopathy. This review will examine from a predominantly clinical perspective the potential importance of myocardial inflammation as a determinant of sudden death in inherited HCM, DCM, and ACM.
Sudden Cardiac Death in Diabetes and Obesity: Mechanisms and Therapeutic Strategies.
Remme CA
Can J Cardiol · 2022 Apr · PMID 35017043 · Publisher ↗
Ventricular arrhythmias and sudden cardiac death (SCD) occur most frequently in the setting of coronary artery disease, cardiomyopathy and heart failure but are also increasingly observed in persons suffering from diabet...
Ventricular arrhythmias and sudden cardiac death (SCD) occur most frequently in the setting of coronary artery disease, cardiomyopathy and heart failure but are also increasingly observed in persons suffering from diabetes mellitus and obesity. The incidence of these metabolic disorders is rising in Western countries, but adequate prevention and treatment of arrhythmias and SCD in affected patients is limited because of our incomplete knowledge of the underlying disease mechanisms. Here, an overview is presented of the prevalence of electrophysiological disturbances, ventricular arrhythmias, and SCD in the clinical setting of diabetes and obesity. Experimental studies are reviewed, which have identified disease pathways and associated modulatory factors, in addition to pro-arrhythmic mechanisms. Key processes are discussed, including mitochondrial dysfunction, oxidative stress, cardiac structural derangements, abnormal cardiac conduction, ion channel dysfunction, prolonged repolarization, and dysregulation of intracellular sodium and calcium homeostasis. In addition, the recently identified pro-arrhythmic effects of dysregulated branched chain amino acid metabolism, a common feature in patients with metabolic disorders, are addressed. Finally, current management options are discussed in addition to the potential development of novel preventive and therapeutic strategies based on recent insight gained from translational studies.
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