Sen P, Hamers J, Sittig T
… +13 more, Shashikadze B, d'Ambrosio L, Stöckl JB, Bierschenk S, Zhang H, d'Alessio C, Zandbergen LM, Pauly V, Clauss S, Wolf E, Dendorfer A, Fröhlich T, Merkus D
Basic Res Cardiol
· 2024 Dec · PMID 39404904
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Chronic kidney disease (CKD) predisposes to cardiac remodeling and coronary microvascular dysfunction. Studies in swine identified changes in microvascular structure and function, as well as changes in mitochondrial stru...Chronic kidney disease (CKD) predisposes to cardiac remodeling and coronary microvascular dysfunction. Studies in swine identified changes in microvascular structure and function, as well as changes in mitochondrial structure and oxidative stress. However, CKD was combined with metabolic derangement, thereby obscuring the contribution of CKD alone. Therefore, we studied the impact of CKD on the heart and combined proteome studies with measurement of cardiac function and perfusion to identify processes involved in cardiac remodeling in CKD. CKD was induced in swine at 10-12 weeks of age while sham-operated swine served as controls. 5-6 months later, left ventricular (LV) function and coronary flow reserve were measured. LC-MS-MS-based proteomic analysis of LV tissue was performed. LV myocardium and kidneys were histologically examined for interstitial fibrosis and oxidative stress. Renal embolization resulted in mild chronic kidney injury (increased fibrosis and urinary NGAL). PV loops showed LV dilation and increased wall stress, while preload recruitable stroke work was impaired in CKD. Quantitative proteomic analysis of LV myocardium and STRING pre-ranked functional analysis showed enrichments in pathways related to contractile function, reactive oxygen species, and extracellular matrix (ECM) remodeling, which were confirmed histologically and associated with impaired total anti-oxidant capacity. HO exposure of myocardial slices from CKD, but not normal swine, impaired contractile function. Furthermore, in CKD, mitochondrial proteins were downregulated suggesting mitochondrial dysfunction which was associated with higher basal coronary blood flow. Thus, mild CKD induces alterations in mitochondrial proteins along with contractile proteins, oxidative stress and ECM remodeling, that were associated with changes in cardiac function and perfusion.
Over the past 50 years, the number and invasiveness of percutaneous cardiovascular procedures globally have increased substantially. However, cardiovascular interventions are inherently associated with a risk of acute br...Over the past 50 years, the number and invasiveness of percutaneous cardiovascular procedures globally have increased substantially. However, cardiovascular interventions are inherently associated with a risk of acute brain injury, both periprocedurally and postprocedurally, which impairs medical outcomes and increases health-care costs. Current international clinical guidelines generally do not cover the area of acute brain injury related to cardiovascular invasive procedures. In this international Consensus Statement, we compile the available knowledge (including data on prevalence, pathophysiology, risk factors, clinical presentation and management) to formulate consensus recommendations on the prevention, diagnosis and treatment of acute brain injury caused by cardiovascular interventions. We also identify knowledge gaps and possible future directions in clinical research into acute brain injury related to cardiovascular interventions.
Basic Res Cardiol
· 2025 Feb · PMID 39311910
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Patients with cancer face a significant risk of cardiovascular death, regardless of time since cancer diagnosis. Elderly patients are particularly more susceptible as cancer-associated cardiac complications present in ad...Patients with cancer face a significant risk of cardiovascular death, regardless of time since cancer diagnosis. Elderly patients are particularly more susceptible as cancer-associated cardiac complications present in advanced stage cancer. These patients may often present with symptoms observed in chronic heart failure (HF). Cardiac wasting, commonly observed in these patients, is a multifaceted syndrome characterized by systemic metabolic alterations and inflammatory processes that specifically affect cardiac function and structure. Experimental and clinical studies have demonstrated that cancer-associated cardiac wasting is linked with cardiac atrophy and altered cardiac morphology, which impairs cardiac function, particularly pertaining to the left ventricle. Therefore, this review aims to present a summary of epidemiologic data and pathophysiological mechanisms of cardiac wasting due to cancer, and future directions in this field.
JAMA Cardiol
· 2024 Nov · PMID 39230897
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IMPORTANCE: Understanding of the genetics of accessory atrioventricular pathways (APs) and affiliated arrhythmias is limited. OBJECTIVE: To investigate the genetics of APs and affiliated arrhythmias. DESIGN, SETTING, AND...IMPORTANCE: Understanding of the genetics of accessory atrioventricular pathways (APs) and affiliated arrhythmias is limited. OBJECTIVE: To investigate the genetics of APs and affiliated arrhythmias. DESIGN, SETTING, AND PARTICIPANTS: This was a genome-wide association study (GWAS) of APs, defined by International Classification of Diseases (ICD) codes and/or confirmed by electrophysiology (EP) study. Genome-wide significant AP variants were tested for association with AP-affiliated arrhythmias: paroxysmal supraventricular tachycardia (PSVT), atrial fibrillation (AF), ventricular tachycardia, and cardiac arrest. AP variants were also tested in data on other heart diseases and measures of cardiac physiology. Individuals with APs and control individuals from Iceland (deCODE Genetics), Denmark (Copenhagen Hospital Biobank, Danish Blood Donor Study, and SupraGen/the Danish General Suburban Population Study [GESUS]), the US (Intermountain Healthcare), and the United Kingdom (UK Biobank) were included. Time of phenotype data collection ranged from January 1983 to December 2022. Data were analyzed from August 2022 to January 2024. EXPOSURES: Sequence variants. MAIN OUTCOMES AND MEASURES: Genome-wide significant association of sequence variants with APs. RESULTS: The GWAS included 2310 individuals with APs (median [IQR] age, 43 [28-57] years; 1252 [54.2%] male and 1058 [45.8%] female) and 1 206 977 control individuals (median [IQR] year of birth, 1955 [1945-1970]; 632 888 [52.4%] female and 574 089 [47.6%] male). Of the individuals with APs, 909 had been confirmed in EP study. Three common missense variants were associated with APs, in the genes CCDC141 (p.Arg935Trp: adjusted odds ratio [aOR], 1.37; 95% CI, 1.24-1.52, and p.Ala141Val: aOR, 1.55; 95% CI 1.34-1.80) and SCN10A (p.Ala1073Val: OR, 1.22; 95% CI, 1.15-1.30). The 3 variants associated with PSVT and the SCN10A variant associated with AF, supporting an effect on AP-affiliated arrhythmias. All 3 AP risk alleles were associated with higher heart rate and shorter PR interval, and have reported associations with chronotropic response. CONCLUSIONS AND RELEVANCE: Associations were found between sequence variants and APs that were also associated with risk of PSVT, and thus likely atrioventricular reentrant tachycardia, but had allele-specific associations with AF and conduction disorders. Genetic variation in the modulation of heart rate, chronotropic response, and atrial or atrioventricular node conduction velocity may play a role in the risk of AP-affiliated arrhythmias. Further research into CCDC141 could provide insights for antiarrhythmic therapeutic targeting in the presence of an AP.
Panuccio G, Correale P, d'Apolito M
… +13 more, Mutti L, Giannicola R, Pirtoli L, Giordano A, Labate D, Macheda S, Carabetta N, Abdelwahed YS, Landmesser U, Tassone P, Tagliaferri P, De Rosa S, Torella D
Basic Res Cardiol
· 2025 Feb · PMID 39225869
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Immunotherapy represents an emergent and heterogeneous group of anticancer treatments harnessing the human immune-surveillance system, including immune-checkpoint inhibitor monoclonal antibodies (mAbs), Chimeric Antigen...Immunotherapy represents an emergent and heterogeneous group of anticancer treatments harnessing the human immune-surveillance system, including immune-checkpoint inhibitor monoclonal antibodies (mAbs), Chimeric Antigen Receptor T Cells (CAR-T) therapy, cancer vaccines and lymphocyte activation gene-3 (LAG-3) therapy. While remarkably effective against several malignancies, these therapies, often in combination with other cancer treatments, have showed unforeseen toxicity, including cardiovascular complications. The occurrence of immuno-mediated adverse (irAEs) events has been progressively reported in the last 10 years. These irAEs present an extended range of severity, from self-limiting to life-threatening conditions. Although recent guidelines in CardioOncology have provided important evidence in managing cancer treatments, they often encompass general approaches. However, a specific focus is required due to the particular etiology, unique risk factors, and associated side effects of immunotherapy. This review aims to deepen the understanding of the prevalence and nature of cardiovascular issues in patients undergoing immunotherapy, offering insights into strategies for risk stratification and management.
Wu L, Li ZZ, Yang H
… +6 more, Cao LZ, Wang XY, Wang DL, Chatterjee E, Li YF, Huang G
Basic Res Cardiol
· 2025 Feb · PMID 39158697
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Exercise is an effective way to alleviate breast cancer-induced cardiac injury to a certain extent. However, whether voluntary exercise (VE) activates cardiac signal transducer and activator of transcription 3 (STAT3) an...Exercise is an effective way to alleviate breast cancer-induced cardiac injury to a certain extent. However, whether voluntary exercise (VE) activates cardiac signal transducer and activator of transcription 3 (STAT3) and the underlying mechanisms remain unclear. This study investigated the role of STAT3-microRNA(miRNA)-targeted protein axis in VE against breast cancer-induced cardiac injury.VE for 4 weeks not only improved cardiac function of transgenic breast cancer female mice [mouse mammary tumor virus-polyomavirus middle T antigen (MMTV-PyMT +)] compared with littermate mice with no cancer (MMTV-PyMT -), but also increased myocardial STAT3 tyrosine 705 phosphorylation. Significantly more obvious cardiac fibrosis, smaller cardiomyocyte size, lower cell viability, and higher serum tumor necrosis factor (TNF)-α were shown in MMTV-PyMT + mice compared with MMTV-PyMT - mice, which were ameliorated by VE. However, VE did not influence the tumor growth. MiRNA sequencing identified that miR-181a-5p was upregulated and miR-130b-3p was downregulated in VE induced-cardioprotection. Myocardial injection of Adeno-associated virus serotype 9 driving STAT3 tyrosine 705 mutations abolished cardioprotective effects above. Myocardial STAT3 was identified as the transcription factor binding the promoters of pri-miR-181a (the precursor of miR-181a-5p) and HOX transcript antisense RNA (HOTAIR, sponged miR-130b-3p) in isolated cardiomyocytes. Furthermore, miR-181a-5p targeting PTEN and miR-130b-3p targeting Zinc finger and BTB domain containing protein 20 (Zbtb20) were proved in AC-16 cells. These findings indicated that VE protects against breast cancer-induced cardiac injury via activating STAT3 to promote miR-181a-5p targeting PTEN and to promote HOTAIR to sponge miR-130b-3p targeting Zbtb20, helping to develop new targets in exercise therapy for breast cancer-induced cardiac injury.
Jabara M, Kose O, Perlman G
… +5 more, Corcos S, Pelletier MA, Possik E, Tsoukas M, Sharma A
Can J Cardiol
· 2024 Oct · PMID 39111729
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Type 2 diabetes mellitus (T2DM), a complex metabolic disorder that burdens the health care system, requires early detection and treatment. Recent strides in digital health technologies, coupled with artificial intelligen...Type 2 diabetes mellitus (T2DM), a complex metabolic disorder that burdens the health care system, requires early detection and treatment. Recent strides in digital health technologies, coupled with artificial intelligence (AI), may have the potential to revolutionize T2DM screening, diagnosis of complications, and management through the development of digital biomarkers. This review provides an overview of the potential applications of AI-driven biomarkers in the context of screening, diagnosing complications, and managing patients with T2DM. The benefits of using multisensor devices to develop digital biomarkers are discussed. The summary of these findings and patterns between model architecture and sensor type are presented. In addition, we highlight the pivotal role of AI techniques in clinical intervention and implementation, encompassing clinical decision support systems, telemedicine interventions, and population health initiatives. Challenges such as data privacy, algorithm interpretability, and regulatory considerations are also highlighted, alongside future research directions to explore the use of AI-driven digital biomarkers in T2DM screening and management.
Sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) or gliflozins, are a new class of cardiovascular drugs with a proven clinical efficacy and a beneficial effect on prognosis in patients with heart failure with...Sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) or gliflozins, are a new class of cardiovascular drugs with a proven clinical efficacy and a beneficial effect on prognosis in patients with heart failure with preserved ejection fraction (HFpEF). Impaired left ventricular (LV) diastolic function (DF) is an important element in the pathogenesis of HFpEF. Experimental studies have found intracellular mechanisms for the so-called diastolic effects in gliflozins. Studies using laboratory models of experimental HFpEF have demonstrated a positive effect of dapagliflozin and empagliflozin on the elastic properties of cardiomyocyte myofilaments, the dynamics of myocardial fibrosis, and intracellular sodium and calcium homeostasis. The significance of anti-inflammatory, antioxidant properties of gliflozins in improving the cardiomyocyte DF has been experimentally established. The effect of SGLT2 inhibitors on LV DF in patients at high risk for cardiovascular diseases and their complications, that has been demonstrated in relatively small clinical studies, is due to primary cardiac and secondary effects. Results of individual studies confirmed the protective (in relation to myocardial relaxation) properties of gliflozins in the conditions of a diastolic stress test. The regression of LV diastolic dysfunction associated with the SGLT2 inhibitor treatment found in small observational studies is important in the context of the significant beneficial effect of empagliflozin and dapagliflozin on the prognosis of cardiovascular diseases that has been demonstrated in large randomized clinical trials in patients with HFpEF.
Hypertension is a leading risk factor for stroke, heart disease and chronic kidney disease. Multiple interacting factors and organ systems increase blood pressure and cause target-organ damage. Among the many molecular e...Hypertension is a leading risk factor for stroke, heart disease and chronic kidney disease. Multiple interacting factors and organ systems increase blood pressure and cause target-organ damage. Among the many molecular elements involved in the development of hypertension are reactive oxygen species (ROS), which influence cellular processes in systems that contribute to blood pressure elevation (such as the cardiovascular, renal, immune and central nervous systems, or the renin-angiotensin-aldosterone system). Dysregulated ROS production (oxidative stress) is a hallmark of hypertension in humans and experimental models. Of the many ROS-generating enzymes, NADPH oxidases are the most important in the development of hypertension. At the cellular level, ROS influence signalling pathways that define cell fate and function. Oxidative stress promotes aberrant redox signalling and cell injury, causing endothelial dysfunction, vascular damage, cardiovascular remodelling, inflammation and renal injury, which are all important in both the causes and consequences of hypertension. ROS scavengers reduce blood pressure in almost all experimental models of hypertension; however, clinical trials of antioxidants have yielded mixed results. In this Review, we highlight the latest advances in the understanding of the role and the clinical implications of ROS in hypertension. We focus on cellular sources of ROS, molecular mechanisms of oxidative stress and alterations in redox signalling in organ systems, and their contributions to hypertension.
The accessibility of the retina with the use of non-invasive and relatively low-cost ophthalmic imaging techniques and analytics provides a unique opportunity to improve the detection, diagnosis and monitoring of systemi...The accessibility of the retina with the use of non-invasive and relatively low-cost ophthalmic imaging techniques and analytics provides a unique opportunity to improve the detection, diagnosis and monitoring of systemic diseases. The National Heart, Lung, and Blood Institute conducted a workshop in October 2022 to examine this concept. On the basis of the discussions at that workshop, this Roadmap describes current knowledge gaps and new research opportunities to evaluate the relationships between the eye (in particular, retinal biomarkers) and the risk of cardiovascular diseases, including coronary artery disease, heart failure, stroke, hypertension and vascular dementia. Identified gaps include the need to simplify and standardize the capture of high-quality images of the eye by non-ophthalmic health workers and to conduct longitudinal studies using multidisciplinary networks of diverse at-risk populations with improved implementation and methods to protect participant and dataset privacy. Other gaps include improving the measurement of structural and functional retinal biomarkers, determining the relationship between microvascular and macrovascular risk factors, improving multimodal imaging 'pipelines', and integrating advanced imaging with 'omics', lifestyle factors, primary care data and radiological reports, by using artificial intelligence technology to improve the identification of individual-level risk. Future research on retinal microvascular disease and retinal biomarkers might additionally provide insights into the temporal development of microvascular disease across other systemic vascular beds.
Nurmohamed NS, Gaillard EL, Malkasian S
… +13 more, de Groot RJ, Ibrahim S, Bom MJ, Kaiser Y, Earls JP, Min JK, Kroon J, Planken RN, Danad I, van Rosendael AR, Choi AD, Stroes ESG, Knaapen P
JAMA Cardiol
· 2024 Sep · PMID 39018040
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IMPORTANCE: Lipoprotein(a) (Lp[a]) is a causal risk factor for cardiovascular disease; however, long-term effects on coronary atherosclerotic plaque phenotype, high-risk plaque formation, and pericoronary adipose tissue...IMPORTANCE: Lipoprotein(a) (Lp[a]) is a causal risk factor for cardiovascular disease; however, long-term effects on coronary atherosclerotic plaque phenotype, high-risk plaque formation, and pericoronary adipose tissue inflammation remain unknown. OBJECTIVE: To investigate the association of Lp(a) levels with long-term coronary artery plaque progression, high-risk plaque, and pericoronary adipose tissue inflammation. DESIGN, SETTING, AND PARTICIPANTS: This single-center prospective cohort study included 299 patients with suspected coronary artery disease (CAD) who underwent per-protocol repeated coronary computed tomography angiography (CCTA) imaging with an interscan interval of 10 years. Thirty-two patients were excluded because of coronary artery bypass grafting, resulting in a study population of 267 patients. Data for this study were collected from October 2008 to October 2022 and analyzed from March 2023 to March 2024. EXPOSURES: The median scan interval was 10.2 years. Lp(a) was measured at follow-up using an isoform-insensitive assay. CCTA scans were analyzed with a previously validated artificial intelligence-based algorithm (atherosclerosis imaging-quantitative computed tomography). MAIN OUTCOME AND MEASURES: The association between Lp(a) and change in percent plaque volumes was investigated in linear mixed-effects models adjusted for clinical risk factors. Secondary outcomes were presence of low-density plaque and presence of increased pericoronary adipose tissue attenuation at baseline and follow-up CCTA imaging. RESULTS: The 267 included patients had a mean age of 57.1 (SD, 7.3) years and 153 were male (57%). Patients with Lp(a) levels of 125 nmol/L or higher had twice as high percent atheroma volume (6.9% vs 3.0%; P = .01) compared with patients with Lp(a) levels less than 125 nmol/L. Adjusted for other risk factors, every doubling of Lp(a) resulted in an additional 0.32% (95% CI, 0.04-0.60) increment in percent atheroma volume during the 10 years of follow-up. Every doubling of Lp(a) resulted in an odds ratio of 1.23 (95% CI, 1.00-1.51) and 1.21 (95% CI, 1.01-1.45) for the presence of low-density plaque at baseline and follow-up, respectively. Patients with higher Lp(a) levels had increased pericoronary adipose tissue attenuation around both the right coronary artery and left anterior descending at baseline and follow-up. CONCLUSIONS AND RELEVANCE: In this long-term prospective serial CCTA imaging study, higher Lp(a) levels were associated with increased progression of coronary plaque burden and increased presence of low-density noncalcified plaque and pericoronary adipose tissue inflammation. These data suggest an impact of elevated Lp(a) levels on coronary atherogenesis of high-risk, inflammatory, rupture-prone plaques over the long term.
Hikino K, Koyama S, Ito K
… +14 more, Koike Y, Koido M, Matsumura T, Kurosawa R, Tomizuka K, Ito S, Liu X, Ishikawa Y, Momozawa Y, Morisaki T, Kamatani Y, Mushiroda T, Terao C, Biobank Japan Project
JAMA Cardiol
· 2024 Aug · PMID 38888930
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IMPORTANCE: Vasospastic angina (VSA) is vasospasm of the coronary artery and is particularly prevalent in East Asian populations. However, the specific genetic architecture for VSA at genome-wide levels is not fully unde...IMPORTANCE: Vasospastic angina (VSA) is vasospasm of the coronary artery and is particularly prevalent in East Asian populations. However, the specific genetic architecture for VSA at genome-wide levels is not fully understood. OBJECTIVE: To identify genetic factors associated with VSA. DESIGN, SETTING, AND PARTICIPANTS: This was a case-control genome-wide association study of VSA. Data from Biobank Japan (BBJ; enrolled patients from 2002-2008 and 2013-2018) were used, and controls without coronary artery disease (CAD) were enrolled. Patients from the BBJ were genotyped using arrays or a set of arrays. Patients recruited between 2002 and 2005 were classified within the first dataset, and those recruited between 2006 and 2008 were classified within the second dataset. To replicate the genome-wide association study in the first and second datasets, VSA cases and control samples from the latest patients in the BBJ recruited between 2013 and 2018 were analyzed in a third dataset. EXPOSURES: Single-nucleotide variants associated with VSA. MAIN OUTCOMES AND MEASURES: Cases with VSA and controls without CAD. RESULTS: A total of 5720 cases (mean [SD] age, 67 [10] years; 3672 male [64.2%]) and 153 864 controls (mean [SD] age, 62 [15] years; 77 362 male [50.3%]) in 3 datasets were included in this study. The variants at the RNF213 locus showed the strongest association with VSA across the 3 datasets (odds ratio [OR], 2.34; 95% CI, 1.99-2.74; P = 4.4 × 10-25). Additionally, rs112735431, an Asian-specific rare deleterious variant (p.Arg4810Lys) experimentally shown to be associated with reduced angiogenesis and a well-known causal risk for Moyamoya disease was the most promising candidate for a causal variant explaining the association. The effect size of rs112735431 on VSA was distinct from that of other CADs. Furthermore, homozygous carriers of rs112735431 showed an association with VSA characterized by a large effect estimate (OR, 18.34; 95% CI, 5.15-65.22; P = 7.0 × 10-6), deviating from the additive model (OR, 4.35; 95% CI, 1.18-16.05; P = .03). Stratified analyses revealed that rs112735431 exhibited a stronger association in males (χ21 = 7.24; P = .007) and a younger age group (OR, 3.06; 95% CI, 2.24-4.19), corresponding to the epidemiologic features of VSA. In the registry, carriers without CAD of the risk allele rs112735431 had a strikingly high mortality rate due to acute myocardial infarction during the follow-up period (hazard ratio, 2.71; 95% CI, 1.57-4.65; P = 3.3 × 10-4). As previously reported, a possible overlap between VSA and Moyamoya disease was not found. CONCLUSIONS AND RELEVANCE: Results of this study suggest that vascular cell dysfunction mediated by variants in the RNF213 locus may promote coronary vasospasm, and the presence of the risk allele could serve as a predictive factor for the prognosis.
Pagliaro P, Weber NC, Femminò S
… +2 more, Alloatti G, Penna C
Basic Res Cardiol
· 2024 Aug · PMID 38878210
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Despite recent progress, ischemic heart disease poses a persistent global challenge, driving significant morbidity and mortality. The pursuit of therapeutic solutions has led to the emergence of strategies such as ischem...Despite recent progress, ischemic heart disease poses a persistent global challenge, driving significant morbidity and mortality. The pursuit of therapeutic solutions has led to the emergence of strategies such as ischemic preconditioning, postconditioning, and remote conditioning to shield the heart from myocardial ischemia/reperfusion injury (MIRI). These ischemic conditioning approaches, applied before, after, or at a distance from the affected organ, inspire future therapeutic strategies, including pharmacological conditioning. Gasotransmitters, comprising nitric oxide, hydrogen sulfide, sulfur dioxide, and carbon monoxide, play pivotal roles in physiological and pathological processes, exhibiting shared features such as smooth muscle relaxation, antiapoptotic effects, and anti-inflammatory properties. Despite potential risks at high concentrations, physiological levels of gasotransmitters induce vasorelaxation and promote cardioprotective effects. Noble gases, notably argon, helium, and xenon, exhibit organ-protective properties by reducing cell death, minimizing infarct size, and enhancing functional recovery in post-ischemic organs. The protective role of noble gases appears to hinge on their modulation of molecular pathways governing cell survival, leading to both pro- and antiapoptotic effects. Among noble gases, helium and xenon emerge as particularly promising in the field of cardioprotection. This overview synthesizes our current understanding of the roles played by gasotransmitters and noble gases in the context of MIRI and cardioprotection. In addition, we underscore potential future developments involving the utilization of noble gases and gasotransmitter donor molecules in advancing cardioprotective strategies.
Köhler D, Leiss V, Beichert L
… +15 more, Killinger S, Grothe D, Kushwaha R, Schröter A, Roslan A, Eggstein C, Focken J, Granja T, Devanathan V, Schittek B, Lukowski R, Weigelin B, Rosenberger P, Nürnberg B, Beer-Hammer S
Basic Res Cardiol
· 2024 Oct · PMID 38811421
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Neutrophils are not only involved in immune defense against infection but also contribute to the exacerbation of tissue damage after ischemia and reperfusion. We have previously shown that genetic ablation of regulatory...Neutrophils are not only involved in immune defense against infection but also contribute to the exacerbation of tissue damage after ischemia and reperfusion. We have previously shown that genetic ablation of regulatory Gα proteins in mice has both protective and deleterious effects on myocardial ischemia reperfusion injury (mIRI), depending on which isoform is deleted. To deepen and analyze these findings in more detail the contribution of Gα proteins in resident cardiac vs circulating blood cells for mIRI was first studied in bone marrow chimeras. In fact, the absence of Gα in all blood cells reduced the extent of mIRI (22,9% infarct size of area at risk (AAR) Gnai2 → wt vs 44.0% wt → wt; p < 0.001) whereas the absence of Gα in non-hematopoietic cells increased the infarct damage (66.5% wt → Gnai2 vs 44.0% wt → wt; p < 0.001). Previously we have reported the impact of platelet Gα for mIRI. Here, we show that infarct size was substantially reduced when Gα signaling was either genetically ablated in neutrophils/macrophages using LysM-driven Cre recombinase (AAR: 17.9% Gnai2 LysM-Cre vs 42.0% Gnai2; p < 0.01) or selectively blocked with specific antibodies directed against Gα (AAR: 19.0% (anti-Gα) vs 49.0% (IgG); p < 0.001). In addition, the number of platelet-neutrophil complexes (PNCs) in the infarcted area were reduced in both, genetically modified (PNCs: 18 (Gnai2; LysM-Cre) vs 31 (Gnai2); p < 0.001) and in anti-Gα antibody-treated (PNCs: 9 (anti-Gα) vs 33 (IgG); p < 0.001) mice. Of note, significant infarct-limiting effects were achieved with a single anti-Gα antibody challenge immediately prior to vessel reperfusion without affecting bleeding time, heart rate or cellular distribution of neutrophils. Finally, anti-Gα antibody treatment also inhibited transendothelial migration of human neutrophils (25,885 (IgG) vs 13,225 (anti-Gα) neutrophils; p < 0.001), collectively suggesting that a therapeutic concept of functional Gα inhibition during thrombolysis and reperfusion in patients with myocardial infarction should be further considered.
van Drie RWA, van de Wouw J, Zandbergen LM
… +8 more, Dehairs J, Swinnen JV, Mulder MT, Verhaar MC, MaassenVanDenBrink A, Duncker DJ, Sorop O, Merkus D
Basic Res Cardiol
· 2024 Oct · PMID 38796544
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Multiple common cardiovascular comorbidities produce coronary microvascular dysfunction. We previously observed in swine that a combination of diabetes mellitus (DM), high fat diet (HFD) and chronic kidney disease (CKD)...Multiple common cardiovascular comorbidities produce coronary microvascular dysfunction. We previously observed in swine that a combination of diabetes mellitus (DM), high fat diet (HFD) and chronic kidney disease (CKD) induced systemic inflammation, increased oxidative stress and produced coronary endothelial dysfunction, altering control of coronary microvascular tone via loss of NO bioavailability, which was associated with an increase in circulating endothelin (ET). In the present study, we tested the hypotheses that (1) ROS scavenging and (2) ET-receptor blockade improve myocardial oxygen delivery in the same female swine model. Healthy female swine on normal pig chow served as controls (Normal). Five months after induction of DM (streptozotocin, 3 × 50 mg kg i.v.), hypercholesterolemia (HFD) and CKD (renal embolization), swine were chronically instrumented and studied at rest and during exercise. Sustained hyperglycemia, hypercholesterolemia and renal dysfunction were accompanied by systemic inflammation and oxidative stress. In vivo ROS scavenging (TEMPOL + MPG) reduced myocardial oxygen delivery in DM + HFD + CKD swine, suggestive of a vasodilator influence of endogenous ROS, while it had no effect in Normal swine. In vitro wire myography revealed a vasodilator role for hydrogen peroxide (HO) in isolated small coronary artery segments from DM + HFD + CKD, but not Normal swine. Increased catalase activity and ceramide production in left ventricular myocardial tissue of DM + HFD + CKD swine further suggest that increased HO acts as vasodilator ROS in the coronary microvasculature. Despite elevated ET-1 plasma levels in DM + HFD + CKD swine, ET blockade did not affect myocardial oxygen delivery in Normal or DM + HFD + CKD swine. In conclusion, loss of NO bioavailability due to 5 months exposure to multiple comorbidities is partially compensated by increased HO-mediated coronary vasodilation.
Daskalopoulou SS, Labos C, Kuate Defo A
… +4 more, Cooke AB, Kalra B, Kumar A, Mantzoros CS
Can J Cardiol
· 2024 Mar · PMID 38787345
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BACKGROUND: Preeclampsia remains a major cause of maternal and fetal adverse outcomes in pregnancy; however, accurate and universally acceptable predictive tools remain elusive. We investigated whether a panel of biomark...BACKGROUND: Preeclampsia remains a major cause of maternal and fetal adverse outcomes in pregnancy; however, accurate and universally acceptable predictive tools remain elusive. We investigated whether a panel of biomarkers could improve risk prediction for preeclampsia when measured at various pregnancy time points. METHODS: In this prospective cohort study, 192 women with first-trimester high-risk singleton pregnancies were consecutively recruited from tertiary obstetrics clinics in Montréal, Canada. Clinical information (height, pre-pregnancy weight, personal and family medical history, medication use) was collected at baseline. Blood pressure was measured and blood samples collected at each trimester to quantify soluble Fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), pregnancy-associated plasma protein A2 (PAPP-A2), PAPP-A, activin A, inhibin A, follistatin, and glycosylated fibronectin. A random-effects hierarchic logistic regression model was used to relate change in biomarker levels to incidence of preeclampsia. RESULTS: When added to a clinical model composed of maternal age, pre-pregnancy body mass index, race, and mean arterial pressure, a positive third-trimester result for both PAPP-A2 and activin A had a better positive predictive value than the sFlt-1:PlGF ratio added to the clinical model (91.67% [95% confidence interval (CI) 78.57%-100%] vs 66.67% [57.14%-100%]), while maintaining a comparable high negative predictive value (97.69% [95% CI 95.34%-100%] vs 96.00% [92.19%-99.21%]). CONCLUSIONS: Whereas the third-trimester sFlt-1:PlGF ratio can predict short-term absence of preeclampsia, PAPP-A2 and activin A had both high positive and negative predictive values and therefore could serve as biomarkers to predict the occurrence (and absence) of preeclampsia; these findings will be validated in future studies.
Basic Res Cardiol
· 2024 Oct · PMID 38771318
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Chronic kidney disease (CKD) adversely affects the heart. The underlying mechanism and the interplay between the kidney and the heart are still obscure. We examined the cardiac effect using the unilateral ureteral obstru...Chronic kidney disease (CKD) adversely affects the heart. The underlying mechanism and the interplay between the kidney and the heart are still obscure. We examined the cardiac effect using the unilateral ureteral obstruction (UUO)-induced CKD pre-clinical model in mice. Echocardiography, histopathology of the heart, myocardial mRNA expression of ANP and BNP, the extent of fibrotic (TGF-β, α-SMA, and collagen I) and epigenetic (histone deacetylases, namely HDAC3, HDAC4, and HDAC6) proteins, and myocardial inflammatory response were assessed. Six weeks of post-UUO surgery, we observed a compromised left-ventricular wall thickness and signs of cardiac hypertrophy, accumulation of fibrosis associated, and inflammatory proteins in the heart. In addition, we observed a perturbation of epigenetic proteins, especially HDAC3, HDAC4, and HDAC6, in the heart. Pharmacological inhibition of HDAC6 using ricolinostat (RIC) lessened cardiac damage and improved left-ventricular wall thickness. The RIC treatment substantially restored the serum cardiac injury markers, namely creatine kinase-MB and lactate dehydrogenase (LDH) activities, ANP and BNP mRNA expression, and heart histological changes. The extent of myocardial fibrotic proteins, phospho-NF-κB (p65), and pro-inflammatory cytokines (TNF-α, IL-18, and IL-1β) were significantly decreased in the RIC treatment group. Further findings revealed the CKD-induced infiltration of CD3, CD8a, CD11c, and F4/80 positive inflammatory cells in the heart. Treatment with RIC substantially reduced the myocardial infiltration of these inflammatory cells. From these findings, we believe that CKD-induced myocardial HDAC6 perturbation has a deteriorative effect on the heart, and inhibition of HDAC6 can be a promising approach to alleviate CKD-induced myocardial remodeling.
Can J Cardiol
· 2024 Aug · PMID 38759726
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Bedrest as an experimental paradigm or as an in-patient stay for medical reasons has negative consequences for cardiovascular health. The effects of severe inactivity parallel many of the changes experienced with natural...Bedrest as an experimental paradigm or as an in-patient stay for medical reasons has negative consequences for cardiovascular health. The effects of severe inactivity parallel many of the changes experienced with natural aging but over a much shorter duration. Cardiac function is reduced, arteries stiffen, neural reflex responses are impaired, and metabolic and oxidative stress responses impose burden on the heart and vascular systems. The effect of these changes is revealed in studies of integrative function. Aerobic fitness progressively deteriorates with bedrest and tolerance of upright posture is rapidly impaired. In this review we consider the similarities of aging and bedrest-induced cardiovascular deconditioning. We concur with many recent clinical recommendations that early and regular mobility with upright posture will reduce likelihood of hospital-associated disability related to bedrest.
INTRODUCTION: Secretoneurin (SN) is a novel biomarker that provides prognostic information in patients with cardiovascular disease. In experimental models, SN production is increased in the failing myocardium. Currently,...INTRODUCTION: Secretoneurin (SN) is a novel biomarker that provides prognostic information in patients with cardiovascular disease. In experimental models, SN production is increased in the failing myocardium. Currently, no information is available on SN production in human myocardium. Accordingly, we wanted to determine the trans-cardiac gradient of SN in patients with Takotsubo syndrome (TTS), and to correlate circulating SN concentrations with indices of cardiac structure and function. METHODS: We included 15 women diagnosed with TTS according to established criteria. Plasma SN concentrations were measured in blood samples obtained simultaneously from the aortic root and the coronary sinus. Coronary physiology was assessed by invasive measurements, and we used cardiac magnetic resonance imaging to determine left ventricular ejection fraction (LVEF) and cardiac mass. RESULTS: Median age was 65 years and median LVEF was 45%. Median SN concentration was 39 (25th-75th percentile 31-44) pmol/L in the coronary sinus and 37 (30-41) pmol/L in the aortic root (p = 0.02 for difference). SN concentrations in the aortic root showed the highest correlations with N-terminal B-type natriuretic peptide (rho = 0.47) and estimated glomerular filtration rate (rho = -0.41). In contrast, we found weak correlations between SN concentrations and index of myocardial resistance (rho = 0.12), LVEF (rho = 0.08), and cardiac mass (rho = -0.09). CONCLUSION: We demonstrate a positive trans-cardiac gradient of SN in patients with TTS, which supports the hypothesis that SN is produced and released in the human myocardium in situations of myocardial dysfunction and stress.