Journal Of Clinical & Experimental Cardiology[JOURNAL]
Sun
200 papers
Association Between Syncope Trigger Type and Risk of Subsequent Life-Threatening Events in Patients With Long QT Syndrome.
Younis A, Bos JM, Zareba W … +10 more , Aktas MK, Wilde AAM, Tabaja C, Bodurian C, Tobert KE, McNitt S, Polonsky B, Shimizu W, Ackerman MJ, Goldenberg I
JAMA Cardiol · 2023 Aug · PMID 37436769 · Full text
IMPORTANCE: Syncope is the most powerful predictor for subsequent life-threatening events (LTEs) in patients with congenital long QT syndrome (LQTS). Whether distinct syncope triggers are associated with differential sub...
IMPORTANCE: Syncope is the most powerful predictor for subsequent life-threatening events (LTEs) in patients with congenital long QT syndrome (LQTS). Whether distinct syncope triggers are associated with differential subsequent risk of LTEs is unknown. OBJECTIVE: To evaluate the association between adrenergic (AD)- and nonadrenergic (non-AD)-triggered syncopal events and the risk of subsequent LTEs in patients with LQT types 1 to 3 (LQT1-3). DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included data from 5 international LQTS registries (Rochester, New York; the Mayo Clinic, Rochester, Minnesota; Israel, the Netherlands, and Japan). The study population comprised 2938 patients with genetically confirmed LQT1, LQT2, or LQT3 stemming from a single LQTS-causative variant. Patients were enrolled from July 1979 to July 2021. EXPOSURES: Syncope by AD and non-AD triggers. MAIN OUTCOMES AND MEASURES: The primary end point was the first occurrence of an LTE. Multivariate Cox regression was used to determine the association of AD- or non-AD-triggered syncope on the risk of subsequent LTE by genotype. Separate analysis was performed in patients with β-blockers. RESULTS: A total of 2938 patients were included (mean [SD] age at enrollment, 29 [7] years; 1645 [56%] female). In 1331 patients with LQT1, a first syncope occurred in 365 (27%) and was induced mostly with AD triggers (243 [67%]). Syncope preceded 43 subsequent LTEs (68%). Syncopal episodes associated with AD triggers were associated with the highest risk of subsequent LTE (hazard ratio [HR], 7.61; 95% CI, 4.18-14.20; P < .001), whereas the risk associated with syncopal events due to non-AD triggers was statistically nonsignificant (HR, 1.50; 95% CI, 0.21-4.77; P = .97). In 1106 patients with LQT2, a first syncope occurred in 283 (26%) and was associated with AD and non-AD triggers in 106 (37%) and 177 (63%), respectively. Syncope preceded 55 LTEs (56%). Both AD- and non-AD-triggered syncope were associated with a greater than 3-fold increased risk of subsequent LTE (HR, 3.07; 95% CI, 1.66-5.67; P ≤ .001 and HR, 3.45, 95% CI, 1.96-6.06; P ≤ .001, respectively). In contrast, in 501 patients with LQT3, LTE was preceded by a syncopal episode in 7 (12%). In patients with LQT1 and LQT2, treatment with β-blockers following a syncopal event was associated with a significant reduction in the risk of subsequent LTEs. The rate of breakthrough events during treatment with β-blockers was significantly higher among those treated with selective agents vs nonselective agents. CONCLUSION AND RELEVANCE: In this study, trigger-specific syncope in LQTS patients was associated with differential risk of subsequent LTE and response to β-blocker therapy.
New Approaches Targeting the Renin-Angiotensin System: Inhibition of Brain Aminopeptidase A, ACE2 Ubiquitination, and Angiotensinogen.
Lazartigues E, Llorens-Cortes C, Danser AHJ
Can J Cardiol · 2023 Dec · PMID 37348757 · Full text
Despite the availability of various therapeutic classes of antihypertensive drugs, hypertension remains poorly controlled, in part because of poor adherence. Hence, there is a need for the development of antihypertensive...
Despite the availability of various therapeutic classes of antihypertensive drugs, hypertension remains poorly controlled, in part because of poor adherence. Hence, there is a need for the development of antihypertensive drugs acting on new targets to improve control of blood pressure. This review discusses novel insights (including the data of recent clinical trials) with regard to interference with the renin-angiotensin system, focusing on the enzymes aminopeptidase A and angiotensin-converting enzyme 2 (ACE2) in the brain, as well as the substrate of renin- angiotensinogen-in the liver. It raises the possibility that centrally acting amino peptidase A inhibitors (eg, firibastat), preventing the conversion of angiotensin II to angiotensin III in the brain, might be particularly useful in African Americans and patients with obesity. Firibastat additionally upregulates brain ACE2, allowing the conversion of angiotensin II to its protective metabolite angiotensin-(1-7). Furthermore, antisense oligonucleotides or small interfering ribonucleic acids suppress hepatic angiotensinogen for weeks to months after 1 injection and thus could potentially overcome adherence issues. Finally, interference with ACE2 ubiquitination is emerging as a future option for the treatment of neurogenic hypertension, given that ubiquitination resistance might upregulate ACE2 activity.
Cardiovascular Protection by Metformin: Latest Advances in Basic and Clinical Research.
Li JZ, Li YR
Cardiology · 2023 · PMID 37307806 · Publisher ↗
BACKGROUND: Metformin is among the most frequently prescribed antidiabetic drugs worldwide and remains the first-line therapy for type 2 diabetes due to its well-established glucose-lowering efficacy and favorable safety...
BACKGROUND: Metformin is among the most frequently prescribed antidiabetic drugs worldwide and remains the first-line therapy for type 2 diabetes due to its well-established glucose-lowering efficacy and favorable safety profile. SUMMARY: Studies over the past decades show that metformin also exerts many other beneficial effects independent of its glucose-lowering effect both in experimental models and human subjects. Among them, the most notable is its cardiovascular protective effect. In this review, we discuss the latest cutting-edge research findings on metformin's cardiovascular protection from both preclinical studies and randomized clinical trials. We focus on describing novel basic research discoveries reported in influential journals and discussing their implications in the context of latest clinical trial findings related to common cardiovascular and metabolic disorders, including atherosclerosis and dyslipidemia, myocardial injury, and heart failure. KEY MESSAGES: While substantial preclinical and clinical evidence suggests metformin as a potential cardiovascular protectant, large-scale randomized controlled trials are warranted to establish its clinical efficacy in treating patients with atherosclerotic cardiovascular disease and heart failure.
Clinical quantitative coronary artery stenosis and coronary atherosclerosis imaging: a Consensus Statement from the Quantitative Cardiovascular Imaging Study Group.
Mézquita AJV, Biavati F, Falk V … +25 more , Alkadhi H, Hajhosseiny R, Maurovich-Horvat P, Manka R, Kozerke S, Stuber M, Derlin T, Channon KM, Išgum I, Coenen A, Foellmer B, Dey D, Volleberg RHJA, Meinel FG, Dweck MR, Piek JJ, van de Hoef T, Landmesser U, Guagliumi G, Giannopoulos AA, Botnar RM, Khamis R, Williams MC, Newby DE, Dewey M
Nat Rev Cardiol · 2023 Oct · PMID 37277608 · Publisher ↗
The detection and characterization of coronary artery stenosis and atherosclerosis using imaging tools are key for clinical decision-making in patients with known or suspected coronary artery disease. In this regard, ima...
The detection and characterization of coronary artery stenosis and atherosclerosis using imaging tools are key for clinical decision-making in patients with known or suspected coronary artery disease. In this regard, imaging-based quantification can be improved by choosing the most appropriate imaging modality for diagnosis, treatment and procedural planning. In this Consensus Statement, we provide clinical consensus recommendations on the optimal use of different imaging techniques in various patient populations and describe the advances in imaging technology. Clinical consensus recommendations on the appropriateness of each imaging technique for direct coronary artery visualization were derived through a three-step, real-time Delphi process that took place before, during and after the Second International Quantitative Cardiovascular Imaging Meeting in September 2022. According to the Delphi survey answers, CT is the method of choice to rule out obstructive stenosis in patients with an intermediate pre-test probability of coronary artery disease and enables quantitative assessment of coronary plaque with respect to dimensions, composition, location and related risk of future cardiovascular events, whereas MRI facilitates the visualization of coronary plaque and can be used in experienced centres as a radiation-free, second-line option for non-invasive coronary angiography. PET has the greatest potential for quantifying inflammation in coronary plaque but SPECT currently has a limited role in clinical coronary artery stenosis and atherosclerosis imaging. Invasive coronary angiography is the reference standard for stenosis assessment but cannot characterize coronary plaques. Finally, intravascular ultrasonography and optical coherence tomography are the most important invasive imaging modalities for the identification of plaques at high risk of rupture. The recommendations made in this Consensus Statement will help clinicians to choose the most appropriate imaging modality on the basis of the specific clinical scenario, individual patient characteristics and the availability of each imaging modality.
Pericardial Immune Cells and Their Evolving Role in Cardiovascular Pathophysiology.
Isidoro CA, Deniset JF
Can J Cardiol · 2023 Aug · PMID 37270165 · Publisher ↗
The pericardium plays several homeostatic roles to support and maintain everyday cardiac function. Recent advances in techniques and experimental models have allowed for further exploration into the cellular contents of...
The pericardium plays several homeostatic roles to support and maintain everyday cardiac function. Recent advances in techniques and experimental models have allowed for further exploration into the cellular contents of the pericardium itself. Of particular interest are the various immune cell populations present in the space within the pericardial fluid and fat. In contrast to immune cells of the comparable pleura, peritoneum and heart, pericardial immune cells appear to be distinct in their function and phenotype. Specifically, recent work has suggested these cells play critical roles in an array of pathophysiological conditions including myocardial infarction, pericarditis, and post-cardiac surgery complications. In this review, we spotlight the pericardial immune cells currently identified in mice and humans, the pathophysiological role of these cells, and the clinical significance of the immunocardiology axis in cardiovascular health.
Hydroxychloroquine Attenuates hERG Channel by Promoting the Membrane Channel Degradation: Computational Simulation and Experimental Evidence for QT-Interval Prolongation with Hydroxychloroquine Treatment.
Wang X, Feng Y, Liu S … +11 more , Liu J, Pan S, Wei L, Ma Y, Liu Z, Xing Y, Wang J, Cui Q, Zhang Y, Wang T, Cai C
Cardiology · 2023 · PMID 37231805 · Publisher ↗
INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic has led to millions of confirmed cases and deaths worldwide and has no approved therapy. Currently, more than 700 drugs are tested in the COVID-19 clinical t...
INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic has led to millions of confirmed cases and deaths worldwide and has no approved therapy. Currently, more than 700 drugs are tested in the COVID-19 clinical trials, and full evaluation of their cardiotoxicity risks is in high demand. METHODS: We mainly focused on hydroxychloroquine (HCQ), one of the most concerned drugs for COVID-19 therapy, and investigated the effects and underlying mechanisms of HCQ on hERG channel via molecular docking simulations. We further applied the HEK293 cell line stably expressing hERG-wild-type channel (hERG-HEK) and HEK293 cells transiently expressing hERG-p.Y652A or hERG-p.F656A mutants to validate our predictions. Western blot analysis was used to determine the hERG channel, and the whole-cell patch clamp was utilized to record hERG current (IhERG). RESULTS: HCQ reduced the mature hERG protein in a time- and concentration-dependent manner. Correspondingly, chronic and acute treatment of HCQ decreased the hERG current. Treatment with brefeldin A (BFA) and HCQ combination reduced hERG protein to a greater extent than BFA alone. Moreover, disruption of the typical hERG binding site (hERG-p.Y652A or hERG-p.F656A) rescued HCQ-mediated hERG protein and IhERG reduction. CONCLUSION: HCQ can reduce the mature hERG channel expression and IhERG via enhancing channel degradation. The QT prolongation effect of HCQ is mediated by typical hERG binding sites involving residues Tyr652 and Phe656.
Vigorous Exercise in Patients With Hypertrophic Cardiomyopathy.
Lampert R, Ackerman MJ, Marino BS … +42 more , Burg M, Ainsworth B, Salberg L, Tome Esteban MT, Ho CY, Abraham R, Balaji S, Barth C, Berul CI, Bos M, Cannom D, Choudhury L, Concannon M, Cooper R, Czosek RJ, Dubin AM, Dziura J, Eidem B, Emery MS, Estes NAM, Etheridge SP, Geske JB, Gray B, Hall K, Harmon KG, James CA, Lal AK, Law IH, Li F, Link MS, McKenna WJ, Molossi S, Olshansky B, Ommen SR, Saarel EV, Saberi S, Simone L, Tomaselli G, Ware JS, Zipes DP, Day SM, LIVE Consortium
JAMA Cardiol · 2023 Jun · PMID 37195701 · Full text
IMPORTANCE: Whether vigorous intensity exercise is associated with an increase in risk of ventricular arrhythmias in individuals with hypertrophic cardiomyopathy (HCM) is unknown. OBJECTIVE: To determine whether engageme...
IMPORTANCE: Whether vigorous intensity exercise is associated with an increase in risk of ventricular arrhythmias in individuals with hypertrophic cardiomyopathy (HCM) is unknown. OBJECTIVE: To determine whether engagement in vigorous exercise is associated with increased risk for ventricular arrhythmias and/or mortality in individuals with HCM. The a priori hypothesis was that participants engaging in vigorous activity were not more likely to have an arrhythmic event or die than those who reported nonvigorous activity. DESIGN, SETTING, AND PARTICIPANTS: This was an investigator-initiated, prospective cohort study. Participants were enrolled from May 18, 2015, to April 25, 2019, with completion in February 28, 2022. Participants were categorized according to self-reported levels of physical activity: sedentary, moderate, or vigorous-intensity exercise. This was a multicenter, observational registry with recruitment at 42 high-volume HCM centers in the US and internationally; patients could also self-enroll through the central site. Individuals aged 8 to 60 years diagnosed with HCM or genotype positive without left ventricular hypertrophy (phenotype negative) without conditions precluding exercise were enrolled. EXPOSURES: Amount and intensity of physical activity. MAIN OUTCOMES AND MEASURES: The primary prespecified composite end point included death, resuscitated sudden cardiac arrest, arrhythmic syncope, and appropriate shock from an implantable cardioverter defibrillator. All outcome events were adjudicated by an events committee blinded to the patient's exercise category. RESULTS: Among the 1660 total participants (mean [SD] age, 39 [15] years; 996 male [60%]), 252 (15%) were classified as sedentary, and 709 (43%) participated in moderate exercise. Among the 699 individuals (42%) who participated in vigorous-intensity exercise, 259 (37%) participated competitively. A total of 77 individuals (4.6%) reached the composite end point. These individuals included 44 (4.6%) of those classified as nonvigorous and 33 (4.7%) of those classified as vigorous, with corresponding rates of 15.3 and 15.9 per 1000 person-years, respectively. In multivariate Cox regression analysis of the primary composite end point, individuals engaging in vigorous exercise did not experience a higher rate of events compared with the nonvigorous group with an adjusted hazard ratio of 1.01. The upper 95% 1-sided confidence level was 1.48, which was below the prespecified boundary of 1.5 for noninferiority. CONCLUSIONS AND RELEVANCE: Results of this cohort study suggest that among individuals with HCM or those who are genotype positive/phenotype negative and are treated in experienced centers, those exercising vigorously did not experience a higher rate of death or life-threatening arrhythmias than those exercising moderately or those who were sedentary. These data may inform discussion between the patient and their expert clinician around exercise participation.
Integration of epigenetic regulatory mechanisms in heart failure.
Sopic M, Robinson EL, Emanueli C … +8 more , Srivastava P, Angione C, Gaetano C, Condorelli G, Martelli F, Pedrazzini T, Devaux Y, EU-CardioRNA COST Action CA17129 and EU-AtheroNET COST Action CA21153
Basic Res Cardiol · 2023 May · PMID 37140699 · Full text
The number of "omics" approaches is continuously growing. Among others, epigenetics has appeared as an attractive area of investigation by the cardiovascular research community, notably considering its association with d...
The number of "omics" approaches is continuously growing. Among others, epigenetics has appeared as an attractive area of investigation by the cardiovascular research community, notably considering its association with disease development. Complex diseases such as cardiovascular diseases have to be tackled using methods integrating different omics levels, so called "multi-omics" approaches. These approaches combine and co-analyze different levels of disease regulation. In this review, we present and discuss the role of epigenetic mechanisms in regulating gene expression and provide an integrated view of how these mechanisms are interlinked and regulate the development of cardiac disease, with a particular attention to heart failure. We focus on DNA, histone, and RNA modifications, and discuss the current methods and tools used for data integration and analysis. Enhancing the knowledge of these regulatory mechanisms may lead to novel therapeutic approaches and biomarkers for precision healthcare and improved clinical outcomes.
[State of the art mathematical methods of the coronary blood flow modelling: background and clinical value].
Suyundukova AT, Demkin VP, Mochula AV … +3 more , Gulya MO, Maltseva AN, Zavadovsky KV
Kardiologiia · 2023 Mar · PMID 37061864 · Publisher ↗
X-ray computed tomography coronary angiography (CTCA) is a current method for diagnosing ischemic heart disease. Although this method has a high specificity and a negative predictive value in diagnosing coronary obstruct...
X-ray computed tomography coronary angiography (CTCA) is a current method for diagnosing ischemic heart disease. Although this method has a high specificity and a negative predictive value in diagnosing coronary obstructions, there are limitations in determining the hemodynamic significance of the stenosis. Extensive use of noninvasive methods for evaluation of coronary hemodynamics, specifically evaluation of the fractional flow reserve (FFR) is limited due to its high cost and risks of complications. Mathematical modeling of coronary circulation and its reserve based on CTCA data is an up-to-date method that has been experimentally confirmed and clinically validated. This method showed a high diagnostic efficacy in several large studies that used the invasive determination of FFR as a "gold standard". This review addresses the current state of studies on mathematical modeling for fractional coronary reserve in patients with ischemic heart disease, as well as the limitations and prospects of this method.
Electrophysiological and calcium-handling development during long-term culture of human-induced pluripotent stem cell-derived cardiomyocytes.
Seibertz F, Sutanto H, Dülk R … +19 more , Pronto JRD, Springer R, Rapedius M, Liutkute A, Ritter M, Jung P, Stelzer L, Hüsgen LM, Klopp M, Rubio T, Fakuade FE, Mason FE, Hartmann N, Pabel S, Streckfuss-Bömeke K, Cyganek L, Sossalla S, Heijman J, Voigt N
Basic Res Cardiol · 2023 Apr · PMID 37020075 · Full text
Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are increasingly used for personalised medicine and preclinical cardiotoxicity testing. Reports on hiPSC-CM commonly describe heterogenous functional...
Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are increasingly used for personalised medicine and preclinical cardiotoxicity testing. Reports on hiPSC-CM commonly describe heterogenous functional readouts and underdeveloped or immature phenotypical properties. Cost-effective, fully defined monolayer culture is approaching mainstream adoption; however, the optimal age at which to utilise hiPSC-CM is unknown. In this study, we identify, track and model the dynamic developmental behaviour of key ionic currents and Ca-handling properties in hiPSC-CM over long-term culture (30-80 days). hiPSC-CMs > 50 days post differentiation show significantly larger I density along with an increased I-triggered Ca-transient. I and I densities significantly increase in late-stage cells, contributing to increased upstroke velocity and reduced action potential duration, respectively. Importantly, our in silico model of hiPSC-CM electrophysiological age dependence confirmed I as the key ionic determinant of action potential shortening in older cells. We have made this model available through an open source software interface that easily allows users to simulate hiPSC-CM electrophysiology and Ca-handling and select the appropriate age range for their parameter of interest. This tool, together with the insights from our comprehensive experimental characterisation, could be useful in future optimisation of the culture-to-characterisation pipeline in the field of hiPSC-CM research.
Clinical and Experimental Study of High Mobility Group Box-2 and Valvular Calcification in Elderly Patients with Degenerative Heart Valve Disease.
Huang H, Sun Q, Huang Y … +6 more , Wang H, Ju L, Peng M, Wu J, Chen L, Gong Y
Cardiology · 2023 · PMID 36958298 · Publisher ↗
INTRODUCTION: The aim of this study was to investigate the relationship between the high mobility group box-2 (HMGB2) and valve calcification in senile degenerative heart valve disease (SDHVD). METHODS: According to the...
INTRODUCTION: The aim of this study was to investigate the relationship between the high mobility group box-2 (HMGB2) and valve calcification in senile degenerative heart valve disease (SDHVD). METHODS: According to the echocardiographic results, patients with calcified heart valves were used as the experimental group and patients without calcified heart valves were used as the control group; blood was drawn for testing, and serum levels of HMGB2 were measured by an enzyme-linked immunosorbent assay. Human heart valve interstitial cells (hVICs) cultured in vitro were randomly divided into two groups. The calcification group was cultured with a medium containing calcification induction solution and cells were induced on days 1, 3, and 5, and the control group was cultured with a standard medium. Expression of bone morphogenetic protein 4 (BMP-4) and HMGB2 in both groups was detected by Western blot. RT-PCR was performed to detect the expression of the HMGB2 gene during calcification. The hVICs were cultured in vitro for 4 days with different concentrations of exogenous HMGB2 (0.01 μg/mL, 0.1 μg/mL, 1 μg/mL, 2 μg/mL), while the control group was cultured with a standard medium and the expression of BMP-4 and NF-κB P65 was detected by Western blot. RESULTS: The serum level of HMGB2 was 7.90 (5.92, 12.39) μg/L, higher than that of 7.06 (5.06, 9.73) μg/L in the valve calcification group in elderly patients with degenerative valve disease (p = 0.005); the differences were statistically significant. In in vitro experiments, the cellular calcification protein BMP-4 and the HMGB2 protein were higher in the calcification group compared to the control group (p < 0.05). Exogenous stimulation of hVICs with HMGB2 was able to upregulate the expression of BMP-4 and NF-κB P65 (p < 0.05). CONCLUSIONS: HMGB2 is correlated with valvular calcification in senile degenerative heart valve disease. The HMGB2 protein may promote the process of SDHVD valve calcification by activating the NF-κB pathway and upregulating the expression of BMP-4.
Standard vs Augmented Ablation of Paroxysmal Atrial Fibrillation for Reduction of Atrial Fibrillation Recurrence: The AWARE Randomized Clinical Trial.
Nair GM, Birnie DH, Nery PB … +21 more , Redpath CJ, Sarrazin JF, Roux JF, Parkash R, Bernier M, Sterns LD, Sapp J, Novak P, Veenhuyzen G, Morillo CA, Singh SM, Sadek MM, Golian M, Klein A, Sturmer M, Chauhan VS, Angaran P, Green MS, Bernick J, Wells GA, Essebag V
JAMA Cardiol · 2023 May · PMID 36947030 · Full text
IMPORTANCE: Recurrent atrial fibrillation (AF) commonly occurs after catheter ablation and is associated with patient morbidity and health care costs. OBJECTIVE: To evaluate the superiority of an augmented double wide-ar...
IMPORTANCE: Recurrent atrial fibrillation (AF) commonly occurs after catheter ablation and is associated with patient morbidity and health care costs. OBJECTIVE: To evaluate the superiority of an augmented double wide-area circumferential ablation (WACA) compared with a standard single WACA in preventing recurrent atrial arrhythmias (AA) (atrial tachycardia, atrial flutter, or atrial fibrillation [AF]) in patients with paroxysmal AF. DESIGN, SETTING, AND PARTICIPANTS: This was a pragmatic, multicenter, prospective, randomized, open, blinded end point superiority clinical trial conducted at 10 university-affiliated centers in Canada. The trial enrolled patients 18 years and older with symptomatic paroxysmal AF from March 2015 to May 2017. Analysis took place between January and April 2022. Analyses were intention to treat. INTERVENTIONS: Patients were randomized (1:1) to receive radiofrequency catheter ablation for pulmonary vein isolation with either a standard single WACA or an augmented double WACA. MAIN OUTCOMES AND MEASURES: The primary outcome was AA recurrence between 91 and 365 days postablation. Patients underwent 42 days of ambulatory electrocardiography monitoring after ablation. Secondary outcomes included need for repeated catheter ablation and procedural and safety variables. RESULTS: Of 398 patients, 195 were randomized to the single WACA (control) arm (mean [SD] age, 60.6 [9.3] years; 65 [33.3%] female) and 203 to the double WACA (experimental) arm (mean [SD] age, 61.5 [9.3] years; 66 [32.5%] female). Overall, 52 patients (26.7%) in the single WACA arm and 50 patients (24.6%) in the double WACA arm had recurrent AA at 1 year (relative risk, 0.92; 95% CI, 0.66-1.29; P = .64). Twenty patients (10.3%) in the single WACA arm and 15 patients (7.4%) in the double WACA arm underwent repeated catheter ablation (relative risk, 0.72; 95% CI, 0.38-1.36). Adjudicated serious adverse events occurred in 13 patients (6.7%) in the single WACA arm and 14 patients (6.9%) in the double WACA arm. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of patients with paroxysmal AF, additional ablation by performing a double ablation lesion set did not result in improved freedom from recurrent AA compared with a standard single ablation set. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02150902.
Indirect epigenetic testing identifies a diagnostic signature of cardiomyocyte DNA methylation in heart failure.
Oeing CU, Pepin ME, Saul KB … +11 more , Agircan AS, Assenov Y, Merkel TS, Sedaghat-Hamedani F, Weis T, Meder B, Guan K, Plass C, Weichenhan D, Siede D, Backs J
Basic Res Cardiol · 2023 Mar · PMID 36939901 · Full text
Precision-based molecular phenotyping of heart failure must overcome limited access to cardiac tissue. Although epigenetic alterations have been found to underlie pathological cardiac gene dysregulation, the clinical uti...
Precision-based molecular phenotyping of heart failure must overcome limited access to cardiac tissue. Although epigenetic alterations have been found to underlie pathological cardiac gene dysregulation, the clinical utility of myocardial epigenomics remains narrow owing to limited clinical access to tissue. Therefore, the current study determined whether patient plasma confers indirect phenotypic, transcriptional, and/or epigenetic alterations to ex vivo cardiomyocytes to mirror the failing human myocardium. Neonatal rat ventricular myocytes (NRVMs) and single-origin human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and were treated with blood plasma samples from patients with dilated cardiomyopathy (DCM) and donor subjects lacking history of cardiovascular disease. Following plasma treatments, NRVMs and hiPSC-CMs underwent significant hypertrophy relative to non-failing controls, as determined via automated high-content screening. Array-based DNA methylation analysis of plasma-treated hiPSC-CMs and cardiac biopsies uncovered robust, and conserved, alterations in cardiac DNA methylation, from which 100 sites were validated using an independent cohort. Among the CpG sites identified, hypo-methylation of the ATG promoter was identified as a diagnostic marker of HF, wherein cg03800765 methylation (AUC = 0.986, P < 0.0001) was found to out-perform circulating NT-proBNP levels in differentiating heart failure. Taken together, these findings support a novel approach of indirect epigenetic testing in human HF.
Effect of Sacubitril/Valsartan vs Valsartan on Left Atrial Volume in Patients With Pre-Heart Failure With Preserved Ejection Fraction: The PARABLE Randomized Clinical Trial.
Ledwidge M, Dodd JD, Ryan F … +10 more , Sweeney C, McDonald K, Fox R, Shorten E, Zhou S, Watson C, Gallagher J, McVeigh N, Murphy DJ, McDonald K
JAMA Cardiol · 2023 Apr · PMID 36884247 · Full text
IMPORTANCE: Pre-heart failure with preserved ejection fraction (pre-HFpEF) is common and has no specific therapy aside from cardiovascular risk factor management. OBJECTIVE: To investigate the hypothesis that sacubitril/...
IMPORTANCE: Pre-heart failure with preserved ejection fraction (pre-HFpEF) is common and has no specific therapy aside from cardiovascular risk factor management. OBJECTIVE: To investigate the hypothesis that sacubitril/valsartan vs valsartan would reduce left atrial volume index using volumetric cardiac magnetic resonance imaging in patients with pre-HFpEF. DESIGN, SETTING, AND PARTICIPANTS: The Personalized Prospective Comparison of ARNI [angiotensin receptor/neprilysin inhibitor] With ARB [angiotensin-receptor blocker] in Patients With Natriuretic Peptide Elevation (PARABLE) trial was a prospective, double-blind, double-dummy, randomized clinical trial carried out over 18 months between April 2015 and June 2021. The study was conducted at a single outpatient cardiology center in Dublin, Ireland. Of 1460 patients in the STOP-HF program or outpatient cardiology clinics, 461 met initial criteria and were approached for inclusion. Of these, 323 were screened and 250 asymptomatic patients 40 years and older with hypertension or diabetes, elevated B-type natriuretic peptide (BNP) greater than 20 pg/mL or N-terminal pro-b-type natriuretic peptide greater than 100 pg/mL, left atrial volume index greater than 28 mL/m2, and preserved ejection fraction greater than 50% were included. INTERVENTIONS: Patients were randomized to angiotensin receptor neprilysin inhibitor sacubitril/valsartan titrated to 200 mg twice daily or matching angiotensin receptor blocker valsartan titrated to 160 mg twice daily. MAIN OUTCOMES AND MEASURES: Maximal left atrial volume index and left ventricular end diastolic volume index, ambulatory pulse pressure, N-terminal pro-BNP, and adverse cardiovascular events. RESULTS: Among the 250 participants in this study, the median (IQR) age was 72.0 (68.0-77.0) years; 154 participants (61.6%) were men and 96 (38.4%) were women. Most (n = 245 [98.0%]) had hypertension and 60 (24.0%) had type 2 diabetes. Maximal left atrial volume index was increased in patients assigned to receive sacubitril/valsartan (6.9 mL/m2; 95% CI, 0.0 to 13.7) vs valsartan (0.7 mL/m2; 95% CI, -6.3 to 7.7; P < .001) despite reduced markers of filling pressure in both groups. Changes in pulse pressure and N-terminal pro-BNP were lower in the sacubitril/valsartan group (-4.2 mm Hg; 95% CI, -7.2 to -1.21 and -17.7%; 95% CI, -36.9 to 7.4, respectively; P < .001) than the valsartan group (-1.2 mm Hg; 95% CI, -4.1 to 1.7 and 9.4%; 95% CI, -15.6 to 4.9, respectively; P < .001). Major adverse cardiovascular events occurred in 6 patients (4.9%) assigned to sacubitril/valsartan and 17 (13.3%) assigned to receive valsartan (adjusted hazard ratio, 0.38; 95% CI, 0.17 to 0.89; adjusted P = .04). CONCLUSIONS AND RELEVANCE: In this trial of patients with pre-HFpEF, sacubitril/valsartan treatment was associated with a greater increase in left atrial volume index and improved markers of cardiovascular risk compared to valsartan. More work is needed to understand the observed increased cardiac volumes and long-term effects of sacubitril/valsartan in patients with pre-HFpEF. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04687111.
The role of aldehyde dehydrogenase 2 in cardiovascular disease.
Zhang J, Guo Y, Zhao X … +9 more , Pang J, Pan C, Wang J, Wei S, Yu X, Zhang C, Chen Y, Yin H, Xu F
Nat Rev Cardiol · 2023 Jul · PMID 36781974 · Publisher ↗
Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme involved in the detoxification of alcohol-derived acetaldehyde and endogenous aldehydes. The inactivating ALDH2 rs671 polymorphism, present in up to 8% of the gl...
Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme involved in the detoxification of alcohol-derived acetaldehyde and endogenous aldehydes. The inactivating ALDH2 rs671 polymorphism, present in up to 8% of the global population and in up to 50% of the East Asian population, is associated with increased risk of cardiovascular conditions such as coronary artery disease, alcohol-induced cardiac dysfunction, pulmonary arterial hypertension, heart failure and drug-induced cardiotoxicity. Although numerous studies have attributed an accumulation of aldehydes (secondary to alcohol consumption, ischaemia or elevated oxidative stress) to an increased risk of cardiovascular disease (CVD), this accumulation alone does not explain the emerging protective role of ALDH2 rs671 against ageing-related cardiac dysfunction and the development of aortic aneurysm or dissection. ALDH2 can also modulate risk factors associated with atherosclerosis, such as cholesterol biosynthesis and HDL biogenesis in hepatocytes and foam cell formation and efferocytosis in macrophages, via non-enzymatic pathways. In this Review, we summarize the basic biology and the clinical relevance of the enzymatic and non-enzymatic, tissue-specific roles of ALDH2 in CVD, and discuss the future directions in the research and development of therapeutic strategies targeting ALDH2. A thorough understanding of the complex roles of ALDH2 in CVD will improve the diagnosis, management and prognosis of patients with CVD who harbour the ALDH2 rs671 polymorphism.
Single-cell transcriptomics for the assessment of cardiac disease.
Miranda AMA, Janbandhu V, Maatz H … +7 more , Kanemaru K, Cranley J, Teichmann SA, Hübner N, Schneider MD, Harvey RP, Noseda M
Nat Rev Cardiol · 2023 May · PMID 36539452 · Publisher ↗
Cardiovascular disease is the leading cause of death globally. An advanced understanding of cardiovascular disease mechanisms is required to improve therapeutic strategies and patient risk stratification. State-of-the-ar...
Cardiovascular disease is the leading cause of death globally. An advanced understanding of cardiovascular disease mechanisms is required to improve therapeutic strategies and patient risk stratification. State-of-the-art, large-scale, single-cell and single-nucleus transcriptomics facilitate the exploration of the cardiac cellular landscape at an unprecedented level, beyond its descriptive features, and can further our understanding of the mechanisms of disease and guide functional studies. In this Review, we provide an overview of the technical challenges in the experimental design of single-cell and single-nucleus transcriptomics studies, as well as a discussion of the type of inferences that can be made from the data derived from these studies. Furthermore, we describe novel findings derived from transcriptomics studies for each major cardiac cell type in both health and disease, and from development to adulthood. This Review also provides a guide to interpreting the exhaustive list of newly identified cardiac cell types and states, and highlights the consensus and discordances in annotation, indicating an urgent need for standardization. We describe advanced applications such as integration of single-cell data with spatial transcriptomics to map genes and cells on tissue and define cellular microenvironments that regulate homeostasis and disease progression. Finally, we discuss current and future translational and clinical implications of novel transcriptomics approaches, and provide an outlook of how these technologies will change the way we diagnose and treat heart disease.
[Cardiac contractility modulation in heart failure with reduced ejection fraction treatment].
Chugunov IA, Mareev YV, Fudim M … +3 more , Mironova NA, Mareev VY, Davtyan RV
Kardiologiia · 2022 Nov · PMID 36521047 · Publisher ↗
Heart failure with reduced left ventricular ejection fraction (LV EF) (HFrEF) is a significant issue of health care due to increasing indexes of morbidity and mortality. The emergence of a number of drugs and implantable...
Heart failure with reduced left ventricular ejection fraction (LV EF) (HFrEF) is a significant issue of health care due to increasing indexes of morbidity and mortality. The emergence of a number of drugs and implantable devices for the treatment of HFrEF has allowed improvement of patients' well-being and prognosis. However, high mortality and recurrent decompensated heart failure remain a substantial issue and stimulate the search for new methods of CHF treatment. Cardiac contractility modulation (CCM) is a method of managing patients with HFrEF. Available data from randomized clinical trials (RCT) indicate the efficacy of CCM in improvement of patients' well-being and quality of life. The question remains open: what effect does CCM have on LV reverse remodeling? Experimental data and results of observational studies suggest a possibility of reverse remodeling by CCM; however, this has not been confirmed in RCT. Also, it remains unclear how CCM influences the frequency of hospitalizations for decompensated heart failure and the death rate of patients with HFrEF. Results of both RCTs and observational studies have shown a moderate improvement of quality of life associated with CCM. Furthermore, RCTs have not found any increase in LV EF due to the therapy, nor has a meta-analysis of RCTs revealed any improvement of the prognosis associated with CCM. Further RCTs are needed to evaluate the effect of CCM on reverse remodeling, survival rate, and to determine the place of CCM in the treatment of patients with CHF.
Analysis of Clinical and Biochemical Characteristics of Patients With Genetically Confirmed Familial Hypercholesterolemia in Russian North Western District Residents.
Korneva VA, Zacharova FM, Mandelstam MY … +4 more , Bogoslovskaya TY, Orlov AV, Vasilyev VB, Kuznetsova TY
Kardiologiia · 2022 Nov · PMID 36521042 · Publisher ↗
Aim To compare results of clinical, laboratory, and genetic examination of patients with familial hypercholesterolemia (FHC).Material and methods 112 patients aged 40.2±17.9 years (49 men) were examined. The gene o...
Aim To compare results of clinical, laboratory, and genetic examination of patients with familial hypercholesterolemia (FHC).Material and methods 112 patients aged 40.2±17.9 years (49 men) were examined. The gene of low-density lipoprotein receptor (LDLR) was analyzed and evaluated using the Dutch Lipid Clinic Network (DLCN) criterion of lipid score ≥6. The LDLR gene mutation was searched for using the conformational polymorphism analysis followed by sequencing of the DNA of isolated LDLR gene exons.Results Mean variables of the blood lipid profile were total cholesterol (C), 10.12±2.32 mmol/l, LDL-C, 7.72±2.3 mmol/l. Corneal arcus was observed in 15 % of patients, tendon xanthomas in 31.8 %, and xanthelasma palpebrarum in 5.3 %. The types of LDLR gene mutations included missense mutations (42.8 %), mutations causing a premature termination of protein synthesis (41.1 %), and frameshift mutations (16.1 %). In the presence of a mutation in exon 4, patients with IHD compared to patients with no IHD had significantly higher levels of total C (10.88±2.08 mmol/l vs. 8.74±1.57 mmol/l, respectively, р=0.001) and LDL-C (8.60±2.14 mmol/l vs. 6.62±1.79 mmol/l, respectively, р=0.005). Patients with IHD compared to patients with no IHD and a mutation in LDLR gene exon 9 had only a higher LDL-C level (8.96±1.53 mmol/l vs. 6.92±1.59 mmol/l, respectively, р=0.022). A differentiated comparison of IHD patients using a logistic regression depending on the identified type of LDLR gene mutation produced formulas for calculating the odds ratio of IHD and myocardial infarction (MI) with adjustments for the patient's age and baseline LDL.Conclusion The detection rate of the LDLR gene mutations was 42.8 % for missense mutations, 41.1 % for mutations causing a premature termination of protein synthesis, and 16.1 % for frameshift mutations. Blood lipid profiles did not differ between patients from different cities and with different types of LDLR gene mutations. Blood lipid profiles were different in IHD patients depending on the mutation type.
Cardiac fibroblasts and mechanosensation in heart development, health and disease.
Pesce M, Duda GN, Forte G … +6 more , Girao H, Raya A, Roca-Cusachs P, Sluijter JPG, Tschöpe C, Van Linthout S
Nat Rev Cardiol · 2023 May · PMID 36376437 · Publisher ↗
The term 'mechanosensation' describes the capacity of cells to translate mechanical stimuli into the coordinated regulation of intracellular signals, cellular function, gene expression and epigenetic programming. This ca...
The term 'mechanosensation' describes the capacity of cells to translate mechanical stimuli into the coordinated regulation of intracellular signals, cellular function, gene expression and epigenetic programming. This capacity is related not only to the sensitivity of the cells to tissue motion, but also to the decryption of tissue geometric arrangement and mechanical properties. The cardiac stroma, composed of fibroblasts, has been historically considered a mechanically passive component of the heart. However, the latest research suggests that the mechanical functions of these cells are an active and necessary component of the developmental biology programme of the heart that is involved in myocardial growth and homeostasis, and a crucial determinant of cardiac repair and disease. In this Review, we discuss the general concept of cell mechanosensation and force generation as potent regulators in heart development and pathology, and describe the integration of mechanical and biohumoral pathways predisposing the heart to fibrosis and failure. Next, we address the use of 3D culture systems to integrate tissue mechanics to mimic cardiac remodelling. Finally, we highlight the potential of mechanotherapeutic strategies, including pharmacological treatment and device-mediated left ventricular unloading, to reverse remodelling in the failing heart.
Non-responsiveness to cardioprotection by ischaemic preconditioning in Ossabaw minipigs with genetic predisposition to, but without the phenotype of the metabolic syndrome.
Kleinbongard P, Lieder HR, Skyschally A … +5 more , Alloosh M, Gödecke A, Rahmann S, Sturek M, Heusch G
Basic Res Cardiol · 2022 Nov · PMID 36374343 · Full text
The translation of successful preclinical and clinical proof-of-concept studies on cardioprotection to the benefit of patients with reperfused acute myocardial infarction has been difficult so far. This difficulty has be...
The translation of successful preclinical and clinical proof-of-concept studies on cardioprotection to the benefit of patients with reperfused acute myocardial infarction has been difficult so far. This difficulty has been attributed to confounders which patients with myocardial infarction typically have but experimental animals usually not have. The metabolic syndrome is a typical confounder. We hypothesised that there may also be a genuine non-responsiveness to cardioprotection and used Ossabaw minipigs which have the genetic predisposition to develop a diet-induced metabolic syndrome, but before they had developed the diseased phenotype. Using a prospective study design, a reperfused acute myocardial infarction was induced in 62 lean Ossabaw minipigs by 60 min coronary occlusion and 180 min reperfusion. Ischaemic preconditioning by 3 cycles of 5 min coronary occlusion and 10 min reperfusion was used as cardioprotective intervention. Ossabaw minipigs were stratified for their single nucleotide polymorphism as homozygous for valine (V/V) or isoleucine (I/I)) in the γ-subunit of adenosine monophosphate-activated protein kinase. Endpoints were infarct size and area of no-reflow. Infarct size (V/V: 54 ± 8, I/I: 54 ± 13% of area at risk, respectively) was not reduced by ischaemic preconditioning (V/V: 55 ± 11, I/I: 46 ± 11%) nor was the area of no-reflow (V/V: 57 ± 18, I/I: 49 ± 21 vs. V/V: 57 ± 21, I/I: 47 ± 21% of infarct size). Bioinformatic comparison of the Ossabaw genome to that of Sus scrofa and Göttingen minipigs identified differences in clusters of genes encoding mitochondrial and inflammatory proteins, including the janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway. The phosphorylation of STAT3 at early reperfusion was not increased by ischaemic preconditioning, different from the established STAT3 activation by cardioprotective interventions in other pig strains. Ossabaw pigs have not only the genetic predisposition to develop a metabolic syndrome but also are not amenable to cardioprotection by ischaemic preconditioning.
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