-
Journal of Cellular Biochemistry Jun 2024Calmodulin (CaM) is a ubiquitous, small cytosolic calcium (Ca)-binding sensor that plays a vital role in many cellular processes by binding and regulating the activity...
Calmodulin (CaM) is a ubiquitous, small cytosolic calcium (Ca)-binding sensor that plays a vital role in many cellular processes by binding and regulating the activity of over 300 protein targets. In cardiac muscle, CaM modulates directly or indirectly the activity of several proteins that play a key role in excitation-contraction coupling (ECC), such as ryanodine receptor type 2 (RyR2), l-type Ca (Ca1.2), sodium (NaV1.5) and potassium (KV7.1) channels. Many recent clinical and genetic studies have reported a series of CaM mutations in patients with life-threatening arrhythmogenic syndromes, such as long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). We recently showed that four arrhythmogenic CaM mutations (N98I, D132E, D134H, and Q136P) significantly reduce the binding of CaM to RyR2. Herein, we investigate in vivo functional effects of these CaM mutations on the normal zebrafish embryonic heart function by microinjecting complementary RNA corresponding to CaM, CaM, CaM, and CaM mutants. Expression of CaM and CaM mutants results in significant reduction of the zebrafish heart rate, mimicking a severe form of human bradycardia, whereas expression of CaM results in an increased heart rate mimicking human ventricular tachycardia. Moreover, analysis of cardiac ventricular rhythm revealed that the CaM and CaM zebrafish groups display an irregular pattern of heart beating and increased amplitude in comparison to the control groups. Furthermore, circular dichroism spectroscopy experiments using recombinant CaM proteins reveals a decreased structural stability of the four mutants compared to the wild-type CaM protein in the presence of Ca. Finally, Ca-binding studies indicates that all CaM mutations display reduced CaM Ca-binding affinities, with CaM exhibiting the most prominent change. Our data suggest that CaM mutations can trigger different arrhythmogenic phenotypes through multiple and complex molecular mechanisms.
PubMed: 38946237
DOI: 10.1002/jcb.30619 -
Pacing and Clinical Electrophysiology :... Jun 2024Postoperative atrial fibrillation (POAF) is one of the most common types of acute AF and can complicate the treatment course of approximately one third of patients...
BACKGROUND
Postoperative atrial fibrillation (POAF) is one of the most common types of acute AF and can complicate the treatment course of approximately one third of patients undergoing cardiac surgery. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are among the newest antidiabetic drugs which can be therapeutic options for preventing POAF by different mechanisms.
METHODS
Empagliflozin to Prevent POAF (EMPOAF) is an interventional, investigator-initiated, double-blind, placebo-controlled, multicenter, randomized controlled trial which will be conducted in two referral teaching cardiology hospitals in Tehran. Four-hundred ninety-two adult patients who are scheduled for elective isolated coronary artery bypass graft (CABG) surgery will be randomly assigned to one of the groups of intervention (empagliflozin 10 mg daily) or placebo starting at least 3 days before surgery until discharge. Key exclusion criteria are a history of diabetes mellitus, AF, ketoacidosis, or recurrent urinary tract infections along with severe renal or hepatic impairment, unstable hemodynamics, and patients receiving SGLT2 inhibitors for another indication. The primary outcome will be the incidence of POAF. Key secondary endpoints will be the composite rate of life-threatening arrhythmias, postoperative acute kidney injury, hospitalization length, in-hospital mortality, stroke, and systemic embolization. Key safety endpoints will be the rate of life-threatening and/or genitourinary tract infections, hypoglycemia, and ketoacidosis.
CONCLUSIONS
EMPOAF will prospectively evaluate whether empagliflozin 10 mg daily can reduce the rate of POAF in patients undergoing elective CABG. Enrolment into this study has started by November 2023 and is expected to be ended before the end of 2025.
PubMed: 38946138
DOI: 10.1111/pace.15038 -
Stem Cells Translational Medicine Jun 2024As research on in vitro cardiotoxicity assessment and cardiac disease modeling becomes more important, the demand for human pluripotent stem cell-derived cardiomyocytes...
As research on in vitro cardiotoxicity assessment and cardiac disease modeling becomes more important, the demand for human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is increasing. However, it has been reported that differentiated hPSC-CMs are in a physiologically immature state compared to in vivo adult CMs. Since immaturity of hPSC-CMs can lead to poor drug response and loss of acquired heart disease modeling, various approaches have been attempted to promote maturation of CMs. Here, we confirm that peroxisome proliferator-activated receptor alpha (PPARα), one of the representative mechanisms of CM metabolism and cardioprotective effect also affects maturation of CMs. To upregulate PPARα expression, we treated hPSC-CMs with fenofibrate (Feno), a PPARα agonist used in clinical hyperlipidemia treatment, and demonstrated that the structure, mitochondria-mediated metabolism, and electrophysiology-based functions of hPSC-CMs were all mature. Furthermore, as a result of multi electrode array (MEA)-based cardiotoxicity evaluation between control and Feno groups according to treatment with arrhythmia-inducing drugs, drug response was similar in a dose-dependent manner. However, main parameters such as field potential duration, beat period, and spike amplitude were different between the 2 groups. Overall, these results emphasize that applying matured hPSC-CMs to the field of preclinical cardiotoxicity evaluation, which has become an essential procedure for new drug development, is necessary.
PubMed: 38946019
DOI: 10.1093/stcltm/szae029 -
Clinical Hypertension Jul 2024This study explores the impact of intensive blood pressure (BP) control on left ventricular hypertrophy (LVH) incidence and evaluates the prognostic implications of LVH...
BACKGROUND
This study explores the impact of intensive blood pressure (BP) control on left ventricular hypertrophy (LVH) incidence and evaluates the prognostic implications of LVH status (pre-existing/new-onset/persistent/regression) using Systolic Blood Pressure Intervention Trial (SPRINT) Electrocardiogram Data.
METHODS
Poisson regression was used to assess new-onset LVH and LVH regression rates. Multivariable-adjusted Cox proportional hazard models determined the risk of adverse cardiovascular events (ACE), a composite of myocardial infarction (MI), non-MI acute coronary syndrome, stroke, heart failure, or cardiovascular death, alongside safety adverse events.
RESULTS
In 8,016 participants, intensive BP control significantly reduced new-onset LVH (8.27 vs. 14.79 per 1000-person years; adjusted p<0.001) and increased LVH regression (14.89 vs. 11.89 per 1000-person years; adjusted p<0.001). Elevated ACE risk was notable in participants with pre-existing LVH [adjusted HR: 1.94 (95% CI: 1.25-2.99); p = 0.003], new-onset LVH [adjusted 1.74 (95% CI: 1.16-2.60); p = 0.007], and persistent LVH[adjusted HR: 1.96 (95% CI: 1.11-3.46); p = 0.020], compared to those without LVH. Intriguingly, LVH regression attenuated this risk increment [adjusted HR: 1.57 (95% CI: 0.98-2.53); p = 0.062]. Achieving a BP target of < 120/80 mmHg nullified the increased ACE risk in those with pre-existing LVH.
CONCLUSIONS
Intensive BP control is instrumental in both reducing the emergence of LVH and fostering its regression. Pre-existing, new-onset LVH and persistent LV remain a predictor of adverse cardiovascular prognosis, whereas LVH regression and achieving on-treatment BP < 120/80 mmHg in pre-existing LVH individuals may further mitigate residual cardiovascular risk.
CLINICAL TRIAL REGISTRATION
URL: ClinicalTrials.gov Unique Identifier: NCT01206062.
PubMed: 38946010
DOI: 10.1186/s40885-024-00275-8 -
American Journal of Critical Care : An... Jul 2024Continuous electrocardiographic (ECG) monitoring was first introduced into hospitals in the 1960s, initially into critical care, as bedside monitors, and eventually into...
Continuous electrocardiographic (ECG) monitoring was first introduced into hospitals in the 1960s, initially into critical care, as bedside monitors, and eventually into step-down units with telemetry capabilities. Although the initial use was rather simplistic (ie, heart rate and rhythm assessment), the capabilities of these devices and associated physiologic (vital sign) monitors have expanded considerably. Current bedside monitors now include sophisticated ECG software designed to identify myocardial ischemia (ie, ST-segment monitoring), QT-interval prolongation, and a myriad of other cardiac arrhythmia types. Physiologic monitoring has had similar advances from noninvasive assessment of core vital signs (blood pressure, respiratory rate, oxygen saturation) to invasive monitoring including arterial blood pressure, temperature, central venous pressure, intracranial pressure, carbon dioxide, and many others. The benefit of these monitoring devices is that continuous and real-time information is displayed and can be configured to alarm to alert nurses to a change in a patient's condition. I think it is fair to say that critical and high-acuity care nurses see these devices as having a positive impact in patient care. However, this enthusiasm has been somewhat dampened in the past decade by research highlighting the shortcomings and unanticipated consequences of these devices, namely alarm and alert fatigue. In this article, which is associated with the American Association of Critical-Care Nurses' Distinguished Research Lecture, I describe my 36-year journey from a clinical nurse to nurse scientist and the trajectory of my program of research focused primarily on ECG and physiologic monitoring. Specifically, I discuss the good, the not so good, and the untapped potential of these monitoring systems in clinical care. I also describe my experiences with community-based research in patients with acute coronary syndrome and/or heart failure.
Topics: Humans; Electrocardiography; Monitoring, Physiologic
PubMed: 38945816
DOI: 10.4037/ajcc2024781 -
Heart & Lung : the Journal of Critical... Jun 2024Factors associated with cardiovascular complications of COVID-19 remain understudied.
Cardiovascular complications in the course of COVID-19 - lessons learned and implications for the future care of patients with viral respiratory diseases: Data from a single center retrospective observational study.
BACKGROUND
Factors associated with cardiovascular complications of COVID-19 remain understudied.
OBJECTIVES
Here we investigate the occurrence and risk factors of arrythmias, myocardial infarction and/or stroke, and thromboembolism in the course of COVID-19.
METHODS
We have performed an observational study with prospectively designed data collection. Data of patients diagnosed with COVID-19 who were admitted from March 6th 2020 to November 30th 2021 in our Hospital were analyzed. Logistic regression was used to identify variables associated with the odds of early hospital death due to COVID-19.
RESULTS
Fourteen-point three percent of 1964 patients had cardiovascular complications, 6.36 % arrhythmias, 5.5 % thromboembolic events and 2.39 % myocardial infarction and/or stroke. Factors independently increasing the odds of arrhythmia were older age (OR=1.49 [95 % CI: 1.17-1.92], p = 0.02), longer time between admission and the first onset of symptoms (1.02 [0.99-1.05], p = 0.049), concomitant atrial fibrillation/flutter (2.84 [1.37-5.70], p = 0.004), nicotinism (2.49 [1.37-4.49], p = 0.002), and eGFR<60 ml/min/1.73m (2.44 [1.08-5.59], p = 0.033). Factors independently increasing the odds of myocardial infarction and/or stroke were dementia (4.55 [0.97-19.3], p = 0.044), hemiplegia (12.67 [3.12-46.1], p < 0.001), nicotinism (3.36 [1.30-10.4], p = 0.013) and higher C-reactive protein concentration (1.01 [1.00-1.01], p = 0.040). Factors independently increasing the odds of thromboembolic events were longer hospitalization (1.08 [1.05-1.10], p < 0.001) and higher d-dimers (1.04 [1.02-1.05], <0.001).
CONCLUSIONS
The risk of cardiovascular complications was especially pronounced in patients with older age, pre-existing cardiovascular disease and more sever pneumonia at presentation to care. This underlines the importance of close and careful clinical follow-up in the course of COVID-19 for specific patients' populations, including a pro-active approach in diagnosis.
PubMed: 38944910
DOI: 10.1016/j.hrtlng.2024.06.009 -
International Journal of Cardiology Jun 2024Guidelines recommend insertable cardiac monitor (ICM) in the early phases of the evaluation of unexplained syncope (US) syncope, when an arrhythmic etiology is...
AIMS
Guidelines recommend insertable cardiac monitor (ICM) in the early phases of the evaluation of unexplained syncope (US) syncope, when an arrhythmic etiology is suspected. We examined the diagnostic yield of the last generation ICM (LG-ICM) to establish the causes of US, by assessing in the clinical practice the incidence of: relevant arrhythmia diagnosis, syncope recurrences and CM-guided cardiac electronic device (CIED) implantation. We investigated also baseline patient characteristics associated to an increased risk of relevant arrhythmias and of syncope recurrence.
METHODS
Data prospectively collected from consecutive patients receiving LG-ICM for investigation of US or presyncope in our institution between November 2020 and January 2023 were analyzed.
RESULTS
A total of 109 patients (mean age 64.4 ± 16.1 years, 40.4% women) with US or pre-syncope episodes underwent implantation of the LG-ICM. During a mean follow-up of 11.7 ± 8.1 months, LG-ICM diagnostic yield was 42% . In particular, LG-ICM detected cardiac arrhythmias in 29 (27%) patients (in 6 out of them during a syncope recurrence) and to exclude the arrhythmic origin of the syncope in additional 19 (17%) patients. LG-ICM guided the implantation of a CIED in 16 (15%) US patients, due to the diagnosis of asystole or severe bradycardia. Age ≥ 65 years (p = 0.012) and atrial arrhythmia history (p = 0.004) are significant independent predictors of arrhythmic diagnoses performed by LG-ICM, while CAD is predictor of syncope recurrence (bordering on statistical significance, p = 0.056).
CONCLUSIONS
The diagnostic yield of LG-ICM in US syncope is comparable to those of ILR and previous generation ICM. The advantages of LG-ICM should be sought in lower hospital workload necessary to manage ICM data. Age ≥ 65 years and atrial arrhythmia history are independent predictors of significant ICM-detected arrhythmias.
PubMed: 38944347
DOI: 10.1016/j.ijcard.2024.132301 -
Computer Methods and Programs in... Jun 2024Atrial fibrillation (AF) is the most common cardiac arrhythmia, inducing accelerated and irregular beating. Beside well-known disabling symptoms - such as palpitations,...
BACKGROUND AND OBJECTIVE
Atrial fibrillation (AF) is the most common cardiac arrhythmia, inducing accelerated and irregular beating. Beside well-known disabling symptoms - such as palpitations, reduced exercise tolerance, and chest discomfort - there is growing evidence that an alteration of deep cerebral hemodynamics due to AF increases the risk of vascular dementia and cognitive impairment, even in the absence of clinical strokes. The alteration of deep cerebral circulation in AF represents one of the least investigated among the possible mechanisms. Lenticulostriate arteries (LSAs) are small perforating arteries mainly departing from the middle cerebral artery (MCA) and susceptible to small vessel disease, which is one of the mechanisms of subcortical vascular dementia development. The purpose of this study is to investigate the impact of different LSAs morphologies on the cerebral hemodynamics during AF.
METHODS
By combining a computational fluid dynamics (CFD) analysis of LSAs with 7T high-resolution magnetic resonance imaging (MRI), we performed different CFD-based multivariate regression analyses to detect which geometrical and morphological vessel features mostly affect AF hemodynamics in terms of wall shear stress. We exploited 17 cerebral 7T-MRI derived LSA vascular geometries extracted from 10 subjects and internal carotid artery data from validated 0D cardiovascular-cerebral modeling as inflow conditions.
RESULTS
Our results revealed that few geometrical variables - namely the size of the MCA and the bifurcation angles between MCA and LSA - are able to satisfactorily predict the AF impact. In particular, the present study indicates that LSA morphologies exhibiting markedly obtuse LSA-MCA inlet angles and small MCA size downstream of the LSA-MCA bifurcation may be more prone to vascular damage induced by AF.
CONCLUSIONS
The present MRI-based computational study has been able for the first time to: (i) investigate the net impact of LSAs vascular morphologies on cerebral hemodynamics during AF events; (ii) detect which combination of morphological features worsens the hemodynamic response in the presence of AF. Awaiting necessary clinical confirmation, our analysis suggests that the local hemodynamics of LSAs is affected by their geometrical features and some LSA morphologies undergo greater hemodynamic alterations in the presence of AF.
PubMed: 38943985
DOI: 10.1016/j.cmpb.2024.108303 -
Cardiovascular Diabetology Jun 2024Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death with type 2 diabetes; however, their... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death with type 2 diabetes; however, their effect on arrhythmias is unclear. The purpose of this study was to investigate the effects of empagliflozin on ventricular arrhythmias in patients with type 2 diabetes.
METHODS
A total of 150 patients with type 2 diabetes who were treated with an implantable cardioverter-defibrillator or cardiac resynchronization therapy defibrillator (ICD/CRT-D) were randomized to once-daily empagliflozin or placebo for 24 weeks. The primary endpoint was the change in the number of ventricular arrhythmias from the 24 weeks before to the 24 weeks during treatment. Secondary endpoints included the change in the number of appropriate device discharges and other values.
RESULTS
In the empagliflozin group, the number of ventricular arrhythmias recorded by ICD/CRT-D decreased by 1.69 during treatment compared to before treatment, while in the placebo group, the number increased by 1.79. The coefficient for the between-group difference was - 1.07 (95% confidence interval [CI] - 1.29 to - 0.86; P < 0.001). The change in the number of appropriate device discharges during and before treatment was 0.06 in the empagliflozin group and 0.27 in the placebo group, with no significant difference between the groups (P = 0.204). Empagliflozin was associated with an increase in blood ketones and hematocrit and a decrease in blood brain natriuretic peptide and body weight.
CONCLUSIONS
In patients with type 2 diabetes treated with ICD/CRT-D, empagliflozin reduces the number of ventricular arrhythmias compared with placebo. Trial registration jRCTs031180120.
Topics: Humans; Diabetes Mellitus, Type 2; Glucosides; Benzhydryl Compounds; Male; Sodium-Glucose Transporter 2 Inhibitors; Female; Aged; Middle Aged; Treatment Outcome; Time Factors; Defibrillators, Implantable; Electric Countershock; Double-Blind Method; Japan; Cardiac Resynchronization Therapy; Blood Glucose
PubMed: 38943159
DOI: 10.1186/s12933-024-02309-9 -
BMC Cardiovascular Disorders Jun 2024Pulmonary transit time (PTT) can be measured automatically from arterial input function (AIF) images of dual sequence first-pass perfusion imaging. PTT has been...
BACKGROUND
Pulmonary transit time (PTT) can be measured automatically from arterial input function (AIF) images of dual sequence first-pass perfusion imaging. PTT has been validated against invasive cardiac catheterisation correlating with both cardiac output and left ventricular filling pressure (both important prognostic markers in heart failure). We hypothesized that prolonged PTT is associated with clinical outcomes in patients with heart failure.
METHODS
We recruited outpatients with a recent diagnosis of non-ischaemic heart failure with left ventricular ejection fraction (LVEF) < 50% on referral echocardiogram. Patients were followed up by a review of medical records for major adverse cardiovascular events (MACE) defined as all-cause mortality, heart failure hospitalization, ventricular arrhythmia, stroke or myocardial infarction. PTT was measured automatically from low-resolution AIF dynamic series of both the LV and RV during rest perfusion imaging, and the PTT was measured as the time (in seconds) between the centroid of the left (LV) and right ventricle (RV) indicator dilution curves.
RESULTS
Patients (N = 294) were followed-up for median 2.0 years during which 37 patients (12.6%) had at least one MACE event. On univariate Cox regression analysis there was a significant association between PTT and MACE (Hazard ratio (HR) 1.16, 95% confidence interval (CI) 1.08-1.25, P = 0.0001). There was also significant association between PTT and heart failure hospitalisation (HR 1.15, 95% CI 1.02-1.29, P = 0.02) and moderate correlation between PTT and N-terminal pro B-type natriuretic peptide (NT-proBNP, r = 0.51, P < 0.001). PTT remained predictive of MACE after adjustment for clinical and imaging factors but was no longer significant once adjusted for NT-proBNP.
CONCLUSIONS
PTT measured automatically during CMR perfusion imaging in patients with recent onset non-ischaemic heart failure is predictive of MACE and in particular heart failure hospitalisation. PTT derived in this way may be a non-invasive marker of haemodynamic congestion in heart failure and future studies are required to establish if prolonged PTT identifies those who may warrant closer follow-up or medicine optimisation to reduce the risk of future adverse events.
Topics: Humans; Heart Failure; Male; Female; Middle Aged; Aged; Predictive Value of Tests; Time Factors; Prognosis; Ventricular Function, Left; Myocardial Perfusion Imaging; Stroke Volume; Risk Factors; Pulmonary Circulation; Natriuretic Peptide, Brain; Peptide Fragments; Pulmonary Artery; Risk Assessment; Ventricular Function, Right; Magnetic Resonance Imaging
PubMed: 38943084
DOI: 10.1186/s12872-024-04003-w