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BioRxiv : the Preprint Server For... Jun 2024-Related Dilated Cardiomyopathy (DCM) is an autosomal-dominant genetic condition with cardiomyocyte and conduction system dysfunction often resulting in heart failure...
-Related Dilated Cardiomyopathy: Single-Cell Transcriptomics during Patient-derived iPSC Differentiation Support Cell type and Lineage-specific Dysregulation of Gene Expression and Development for Cardiomyocytes and Epicardium-Derived Cells with Lamin A/C Haploinsufficiency.
-Related Dilated Cardiomyopathy (DCM) is an autosomal-dominant genetic condition with cardiomyocyte and conduction system dysfunction often resulting in heart failure or sudden death. The condition is caused by mutation in the Lamin A/C ( ) gene encoding Type-A nuclear lamin proteins involved in nuclear integrity, epigenetic regulation of gene expression, and differentiation. Molecular mechanisms of disease are not completely understood, and there are no definitive treatments to reverse progression or prevent mortality. We investigated possible mechanisms of -Related DCM using induced pluripotent stem cells derived from a family with a heterozygous splice-site mutation. We differentiated one mutant iPSC line derived from an affected female (Patient) and two non-mutant iPSC lines derived from her unaffected sister (Control) and conducted single-cell RNA sequencing for 12 samples (4 Patient and 8 Control) across seven time points: Day 0, 2, 4, 9, 16, 19, and 30. Our bioinformatics workflow identified 125,554 cells in raw data and 110,521 (88%) high-quality cells in sequentially processed data. Unsupervised clustering, cell annotation, and trajectory inference found complex heterogeneity: ten main cell types; many possible subtypes; and lineage bifurcation for Cardiac Progenitors to Cardiomyocytes (CM) and Epicardium-Derived Cells (EPDC). Data integration and comparative analyses of Patient and Control cells found cell type and lineage differentially expressed genes (DEG) with enrichment to support pathway dysregulation. Top DEG and enriched pathways included: 10 genes and RNA polymerase II transcription in Pluripotent cells (PP); and TGF Beta/BMP signaling, sarcomere gene subsets and cardiogenesis, and EMT in CM; and epigenetic regulation and and mTORC1 signaling in EPDC. Top DEG also included: and other X-linked genes, six imprinted genes: , , , , , , and enriched gene sets in metabolism, proliferation, and homeostasis. We confirmed Lamin A/C haploinsufficiency by allelic expression and Western blot. Our complex Patient-derived iPSC model for Lamin A/C haploinsufficiency in PP, CM, and EPDC provided support for dysregulation of genes and pathways, many previously associated with Lamin A/C defects, such as epigenetic gene expression, signaling, and differentiation. Our findings support disruption of epigenomic developmental programs as proposed in other disease models. We recognized other factors influencing epigenetics and differentiation; thus, our approach needs improvement to further investigate this mechanism in an iPSC-derived model.
PubMed: 38915555
DOI: 10.1101/2024.06.12.598335 -
Nature and Science of Sleep 2024Mental stress induced myocardial ischemia (MSIMI) is regarded as the primary cause of the angina with no obstructive coronary artery disease (ANOCA). Obstructive sleep...
PURPOSE
Mental stress induced myocardial ischemia (MSIMI) is regarded as the primary cause of the angina with no obstructive coronary artery disease (ANOCA). Obstructive sleep apnea (OSA) is autonomously linked to obstructive coronary heart disease, hypertension, and sudden cardiac death. Similar to the impact of psychological stress on the cardiovascular system, individuals with OSA experience periodic nocturnal hypoxia, resulting in the activation of systemic inflammation, oxidative stress, endothelial dysfunction, and sympathetic hyperactivity. The contribution of OSA to MSIMI in ANOCA patients is unclear. To explore the prevalence of OSA in ANOCA patients and the correlation between OSA and MSIMI, a prospective cohort of female ANOCA patients was recruited.
PATIENTS AND METHODS
We recruited female patients aged 18 to 75 years old with ANOCA and evaluated MSIMI using positron emission tomography-computed tomography. Subsequently, Level III portable monitors was performed to compare the relationship between OSA and MSIMI.
RESULTS
There is higher REI (7.8 vs 2.6, =0.019), ODI (4.7 vs 9.2, =0.028) and percentage of OSA (67.74% vs 33.33%, =0.004) in MSIMI patients. The patients diagnosed with OSA demonstrated higher myocardial perfusion imaging scores (SSS: 1.5 vs 3, = 0.005, SDS: 1 vs 3, P = 0.007). Adjusted covariates, the risk of developing MSIMI remained 3.6 times higher in OSA patients (β=1.226, OR = 3.408 (1.200-9.681), = 0.021).
CONCLUSION
Patients with MSIMI exhibit a greater prevalence of OSA. Furthermore, the myocardial blood flow perfusion in patients with OSA is reduced during mental stress.
PubMed: 38911317
DOI: 10.2147/NSS.S445219 -
Cureus May 2024Intramyocardial bridging (IMB) is a congenital anomaly characterized by the tunneling of a coronary artery segment through the myocardium, potentially leading to serious...
Intramyocardial bridging (IMB) is a congenital anomaly characterized by the tunneling of a coronary artery segment through the myocardium, potentially leading to serious cardiac complications, such as myocardial ischemia, infarction, and sudden death, challenging the traditional view of it being benign. A case involving a 42-year-old man with a seven-day history of atypical chest pain highlights the significance of considering IMB in the differential diagnosis. Despite normal troponin levels, creatine kinase (CK), CK-MB, D-dimer, a negative drug screen, a normal ECG, and chest X-ray and no apparent issues on echocardiogram, left heart catheterization revealed IMB in the left anterior descending artery. This case underscores the necessity of including IMB in the differential diagnosis for chest pain, particularly in young males with familial cardiovascular disease history. While noninvasive imaging methods are useful for diagnosis, coronary angiography is the definitive diagnostic tool. Treatment primarily involves beta-blockers and calcium-channel blockers, with revascularization as a secondary option for those unresponsive to medication.
PubMed: 38910665
DOI: 10.7759/cureus.60874 -
Circulation Journal : Official Journal... Jun 2024The incidence and prognostic predictors of heart failure (HF) without left ventricular systolic dysfunction (LVSD) in hypertrophic cardiomyopathy (HCM), particularly...
BACKGROUND
The incidence and prognostic predictors of heart failure (HF) without left ventricular systolic dysfunction (LVSD) in hypertrophic cardiomyopathy (HCM), particularly their differences in terms of developing LVSD (progression to end-stage) or sudden cardiac death (SCD), are not fully elucidated.Methods and Results: This study included 330 consecutive HCM patients with left ventricular ejection fraction (LVEF) ≥50%. HF hospitalization without LVSD and development of LVSD were evaluated as main outcomes. During a median follow-up of 7.3 years, the incidence of HF hospitalization without LVSD was 18.8%, which was higher than the incidence of developing LVSD (10.9%) or SCD (8.8%). Among patients who developed LVSD, only 19.4% experienced HF hospitalization without LVSD before developing LVSD. Multivariable analysis showed that predictors for HF hospitalization without LVSD (higher age, atrial fibrillation, history of HF hospitalization, and higher B-type natriuretic peptide concentrations) were different from those of developing LVSD (male sex, lower LVEF, lower left ventricular outflow tract gradient, and higher tricuspid regurgitation pressure gradient). Known risk factors for SCD did not predict either HF without LVSD or developing LVSD.
CONCLUSIONS
In HCM with LVEF ≥50%, HF hospitalization without LVSD was more frequently observed than development of LVSD or SCD during mid-term follow-up. The overlap between HF without LVSD and developing LVSD was small (19.4%), and these 2 HF events had different predictors.
PubMed: 38910134
DOI: 10.1253/circj.CJ-24-0049 -
Heart Rhythm Jun 2024The subcutaneous implantable cardioverter-defibrillator (S-ICD) has emerged as a feasible alternative for the transvenous ICD in the treatment of ventricular... (Review)
Review
The subcutaneous implantable cardioverter-defibrillator (S-ICD) has emerged as a feasible alternative for the transvenous ICD in the treatment of ventricular tachyarrhythmias in patients without pacing or cardiac resynchronization therapy indications. Since its introduction, numerous innovations have been made and clinical experience was gained leading to its adoption in current practice and preference in certain populations. Moreover, emerging technologies like the extravascular ICD or the combination of the S-ICD with the leadless pacemaker offer new possibilities for the future. These advancements underscore the S-ICD's evolving role in ventricular tachyarrhythmia management. This review outlines implantation considerations, patient selection and troubleshooting advancements in the last 15 years and also provides insights into future perspectives.
PubMed: 38908460
DOI: 10.1016/j.hrthm.2024.06.028 -
JACC. Clinical Electrophysiology May 2024Cardiac troponins (cTns) and biomarkers of inflammation are elevated in heart failure (HF) and predict cardiovascular risk. Whether these biomarkers associate with risk...
BACKGROUND
Cardiac troponins (cTns) and biomarkers of inflammation are elevated in heart failure (HF) and predict cardiovascular risk. Whether these biomarkers associate with risk of ventricular arrhythmias (VAs) is unclear.
OBJECTIVES
This study sought to assess whether cTnT, growth differentiation factor 15 (GDF-15), interleukin-6 (IL-6), and C-reactive protein (CRP) concentrations are associated with incident VA.
METHODS
In a prospective, observational study of patients treated with implantable cardioverter-defibrillator, cTnT, GDF-15, IL-6, and CRP were measured at baseline and after 1.4 ± 0.5 years and were associated with implantable cardioverter-defibrillator-detected incident VA, HF hospitalizations, and mortality.
RESULTS
This study included 489 patients aged 66 ± 12 years and 83% were men. Median concentrations of cTnT were 15 (Q1-Q3: 9-25) ng/L at inclusion, and higher concentrations were associated with higher age, male sex, diabetes mellitus, coronary artery disease, and HF. During 3.1 ± 0.7 years of follow-up, 137 patients (28%) had ≥1 VA. cTnT concentrations were associated with an increased VA risk (per log-unit, HR: 1.63; 95% CI: 1.31-2.01; P < 0.001), also after adjustment for age, sex, body mass index, coronary artery disease, HF, renal function, and left ventricular ejection fraction (P < 0.001). GDF-15, IL-6, and CRP concentrations were not associated with incident VA, but all (including cTnT) were associated with HF hospitalization and mortality. Changes in cTnT, GDF-15, IL-6, and CRP from baseline to 1.4 years were not associated with subsequent VA.
CONCLUSIONS
Higher concentrations of cTnT, GDF-15, IL-6, and CRP associate with HF hospitalization and death, but only cTnT predict incident VA. These findings suggest that myocardial injury rather than inflammation may play a pathophysiological role in VA and sudden cardiac death.
PubMed: 38904572
DOI: 10.1016/j.jacep.2024.04.017 -
Cureus May 2024Iatrogenic aorto-coronary dissection (IACD) is a rare complication of interventional and surgical cardiac procedures, with a very high mortality burden. Here, we report...
Iatrogenic aorto-coronary dissection (IACD) is a rare complication of interventional and surgical cardiac procedures, with a very high mortality burden. Here, we report the case of a 71-year-old female with a past medical history of paroxysmal atrial fibrillation, mild to moderate aortic insufficiency, hypertension, and hyperlipidemia, who presented with classic anginal symptoms and underwent a cardiac catheterization, during which she suffered Iatrogenic right coronary artery (RCA) dissection and ascending aortic dissection resulting in sudden death. IACD is a rare complication, with a fatal prognosis. Coronary angiography and percutaneous coronary intervention (PCI) are considered safe, with a low risk of major complications including coronary perforations, and a very low risk of Iatrogenic aortic dissection (IAD). The coronary injury occurs more commonly during PCI of chronic total occlusion (CTO) or RCA interventions and can extend to the aortic root. IAD is often fatal and has worse outcomes than spontaneous dissection.
PubMed: 38899246
DOI: 10.7759/cureus.60690 -
European Journal of Radiology Jun 2024Takotsubo syndrome (TS) is characterized by transient myocardial dysfunction with outcomes ranging from favorable to life-threatening. Cardiovascular magnetic resonance... (Review)
Review
BACKGROUND
Takotsubo syndrome (TS) is characterized by transient myocardial dysfunction with outcomes ranging from favorable to life-threatening. Cardiovascular magnetic resonance (CMR) has emerged as an essential tool in its diagnosis and management and is consistently recommended by current guidelines in the diagnostic work-up. However, the prognostic value of CMR in patients with TS remains undetermined. The aim of this study was to assess the prognostic value of CMR in managing patients with TS.
METHOD
PubMed, MEDLINE via Ovid, Scopus, and the Cochrane Library were searched to identify studies reporting the prognostic role of multiparameteric CMR in patients with TS with a follow-up ≥ 12 months. The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE), defined as all-cause mortality, cardiac death, heart failure, sudden cardiac death, recurrence of TS, and cerebrovascular events.
RESULTS
Five studies with 564 patients were included for reporting correlation of CMR parameters with MACCE. Primary endpoint occurred in 69 (12%) patients. Among the CMR parameters assessed, myocardial strain parameters (including measurements of the left atrium, left and right ventricle), right ventricle involvement, and a CMR-based radiomics model demonstrated correlations with MACCE. Additionally, one study showed the predictive ability of a CMR score.
CONCLUSION
The current systematic review suggests that CMR may offer prognostic insights in TS patients, underscoring its potential clinical utility for integration into clinical practice. However, scarce data are currently available; hence, further research is needed.
PubMed: 38897052
DOI: 10.1016/j.ejrad.2024.111576 -
Journal of Cellular and Molecular... Jun 2024Cardiac hypertrophy, worldwide known as an adaptive functional compensatory state of myocardial stress, is mainly believed to proceed to severe heart diseases, even to...
Cardiac hypertrophy, worldwide known as an adaptive functional compensatory state of myocardial stress, is mainly believed to proceed to severe heart diseases, even to sudden death. Emerging studies have explored the microRNA alteration during hypertrophy. However, the mechanisms of microRNAs involved in cardiac hypertrophy are still uncertain. We studied young rats to establish abdominal aorta coarctation (AAC) for 4 weeks. With the significant downregulated cardiac function and upregulated hypertrophic biomarkers, AAC-induced rats showed enlarged myocardiocytes and alterations in microRNAs, especially downregulated miR-31-5p. miR-31-5p targets the 3'UTR of Nfatc2ip and inhibits myocardial hypertrophy in vitro and in vivo. Furthermore, we verified that Nfatc2ip is necessary and sufficient for cardiac hypertrophy in neonatal rat cardiomyocytes. Moreover, we found miR-31-5p inhibited the colocalization of Nfatc2ip and hypertrophic gene β-Mhc. Luciferase assay and ChiP-qPCR test demonstrated that Nfatc2ip binded to the core-promoter of β-Mhc and enhanced its transcriptional activity. Above all, our study found a new pathway, mir-31-5p/Nfatc2ip/β-Mhc, which is involved in cardiac hypertrophy, suggesting a potential target for intervention of cardiac hypertrophy.
Topics: MicroRNAs; Animals; Cardiomegaly; NFATC Transcription Factors; Myocytes, Cardiac; Rats; Male; Rats, Sprague-Dawley; Gene Expression Regulation; 3' Untranslated Regions; Disease Models, Animal
PubMed: 38894694
DOI: 10.1111/jcmm.18413 -
Diagnostics (Basel, Switzerland) Jun 2024Frequent and excessive consumption of alcohol, be it episodic or sustained misuse, ranks among the top causes of mortality globally. This comprehensive analysis seeks to... (Review)
Review
Frequent and excessive consumption of alcohol, be it episodic or sustained misuse, ranks among the top causes of mortality globally. This comprehensive analysis seeks to elucidate how alcohol misuse precipitates death, with a particular focus on associated cardiac anomalies. Notably, the phenomenon of "Holiday Heart Syndrome", linked to binge drinking, is recognized for inducing potentially fatal cardiac arrhythmias. Moreover, persistent alcohol consumption is implicated in the development of alcoholic cardiomyopathy, a condition that underlies heart failure and arrhythmic disturbances of the heart. Additionally, individuals undergoing withdrawal from alcohol frequently exhibit disruptions in normal heart rhythm, posing a risk of death. This review further delves into additional alcohol-related mortality factors, including the heightened likelihood of hypertension, cerebrovascular accidents (strokes), and the connection between excessive alcohol use and Takotsubo syndrome.
PubMed: 38893715
DOI: 10.3390/diagnostics14111189