Transplantation of IPSC-Derived Cardiomyocyte Patches for Ischemic Cardiomyopathy

Background: Despite major therapeutic advances, heart failure remains a life-threatening disorder, with 26 million patients worldwide, causing more deaths than cancer as a non-communicable disease. Therefore, novel strategies for the treatment of heart failure continue to be an important clinical need. Based on preclinical studies, allogenic human-induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) patches have been proposed as a potential therapeutic candidate for heart failure. We report the implantation of allogeneic hiPSC-CM patches in a patient with ischemic cardiomyopathy (ClinicalTrials.gov, #jRCT2053190081). Methods: The patches were produced under clinical-grade conditions and displayed cardiogenic phenotypes and safety in vivo (severe immunodeficient mice) without any genetic mutations in cancer-related genes. The patches were then implanted via thoracotomy into the left ventricle epicardium of the patient under immunosuppressive agents. Results: Positron emission tomography and computed tomography confirmed the possible efficacy and did not detect tumorigenesis in either the heart or other organs; the clinical symptoms improved 6 months after surgery, without any major adverse events, suggesting that the patches were well-tolerated. Furthermore, changes in the wall motion in the transplanted site were recovered, suggesting a favorable prognosis and the potential tolerance to exercise. Conclusions: This study is the first report of a successful transplant of hiPSC-CMs for severe ischemic cardiomyopathy.

Statistical Study Regarding the Presence of Gram Bacteria in Patients with Cardiovascular Disease and Periodontal Disease

Pathogenic bacteria, originating in the inflamed periodontium, can make their way into the body through the vascular system, either by entering the bloodstream or lymph directly or as internalized particles of immune cells. This research aims to investigate the existence of a potential connection between two pathologies – periodontitis and ischemic heart disease – by utilizing a DNA-DNA hybridization technique to highlight the presence of seven periodontal pathogens: A. actinomycetemcomitans, P. gingivalis, P. endodontalis, P. intermedia, T. forsythia, C. rectus and F. Nucleatum. The study was conducted over a period of 3 years on a sample consisting of 119 patients with cardiovascular disease and periodontal disease, divided into 3 groups by pathologies, as follows: the first group consisted of 31 patients with ischemic cardiomyopathy, the second group consisted of 43 patients with periodontal disease and ischemic cardiomyopathy, and the third group consisted of 45 patients with periodontal disease. The results show the possibility of a correlation between the composition of the bacterial flora in the group of patients with cardiac disease and those with associated pathologies. In conclusion, we may state that periodontitis may be seen as a risk factor in heart disease, which may certify the possibility of an etiological connection between the two pathologies.

Not Baseline Atrial Fibrillation but New-Onset Atrial Fibrillation and the Loss of Left Atrial Function Are Essential for Predicting Poor Outcomes in Non-ischemic Cardiomyopathy

Aims: The clinical impact of the type of atrial fibrillation (AF) has not been completely elucidated in non-ischemic cardiomyopathy (NICM). Although the structure and function of the left atrium (LA) provide prognostic information in patients with heart failure, the relationship of the AF type with LA structure and function in NICM is unclear.Methods: Consecutive patients with NICM who underwent cardiac magnetic resonance were evaluated and followed. Multivariable Cox regression models were used to estimate hazard ratios (HRs) for major adverse cardiovascular events (MACE) related to the AF type, such as paroxysmal AF, chronic AF, and new-onset AF (NOAF).Results: Among 625 patients with NICM (mean age, 64.4 ± 14.2 years; women, 39.7%), 133 had a history of AF at baseline; of these, 60 had paroxysmal AF. Each baseline AF type was associated with higher LA volume and lower LA emptying fraction but not with an increased incidence of MACE (p = 0.245). New-onset AF developed in 5.9% of patients with sinus rhythm over a median follow-up period of 609 days, and maximum LA volume was a strong and independent predictor [p < 0.001, area under the ROC curve (AUC): 0.795]. Maximum LA volume was superior to LA emptying fraction and B-type natriuretic peptide (AUC: 0.683 and 0.680, respectively). The use of β-blocker and the age of the patient were associated with the incidence of NOAF (HR: 0.37, 95% CI: 0.16–0.84 and HR: 1.05, 95% CI: 1.01–1.09, respectively). Kaplan–Meier analysis showed that patients with NOAF had a higher incidence of MACE than those with sinus rhythm or baseline AF (p = 0.002). NOAF and LA emptying fraction were independent predictors of MACE (HR: 2.28, 95% CI: 1.20–3.97 and HR: 0.98, 95% CI: 0.96–0.99, respectively) after adjusting for age, sex, body mass index, and diagnosis.Conclusions: Paroxysmal and chronic AF in patients with NICM were not associated with an increased incidence of MACE despite their association with LA volume and function. NOAF was independently associated with poor prognosis. Higher maximum LA volume predicted the onset and lower LA emptying fraction was independently associated with poor prognosis.

Transcriptional Active Parvovirus B19 Infection Predicts Adverse Long-Term Outcome in Patients with Non-Ischemic Cardiomyopathy

Parvovirus B19 (B19V) is the predominant cardiotropic virus currently found in endomyocardial biopsies (EMBs). However, direct evidence showing a causal relationship between B19V and progression of inflammatory cardiomyopathy are still missing. The aim of this study was to analyze the impact of transcriptionally active cardiotropic B19V infection determined by viral RNA expression upon long-term outcomes in a large cohort of adult patients with non-ischemic cardiomyopathy in a retrospective analysis from a prospective observational cohort. In total, the analyzed study group comprised 871 consecutive B19V-positive patients (mean age 50.0 ± 15.0 years) with non-ischemic cardiomyopathy who underwent EMB. B19V-positivity was ascertained by routine diagnosis of viral genomes in EMBs. Molecular analysis of EMB revealed positive B19V transcriptional activity in n = 165 patients (18.9%). Primary endpoint was all-cause mortality in the overall cohort. The patients were followed up to 60 months. On the Cox regression analysis, B19V transcriptional activity was predictive of a worse prognosis compared to those without actively replicating B19V (p = 0.01). Moreover, multivariable analysis revealed transcriptional active B19V combined with inflammation [hazard ratio 4.013, 95% confidence interval 1.515–10.629 (p = 0.005)] as the strongest predictor of impaired survival even after adjustment for age and baseline LVEF (p = 0.005) and independently of viral load. The study demonstrates for the first time the pathogenic clinical importance of B19V with transcriptional activity in a large cohort of patients. Transcriptionally active B19V infection is an unfavourable prognostic trigger of adverse outcome. Our findings are of high clinical relevance, indicating that advanced diagnostic differentiation of B19V positive patients is of high prognostic importance.

Ejection Fraction Recovery after Coronary Artery Bypass Grafting for Ischemic Cardiomyopathy

Background Controversy exists about left ventricular systolic function recovery after coronary artery bypass grafting in patients with ischemic cardiomyopathy. The aim of this study is to evaluate the temporal evolvement of left ventricular systolic function after coronary artery bypass surgery in patients with ischemic cardiomyopathy. Patients and Methods A total of 50 patients with coronary artery disease and left ventricular ejection fraction (LVEF) ≤35% underwent isolated coronary artery bypass grafting in a single center in the period 2017 to 2019. We performed a retrospective analysis of the echocardiographic and clinical follow-up data at 3 months and 1 year postoperatively. Results Median LVEF preoperatively was 25% (20–33%), mean patient age was 66 ± 8.2 years, 33 (66%) patients were operated off-pump, and 22 (44%) procedures were non-elective. There was no in-hospital myocardial infarction, stroke, and repeat revascularization. Three (6%) patients underwent re-exploration for bleeding or tamponade. In-hospital mortality was 8% and 1-year mortality was 12%. At 1 year postoperatively, there was no repeat revascularization, no myocardial infarction, 1 (2.6%) patient had a transient ischemic attack, and 10 (20%) patients required an implantable defibrillator. There was a statistically significant median ejection fraction increase at 3 months (15% [5–22%], p < 0.0001) and 1 year (23% [13–25%], p < 0.0001) postoperatively, with an absolute increase ≥10% in 32 (74.4%) and 30 (78.9%) patients at 3 months and 1 year, respectively. Conclusion Patients with ischemic cardiomyopathy undergoing coronary artery bypass surgery show continuous recovery of left ventricular systolic function in the first postoperative year.

Periodic Repolarization Dynamics Identifies ICD-responders in Non-ischemic Cardiomyopathy: A DANISH Substudy

Background: Identification of patients with non-ischemic cardiomyopathy who benefit from prophylactic implantation of a cardioverter-defibrillator (ICD) remains an unmet clinical need. We hypothesized that periodic repolarization dynamics (PRD), a marker of repolarization instability associated with sympathetic activity, could be used to identify patients that benefit from prophylactic ICD-implantation. Methods: Heart-failure (DANISH) study, in which patients with non-ischemic cardiomyopathy, left-ventricular ejection fraction (LVEF) ≤35% and elevated N-terminal pro-brain natriuretic peptides (NT-proBNP) were randomized to ICD-implantation or control group. Patients were included in the PRD-substudy if they had a 24-hour Holter monitor recording at baseline with technically acceptable ECG signals during the night hours (00:00-06.00 AM). PRD was assessed using wavelet analysis according to previously validated methods. Primary endpoint was all-cause mortality. Cox-regression models were adjusted for age, sex, NT-proBNP, estimated glomerular filtration rate, LVEF, atrial fibrillation, ventricular pacing, diabetes mellitus, cardiac resynchronization therapy and mean heart rate. We proposed PRD ≥10deg 2 as exploratory cut-off value for ICD-implantation. Results: Seven-hundred and forty-eight of the 1,116 DANISH patients qualified for the PRD-substudy. During a mean follow−up period of 5.1±2.0 years, 82 of 385 patients died in the ICD group and 85 of 363 patients died in the control group (p−value=0.40). In Cox-regression analysis, PRD was independently associated with mortality (HR 1.28 [1.09−1.50] per SD increase; p−value = 0.003). Moreover, PRD was significantly associated with mortality in the control group (HR 1.51 [1.25−1.81]; p<0.001) but not in the ICD-group 1.04 [0.83−1.54]; p−value=0.71). There was a significant interaction between PRD and the effect of ICD−implantation on mortality (p−value 0.008), with patients with higher PRD having the greater benefit in terms of mortality reduction. ICD-implantation was associated with an absolute mortality reduction of 17.5% in the 280 patients with PRD ≥10deg 2 (HR 0.54 [0.34-0.84]; p−value=0.006; number needed to treat 6), but not in the 468 patients with PRD<10deg 2 (HR 1.17 [0.77−1.78]; p−value=0.46; p−value for interaction 0.01). Conclusions: Increased PRD identified patients with non-ischemic cardiomyopathy, where prophylactic ICD-implantation led to significant mortality reduction.

Identified Three Interferon Induced Proteins as Novel Biomarkers of Human Ischemic Cardiomyopathy

Ischemic cardiomyopathy is the most frequent type of heart disease, and it is a major cause of myocardial infarction (MI) and heart failure (HF), both of which require expensive medical treatment. Precise biomarkers and therapy targets must be developed to enhance improve diagnosis and treatment. In this study, the transcriptional profiles of 313 patients’ left ventricle biopsies were obtained from the PubMed database, and functional genes that were significantly related to ischemic cardiomyopathy were screened using the Weighted Gene Co-Expression Network Analysis and protein–protein interaction (PPI) networks enrichment analysis. The rat myocardial infarction model was developed to validate these findings. Finally, the putative signature genes were blasted through the common Cardiovascular Disease Knowledge Portal to explore if they were associated with cardiovascular disorder. Three interferon stimulated genes (IFIT2, IFIT3 and IFI44L), as well as key pathways, have been identified as potential biomarkers and therapeutic targets for ischemic cardiomyopathy, and their alternations or mutations have been proven to be strongly linked to cardiac disorders. These novel signature genes could be utilized as bio-markers or potential therapeutic objectives in precise clinical diagnosis and treatment of ischemic cardiomyopathy.