Nonischemic Dilated Cardiomyopathy Research Articles

Association between RDW-SD and prognosis across glycemic status in patients with dilated cardiomyopathy

IntroductionThe prognostic significance of red cell distribution width-SD (RDW-SD) as a promising inflammatory biomarker in individuals with non-ischemic dilated cardiomyopathy (DCM) and varying glycemic status remains unexplored.Research design and methodsPatients...

Abstract 4136581: Shared Genetic Burden of Ischemic and Non-Ischemic Dilated Cardiomyopathy

Introduction: Ischemic dilated cardiomyopathy (IDCM) is defined as DCM caused by severe stenosis of one or more coronary arteries. Patients with non-ischemic dilated cardiomyopathy (NIDCM) have normal coronary arteries and may possess rare disease-causing variants in cardiac proteins such as TTN . However, IDCM and NIDCM share echocardiographic and pathologic features, possibly suggesting a shared etiology. Hypothesis: There is a similar prevalence of pathogenic (P)/likely pathogenic (LP) variants in patients with IDCM compared to patients with NIDCM. Aims: We compared the prevalence of P/LP genetic variants in DCM-associated genes in a cohort of patients with NIDCM or IDCM who received a heart transplant. Methods: We conducted a retrospective cohort study of patients who received a heart transplant between May 2017 and October 2023 at Cedars Sinai Medical Center in Los Angeles, CA. All subjects had LVEF ≤ 50% and LVEDD ≥ 95 th percentile for sex and height. Whole exome sequencing was performed on explanted heart tissue. We assessed for rare variants (minor allele frequency <0.1%) in genes with a definite, strong, or moderate rating in the ClinGen DCM Gene Curation Expert Panel. Variant pathogenicity was interpreted using the American College of Genetics and Genomics criteria for DCM. Ischemic cardiomyopathy was defined by the Felker criteria (Felker et al., JACC 2002). Results: We included 60 subjects: 16 with IDCM and 44 with NIDCM. There was no difference in LVEF or LVEDD between groups (TABLE). 2/16 (12.5%) patients with IDCM carried a P/LP variant, both of which were in TTN . 11/44 (25.0%) patients with NIDCM carried a P/LP variant: 6 in TTN and 1 each in FLNC, ILK, LMNA, MYH7 , and RBM20 . The prevalence of TTN variants in each group was similar (12.5% in IDCM vs. 13.6% in NIDCM) and higher than the expected frequency in the general population (0.2%). There was no significant difference in the prevalence of P/LP variants between the groups (chi-squared p-value 0.493, Bayes factor 0.45). Conclusion: Patients with IDCM exhibited a similar prevalence of P/LP variants to NIDCM patients, which suggests a shared genetic burden. If further studies confirm our findings, genetic testing for individuals with IDCM may be warranted.

Abstract 4119680: First-in-Man Treatment of Heart Failure by Repeated Intravenous Infusions of a Cardiovascular Cell-Derived Extracellular Vesicle-Enriched Secretome

Background: Most of the effects of intramyocardially transplanted stem cells can be duplicated by the sole administration of their secretome but this approach has not yet been tested in heart failure (HF). Methods: The SECRET-HF phase I trial (NCT05774509) was designed according to a Bayesian optimal interval scheme to assess the effects of repeated intravenous infusions of a cellular secretome in 12 patients with a non-ischemic dilated cardiomyopathy. The main inclusion criteria are severe symptoms (NYHA Class III despite an optimal guideline-directed medical therapy), a reduced left ventricular (LV) ejection fraction (EF ≤40%) and ineligibility for a heart transplant. The Investigational Medicinal Product was derived from human induced pluripotent stem cells reprogrammed from a healthy donor and differentiated in cardiovascular progenitor cells (CPC). Following CPC culture in a dedicated "vesiculation" medium, the conditioned media were collected, filtered, enriched for extracellular vesicles, concentrated by tangential flow filtration and scaled out into glass vials stored at -80°C. Quality controls were implemented throughout the whole process which was conducted according to current Good Manufacturing Practices. Results: Three patients, out of the 4 of the initial low-dose cohort, have now been treated. All had been previously fitted with an automatic internal cardioverter defibrillator (AICD). The secretome was delivered intravenously 3 times, 3 weeks apart, at a dose of 20 x10 9 particles/kg for each infusion. By November, 2024, the follow-up will be 16, 9, 6 and 2 months for each of them (mean: 8 months). So far, none of the treated patients has experienced a dose-limiting toxicity; in particular, there have been no post-treatments ventricular arrhythmia detected by the AICD, no allo-immunization and no inflammation based on the enumeration of lymphocyte subpopulations by flow cytometry. At 6 months, the first patient improved to NYHA Class II with a decrease in echographic LVEDV and LVESV (from 108 mL/m 2 to 87 mL/m 2 and from 80 mL/m 2 to 60 mL/m 2 , respectively) and a concomitant increase in LVEF from 25% to 32%. At 1 month post-treatment, the second patient also reports a symptomatic improvement (NYHA Class II) with an increase in EF from 21% to 28%. Conclusions: This initial experience supports the safety of repeated intravenous administrations of a cardiovascular cellular secretome as a potential noninvasive and user-friendly treatment of severe HF.

Stem cell therapy for non-ischemic dilated cardiomyopathy: a systematic review and meta-analysis

BackgroundStem cell therapy is the transplantation of human cells to aid the healing of damaged or wounded tissues and cells. Only a few small-scale trials have been conducted to investigate stem cell therapy for non-ischemic dilated cardiomyopathy (DCM). We aimed to perform a systematic review and meta-analysis to assess the efficacy and safety of stem cell therapy for DCM.MethodsA comprehensive search of the databases of PubMed, Embase, Web of Science Core Collection, Cochrane Library, and ProQuest was conducted from their inception to June 30, 2024, to access randomized controlled trials (RCTs) that were centered on stem cell therapy for DCM. The primary outcome was left ventricular ejection fraction (LVEF), and the secondary outcomes included left ventricular end-diastolic dimension (LVEDD), left ventricular end-diastolic volume (LVEDV), 6-min walk test (6MWT), NYHA functional classification, quality of life (QoL) such as Minnesota Living with Heart Failure Questionnaire (MLHFQ) and Kansas City Cardiomyopathy Questionnaire (KCCQ), N-terminal pro-brain natriuretic peptide (NT-proBNP), and VO2 peak. Moreover, major adverse cardiovascular events (MACEs) were also recorded. The Cochrane risk-of-bias assessment tool was used to evaluate the quality of the included RCTs, and the certainty of the evidence was assessed using the GRADE method. Sensitivity analysis was taken into consideration to determine the stability of the results. This review was registered with PROSPERO (CRD42024568912).ResultsEleven RCTs involving 637 participants were included in the quantitative analysis. The results indicated that there was a significant increase in mean LVEF (MD = 4.84, 95% CI 3.25–6.42, P < 0.00001) and considerable decrease in LVEDV (MD = − 29.51, 95% CI − 58.07 to − 0.95, P = 0.04) and NT-proBNP (MD = − 737.55, 95% CI − 904.28 to − 570.82, P < 0.00001) in DCM patients treated with stem cell therapy compared with controls. Stem cell therapy was also related to the improvement in functional capacity, as evaluated by 6MWT (MD = 44.32, 95% CI 34.70 − 53.94, P < 0.00001) and NYHA functional classification (MD = − 0.63, 95% CI − 0.96 to − 0.30, P = 0.0002). It also had positive effects on improving QoL, including significantly decreasing MLHFQ score (MD = − 16.60, 95% CI − 26.57 to − 6.63, P = 0.001) and increasing the KCCQ score (MD = 14.76, 95% CI 7.76 − 21.76, P < 0.0001). No significant differences were observed in LVEDD, VO2 peak, and MACEs between the two groups. The GRADE analysis revealed that the evidence was graded from low to moderate. Sensitivity analysis of the results suggested that the results were stable.ConclusionThe systematic review and meta-analysis indicates that stem cell therapy may be an effective and safe approach to improve cardiac function and quality of life in DCM patients. Nevertheless, given the limitations of existing studies, larger well-designed RCTs are required to confirm and support our findings.

Propensity score-matched analysis in isolated left ventricular dilation and non-ischaemic dilated cardiomyopathy

Abstract Background The presence and extent of late gadolinium enhancement (LGE) assessed by cardiac magnetic resonance imaging (CMR) are strong prognosticators of death in patients with non-ischaemic dilated cardiomyopathy (DCM), defined by the current guidelines as left ventricular (LV) dilation and left ventricular ejection fraction (LVEF)&amp;lt;50%. Although the current guidelines defined the concept of "isolated LV dilation" as LV dilation with preserved LVEF≥50%, the prognostic value of the LGE granularity including its extent, location and pattern is not established in this population. Purpose To assess the prognostic value of the concept of "LGE granularity" including its extent, location, and pattern for predicting all-cause death above traditional prognosticators in patients with LV dilation and reduced LVEF (i.e. DCM) or preserved LVEF (i.e. isolated LV dilation), separately. Methods Between 2008 and 2021, all consecutive patients with DCM and isolated LV dilation without ICD or history of sustained ventricular arrhythmia referred for CMR were included in two centres. All patients with history of coronary artery disease or myocarditis were excluded. The primary outcome was all-cause death using the French National Registry of Death. A 1:1 propensity score matching was performed to balance baseline characteristics in patients with DCM vs. those with isolated LV dilation. Cox regressions were performed to determine the prognostic value of each LGE findings. Results Of 2,752 patients analysed (age 52±8 years, 56% male), 408 (15%) patients died after a median (interquartile range) follow-up of 9 (7-12) years. A total of 737 (27%) patients had LGE. Patients with DCM had a higher rate of death than patients with isolated LV dilation (16% versus 13%, p=0.02). In the propensity-score matched population (N=1,084 in DCM subgroup and N=1,084 in isolated LV dilation), the LGE presence was associated with death (HR=2.98, 95%CI: 1.97-4.50, p&amp;lt;0.001). In isolated LV dilation patients with LGE (N=265), the LGE extent (HR=1.41, 95%CI:1.09-1.83, p=0.009), the presence of LGE in multiple areas (HR=3.86, 95%CI: 1.73-8.61, p&amp;lt;0.001) and the septal location (HR=2.97, 95%CI:1.37-6.46, p=0.006) were strong prognosticators of death after adjustment for traditional prognosticators. Similarly, in DCM patients with LGE (N=268), the LGE extent (HR=1.42, 95% CI:1.07-1.89, p=0.014), the presence of LGE in multiple areas (HR=8.41, 95%CI: 3.32-21.3, p&amp;lt;0.001) and the septal location (HR=6.65, 95% CI: 3.02-14.6, p&amp;lt;0.001) were strongly associated with death after adjustment. Conclusion In a large cohort of DCM and isolated LV dilation patients, the concept of "LGE granularity" was independently associated with all-cause death after adjustment for all traditional prognosticators in both DCM and isolated LV dilation. These results suggest the existence of a continuum between isolated LV dilation and DCM, and that CMR assessment could improve the risk stratification in this population.

Quantifying late gadolinium enhancement improved sudden cardiac death risk prediction in non-ischemic dilated cardiomyopathy

Abstract Background While previous studies have proved the late gadolinium enhancement (LGE) was associated with poor prognosis in non-ischemic dilated cardiomyopathy (DCM), the optimal method for LGE quantification and the ability of LGE extent in identifying sudden cardiac death (SCD) remain less clarified. Purpose This study sought to compare the reproducibility of LGE quantification methods and explore the asssociation between LGE extent and SCD endpoint in DCM patients. Methods In this prospective study, LGE was quantified by the 2-6 standard deviations (SD) above the remote myocardium and full-wide half-maximum (FWHM) methods. The primary endpoint was SCD and arrythmia endpoint included SCD and aborted SCD. Reproducibility of LGE quantification was measured by Bland-Altman analysis and intra-class correlation coefficients (ICC). Competing risk regression analysis, C-index and area under the curve (AUC) were performed to identify the prognostic value. Results Among the 770 patients, 336 (44%) patients had LGE. FWHM demonstrated the best reproducibility compared with other quantification methods (intraobserver variability: ICC = 0.94, mean bias: -0.43 ± 4.89%; interobserver variability: ICC = 0.90, mean bias: -2.65 ± 6.40%). After a median follow-up of 49 months, SCD occurred in 61 (8%) patients and arrythmia endpoint occurred in 87 (11%) patients. Among all quantification method, LGE extent measured by FWHM showed the highest predictive value of SCD (C index: 0.72) and arrythmia events (C index: 0.71) than other methods. In the competing risk analysis, LGE extent was independently association with SCD (Hazard ratio [HR] 1.05, 95% confidence interval [CI] 1.03 - 1.07, P &amp;lt; 0.001) and arrythmia endpoint (HR 1.05, 95% CI 1.03 - 1.06, P &amp;lt; 0.001). LGE extent &amp;gt;8% showed significantly higher risk of SCD and arrythmia endpoint than those with LGE extent ≤8% (P &amp;lt; 0.001). Incoporating LGE exent and 35% left ventricular ejection fraction (LVEF) significantly improved the SCD (C index: 0.74 vs 0.61, P &amp;lt; 0.001) and arrythmia endpoint (C index: 0.73 vs 0.59, P &amp;lt; 0.001) prediction compared with LVEF. Conclusions FWHM demonstrated best reproducibility and highest SCD prediction ability among LGE quantification methods. Adding LGE extent to LVEF significantly improved the predictive value of SCD and arrythmia endpoint.Figure 1

Prognostic impact of the concept of late gadolinium enhancement granularity in non-ischaemic dilated cardiomyopathy

Abstract Background The prognostic stratification of non-ischaemic dilated cardiomyopathy (DCM) to predict the risk of death is mainly driven by the left ventricular ejection fraction (LVEF). Indeed, LVEF&amp;lt;35% is currently the only indication for primary prevention with implantable cardioverter-defibrillator (ICD) in these patients. Beyond LVEF, several cardiac magnetic resonance imaging (MRI) studies have suggested the strong prgnostic impact of late gadolinium enhancement (LGE), and particularly its extent and location. Therefore, we assumed that a more granular approach combining detailed LGE findings including extent, location and pattern could improve risk stratification in this population. Purpose To assess the additional prognostic value of the concept of "Late Gadolinium Enhancement (LGE) Granularity" that includes extent, location, and pattern in non-ischaemic dilated cardiomyopathy (DCM) patients to predict all-cause death. Methods Between 2008-2021, all consecutive patients with DCM without ICD or history of sustained ventricular arrythmia referred for cardiac MRI were included in two French centres. In line with the current ESC and AHA guidelines, DCM was defined by the LV dilation and LVEF&amp;lt; 50% using cardiac MRI. All patients with history of coronary artery disease or clinical history of myocarditis were excluded. The primary outcome was all-cause death using the French National Registry of Death. Cox regressions were performed to determine the prognostic value of each LGE findings. The additional prognostic value of the LGE granularity was assessed by the C-statistic increment, the continuous net reclassification improvement (NRI), and the integrative discrimination index (IDI). Results Of 1,668 DCM patients (age 52±8 years, 54% males), 268 (16%) died after a median (interquartile range) follow-up of 9 (7-12) years. With a median LVEF value of 39% (30-46), 472 (28%) patients had non-ischemic LGE. Using survival curves, patients with LVEF&amp;gt;35% but the LGE septal location showed a higher risk of death compared to all patients with LVEF≤35% with or without LGE (except for the septal location, all p&amp;lt;0.001). In DCM patients with LGE (N=472), LGE extent (adjusted HR: 4.27, 95% CI: 2.22-8.22), septal location (HR: 5.74, 95% CI: 3.35-9.85) and multiple areas of LGE (HR: 4.38, 95% CI: 2.08-9.22; all p&amp;lt;0.001) were all independently associated with death after adjustment for prognosticators. The concept of "LGE granularity" combining all these LGE features showed the best improvement in model discrimination and reclassification over traditional prognosticators including LVEF (C-statistic improvement: 0.14; net reclassification improvement=64.3%; integrative discrimination index=29.0%; all p&amp;lt;0.05). Conclusion In a large cohort of DCM patients, the concept of "LGE granularity" combining LGE extent, location and the presence of multiple areas had an additional prognostic value above traditional prognosticators including LVEF to predict all-cause death.

All-cause mortality and incidence of appropriate therapy from a primary preventive implantable cardioverter defibrillator in patients with non-ischemic dilated cardiomyopathy

Abstract Background The DANISH study published in 2016 indicated limited benefit of primary prevention implantable cardioverter-defibrillator (ICD) in patients with non-ischemic dilated cardiomyopathy (niDCM). We aimed to investigate the long-term outcome and incidence of ICD therapy in patients with niDCM implanted on primary prevention indication during 2014-2022. Methods A total of 116 patients with niDCM were prospectively included for primary prevention ICD implantation between 2014 and 2022 in the multicenter IMPROVE study (clinical trials NCT02286908). All patients were examined with electrocardiogram, echocardiography and blood sampling at inclusion. The primary outcome was all-cause mortality, and the secondary outcome was appropriate ICD therapy. Outcomes were compared in patients included from 2014 to end of 2016 (DCM2014-16, n=49) and from 2017-2022 (DCM2017-22, n=67). Results At inclusion, patients in DCM2017-22 were younger (54 years [interquartile range (IQR) 44-68] vs. 64 years [IQR 55-70], p=0.001), had higher left ventricular ejection fraction (LVEF) (33% [IQR 25-38] vs. 24% [IQR 21-31], p&amp;lt;0.001) and less frequently received cardiac-resynchronization therapy defibrillator (6% vs. 29%, p=0.001) compared to DCM2014-16. Over a median 4.4-year follow-up, the all-cause mortality was 14%, of which 10% occurred in the DCM2017-22 patients (2.6 events/100 person-years), and 18% in the DCM2014-16 patients (4.0 events/100 person-years), p=0.38. There was no difference in appropriate ICD therapy between the two groups (p=0.90). Conclusion Patients receiving primary prevention ICD for niDCM after publication of the DANISH study were younger with higher LVEF, indicating a change in clinical practice after the publication. Despite this, there was no significant reduction in all-cause mortality or difference in appropriate ICD therapies. Unchanged mortality and event-rates may indicate the correct identification of high-risk patients.

Prognostic implications of genotype findings in non-ischemic dilated cardiomyopathy: a network meta-analysis

Abstract Background Evidence on the relative impact of diverse genetic backgrounds associated with non-ischemic dilated cardiomyopathy (DCM) remains contradictory. Aim This study sought to synthesize the available data regarding long-term outcomes of different gene groups in DCM. Methods Electronic databases were systematically screened to identify studies reporting prognostic data on pre-specified gene groups. Those included pathogenic/likely pathogenic (P/LP) variants, truncating titin variants (TTNtv), lamin A/C mutations (LMNA), and desmosomal proteins. Outcomes were divided into composite adverse events (CAEs), major ventricular arrhythmic events (MVAEs) and heart failure events (HFEs). Random effects meta-analyses were conducted to quantify the pooled odds ratio (ORs) for each gene group. A frequentist network meta-analysis was executed to allow indirect within-gene group comparisons. Results Twenty-six studies comprising 7,255 genotyped DCM individuals were included. Patients with P/PL variants had a higher risk for CAEs [OR, 2.10 (95% CI, 1.67-2.65)], MVAEs [OR, 1.86 (95% CI, 1.52-2.26)], and HFEs [OR, 2.01 (95% CI, 1.08-3.73)] than genotype negative patients. The presence of TTNtv was linked to a higher risk for CAEs [OR, 1.78 (95% CI, 1.20-2.63)], but not MVAEs or HFEs. LMNA and desmosomal groups suffered a higher risk for CAEs, MVAEs, and HFEs compared to non-LMNA and non-desmosomal groups respectively (Picture 1). When genes were indirectly compared, the presence of LMNA resulted in a more detrimental effect that TTNtv, with respect to all composite outcomes but no significant difference was found between LMNA and desmosomal genes. Desmosomal genes harbored a higher risk for MVAEs compared to TTNtv (Picture 2). Conclusion Different genetic substrates associated with DCM result in divergent natural histories. Routine utilization of genetic testing should be employed to refine risk stratification and inform therapeutic strategies in DCM.Natural history of DCM based on genotypeNetwork meta-analysis of gene variants

Comparison of different non-invasive estimates of right ventriculo-arterial coupling as outcome predictors in dilated cardiomyopathy

Abstract Right ventriculo-arterial coupling (RVAC) has emerged as an outcome predictor in pulmonary hypertension, but its role in left-sided HF remains to be clarified. Different non-invasive estimates for RVAC have been proposed, but a direct comparison of their prognostic ability is lacking. We sought to evaluate RVAC non-invasively using five different methods in a cohort of patients with dilated cardiomyopathy (DCM) and to assess their prognostic role. We enrolled 121 consecutive patients with non-ischemic DCM in sinus rhythm, who underwent comprehensive echocardiography, including speckle-tracking and 3D analysis. They were prospectively followed for 19±11 months for a composite endpoint of death, nonfatal cardiac arrest and hospitalization. RVAC was measured using five non-invasive estimates: (1) as the tricuspid annular plane systolic excursion (TAPSE)/pulmonary artery systolic pressure (PASP) ratio; (2) as the right ventricular (RV) global longitudinal strain (RV-GLS)/PASP ratio; (3) as the longitudinal strain of the RV free wall (LS-RVFW)/PASP ratio; (4) as the 3D RV ejection fraction (RVEF)/PASP ratio; and (5) as the 3D RV stroke volume (SV)/3D RV end-systolic volume (ESV) ratio. Mean age in the study cohort was 59±14 years and the majority (74%) were men. 55 patients (46%) reached the endpoint: there were 27 deaths, 5 nonfatal cardiac arrests and 23 readmissions for heart failure. Patients with adverse outcome had lower TAPSE/PASP (0.42±0.23 vs. 0.62±0.33, p&amp;lt;0.001), lower RVEF/PASP (0.96±0.49 vs. 1.47±0.67, p&amp;lt;0.001), lower RV SV/ESV (0.57±0.20 vs. 0.93±0.29, p&amp;lt;0.001) and higher RV-GLS/PASP (-0.25±0.20 vs. -0.38±0.23, p=0.002) and LS-RVFW/PASP (-0.28±0.30 vs. -0.51±0.33, p&amp;lt;0.001), reflecting greater ventriculo-vascular decoupling. In univariate Cox regression, all three RVAC indices were outcome predictors: HR=0.09 [95% CI, 0.02-0.37], p=0.001 for TAPSE/PASP, HR=13.67 [95% CI, 2.77-67.48], p=0.001 for RV-GLS/PASP, HR=8.72 [95% CI, 3.24-23.45], p&amp;lt;0.001 for LS-RVFW/PASP, HR=0.27 [95% CI, 0.14-0.50], p&amp;lt;0.001 for RVEF/PASP, HR=0.004 [95% CI, 0.001-0.019], p&amp;lt;0.001 for RV SV/ESV. In ROC analysis, the SV/ESV ratio had the highest AUC (AUC=0.88, p&amp;lt;0.001), a value lower than 0.74 having 86% sensitivity and 77% specificity for event prediction. After adjustment for age, NYHA class, left ventricular ejection fraction, and maximal left atrial volume, all coupling indices remained independent predictors of outcome: HR=1.90 [95% CI, 1.01-3.57], p=0.047 for TAPSE/PASP, HR=2.15 [95% CI, 1.17-3.96], p=0.01 for RV-GLS/PASP, HR=2.48 [95% CI, 1.34-4.60], p=0.004 for LS-RVFW/PASP, HR=3.19 [95% CI, 1.19-8.52], p=0.02 for RVEF/PASP, HR=7.50 [95% CI, 3.47-16.22], p&amp;lt;0.001 for RV SV/ESV. In DCM, RVAC is significantly more impaired in patients with major adverse events. Non-invasive RVAC was an independent predictor of adverse outcome irrespective of the formula used for estimation, but 3D RV SV/ESV ratio had the greatest prognostic power.

The myocardium of human dilated nonischemic cardiomyopathy harbors unique tissue-resident lymphocyte subsets

Abstract Purpose The etiology of dilated nonischemic cardiomyopathy (NICM) is often unclear, but thought to be multifactorial, involving an interplay between genetic factors and direct myocardial damage caused by infection, autoimmunity, or toxins. Tissue-resident lymphocytes are non-circulating immune cells which are retained within various tissues and play integral roles in maintaining homeostasis, responding to infection, regulating inflammation, and mediating tissue repair. Despite their likely involvement in various cardiac pathologies, the presence of tissue-resident lymphocytes in the human heart has not yet been well-characterized, neither in health nor in disease. Methods Human left ventricular tissue and paired peripheral blood samples were obtained from six adult organ donors with normal heart function who died of noncardiac causes and from the explants of six adult patients with end-stage nonischemic cardiomyopathy. Heart tissue was processed using mechanical and enzymatic digestion. Mononuclear cells were isolated from both heart and paired blood by density centrifugation. Isolated mononuclear cells were surface stained with an antibody cocktail and interrogated using multidimensional flow cytometry. Results The adult human heart contains a diverse immune cell population (Fig 1A). Both healthy and NICM cardiac lymphocytes express distinct phenotypic profiles which resemble those of resident lymphocytes found across various tissues, distinct from those isolated from paired blood. Frequencies of effector memory T (Tem) cells (CD45RA- CCR7-) were higher in heart than in blood among both CD4+ and CD8+ T-cells. In heart compared to blood, significantly more Tem expressed CD69, a canonical marker of tissue-resident memory T (Trm) cells (Fig 1B). Cardiac Trm, especially CD8+ Trm, expressed classical Trm signature markers including integrins CD103 (epithelial binding) and CD49a (collagen binding). NICM Trm expressed more CD49a than healthy heart Trm (Fig 1C). NK-cells also demonstrated higher CD69 expression (trNK) in heart than in blood, with associated expression of CD103, CD49a, and CXCR6 (Fig 1D). Compared to healthy hearts, NICM trNK were predominantly CD56bright/CD16- (Fig 1E and 1F) and expressed less CD57 (Fig 1D), overall indicating a less mature state with lower cytotoxic potential. Confocal imaging of cardiac tissue revealed CD69-expressing tissue-resident lymphocytes within the cardiac interstitium. Conclusions The adult human heart contains diverse populations of lymphocytes which express canonical markers of tissue residency, similar to lymphocytes resident in other tissues. Compared to healthy hearts, NICM hearts have more CD49a+ Trm, perhaps related to greater fibrosis, and also harbor a distinct subset of immature tissue-resident NK cells which may shed light on pathophysiology. Future work is focused on better exploring the functional phenotypes of these resident cells and better localizing them within the myocardium.FA - Figure 1

Heart Rate Recovery Index and Improved Diastolic Dyssynchrony in Fusion Pacing Cardiac Resynchronization Therapy.

Background: Restoring electrical synchrony with cardiac resynchronization therapy (CRT) reverses the heart failure phenotype developed by left-ventricular (LV) dyssynchrony. This study aimed to identify new predictors of response to LV-only fusion pacing CRT. Methods: A select group of patients with CRT-P indications received a right atrium (RA)/LV DDD pacing system. LV dyssynchrony was assessed via offline TDI timing focusing on the temporal difference between peak septal (E″T) and lateral wall (A"T) motion. CRT effectiveness was evaluated at each follow-up, involving the heart rate recovery index (HRRI) parameter (acceleration/deceleration time) derived from exercise testing along with the echocardiographic parameters. Patients were classified into super-responders (SR), responders (R), and non-responders (NR). Results: Baseline initial characteristics: 62 patients (35 male) aged 62 ± 11 y.o. with non-ischemic dilated cardiomyopathy (DCM). Ejection fraction (EF) 27 ± 5.2%; QRS 164 ± 18 ms; 29% had type III diastolic dysfunction (DD), 63% type II DD, and 8% type I DD. Average follow-up was 45 ± 19 months: 34% of patients were SR, 61% R, and 5% NR. The E″T decreased from 90 ± 20 ms to 25 ± 10 ms in SR, with a shorter deceleration time (DT) during exercise test compared to NR (109 ± 68 ms vs. 330 ± 30 ms; p < 0.0001). The responders present a higher HRRI (2.87 ± 1.47 vs. 0.98 ± 0.08; p = 0.03) compared to NR and a significantly decrease in E"T and A"T from 76 ± 13 ms to 51 ± 11 ms (p < 0.0001). Prolonged DT was associated with an accentuated LV dyssynchrony and nonoptimal response to CRT. Conclusions: The study identified new parameters for assessing responsiveness to LV-only fusion pacing CRT, which could improve candidate selection and CRT implementation.

Prognostic value of myocardial tissue characterization by cardiac magnetic resonance imaging using T1 mapping in nonischemic dilated cardiomyopathy: a systematic review and meta-analysis

Prognostic value of myocardial tissue characterization by cardiac magnetic resonance imaging using T1 mapping in nonischemic dilated cardiomyopathy: a systematic review and meta-analysis

Comparison of left bundle branch area pacing between patients with pacing-induced cardiomyopathy and non-ischemic dilated cardiomyopathy.

Left bundle branch area pacing (LBBAP) seems to be an alternative to coronary sinus pacing in patients with non-ischaemic dilated cardiomyopathy (NI-DCM) with left bundle branch block (LBBB) and in pacing-induced cardiomyopathy (PICM). The aim of the study was to compare the response of LBBAP in severe forms of both entities. Prospective study of patients with severe forms of PICM and NI-DCM in NYHA II-IV who underwent LBBAP. Clinical, electrocardiographic, echocardiographic and electrical parameters were analysed and the medium-term prognostic impact was assessed. Eighty patients were included, 25 with PICM and 55 with NI-DCM. PICM patients were older (PICM 75 [IQR 71-83.5] y.o vs NI-DCM 72 [IQR 60-78.5] y.o;p=0.01) and with longer baseline QRS duration (PICM 180 [IQR 167-194] ms vs NI-DCM 168 [IQR 153-178] ms;p<0.01), with no differences in left ventricular ejection fraction (LVEF) or medical treatment. QRS reduction occurred in both groups, being greater in PICM (PICM CI 95% 54±20 ms, p<0.01; NI-DCM CI 95% 40±15 ms;p<0.01). A NT-ProBNP levels reduction and LVEF improvement were observed without differences between groups. At follow-up, there were no differences in admissions for HF (PICM 4.2% vs NI-DCM 11%;p=0.413), cardiac mortality (PICM 14.9% vs NI-DCM 2.9%;p=0.13) and all-cause mortality (PICM 21.7% vs NI-DCM 10.9%;p=0.08). LBBAP is an effective technique with a NT-ProBNP levels reduction and LVEF improvement in both groups without differences. At follow-up, both groups had a low rate of HF readmissions and there was a non-significant trend toward higher total mortality in PICM.

Clostridium Limosum Lung Abscess in a Heart Transplant Recipient: A Rare Case Report

We report a case of Clostridium limosum lung abscess in a 71-year-old male heart transplant recipient. The patient presented with a week-long history of productive cough and confusion. His medical history included nonischemic dilated cardiomyopathy, chronic renal disease, and past Klebsiella pneumoniae bacteremia, among others. Imaging revealed a thick-walled cavitary lesion in the right lung, initially suspected to be a pulmonary abscess. Lung biopsy culture confirmed the presence of Clostridium limosum, a rare pathogen in humans, typically associated with farm animals. Following six weeks of Piperacillin/Tazobactam treatment, the patient showed significant clinical improvement. This case emphasizes the importance of considering zoonotic pathogens in immunosuppressed patients, especially those with occupational exposure.

Risk of Stroke and Incident Atrial Fibrillation in Patients in Sinus Rhythm With Nonischemic Dilated Cardiomyopathy

Background: Non-ischemic dilated cardiomyopathy (NIDCM) is associated with an increased risk of atrial fibrillation (AF) and stroke, especially in patients with high CHA2DS2-VASc. We aimed to identify variables associated with incident AF or stroke using left atrial (LA) deformation analysis and its prognostic value added to CHA2DS2-VASc score. Patients with NIDCM and LVEF <50% in sinus rhythm were included between January 2015 and December 2019. LA volume index (LAVI) and atrial strain were used in combination with the CHA2DS2-VAS score to predict ischemic stroke or incident AF. Proportional hazards Cox regression was used to provide hazard ratios (HR). There were 338 patients included. After a median follow-up of 3.6 years, the endpoint occurred in 41 (12.1%) patients. LAVI outperformed other echocardiographic parameters, with significant improvement in risk reclassification compared to CHA2DS2-VASc alone (net reclassification index 0.6, increase in Harrell's C from 0.63 to 0.73, P=0.003) and remained significant after multivariate adjustment. LAVI was associated with both components of the endpoint separately. The best cutoff for LAVI was 44 ml/m2. LAVI ≥44ml/m2 increased the risk of the endpoint among those with CHA2DS2-VASc ≥3 (HR=6.0, 95%CI 2.6-13.5), but not in those with CHA2DS2-VASc <3 (HR=1.2, 95%CI 0.3-4.5). Competing risk analysis did not alter the results. In conclusion, LAVI might be used to assess the risk of incident AF or stroke in NIDCM. Patients with LAVI ≥44 ml/m2 and CHA2DS2-VASc ≥3 could be at high risk of AF and stroke and may benefit from more intensive surveillance.

Risk Stratification in Nonischemic Dilated Cardiomyopathy Using CMR Imaging

Accurate risk stratification of nonischemic dilated cardiomyopathy (NIDCM) remains challenging. To evaluate the association of cardiac magnetic resonance (CMR) imaging-derived measurements with clinical outcomes in NIDCM. MEDLINE, Embase, Cochrane Library, and Web of Science Core Collection databases were systematically searched for articles from January 2005 to April 2023. Prospective and retrospective nonrandomized diagnostic studies reporting on the association between CMR imaging-derived measurements and adverse clinical outcomes in NIDCM were deemed eligible. Prespecified items related to patient population, CMR imaging measurements, and clinical outcomes were extracted at the study level by 2 independent reviewers. Random-effects models were fitted using restricted maximum likelihood estimation and the method of Hartung, Knapp, Sidik, and Jonkman. All-cause mortality, cardiovascular mortality, arrhythmic events, heart failure events, and major adverse cardiac events (MACE). A total of 103 studies including 29 687 patients with NIDCM were analyzed. Late gadolinium enhancement (LGE) presence and extent (per 1%) were associated with higher all-cause mortality (hazard ratio [HR], 1.81 [95% CI, 1.60-2.04]; P < .001 and HR, 1.07 [95% CI, 1.02-1.12]; P = .02, respectively), cardiovascular mortality (HR, 2.43 [95% CI, 2.13-2.78]; P < .001 and HR, 1.15 [95% CI, 1.07-1.24]; P = .01), arrhythmic events (HR, 2.69 [95% CI, 2.20-3.30]; P < .001 and HR, 1.07 [95% CI, 1.03-1.12]; P = .004) and heart failure events (HR, 1.98 [95% CI, 1.73-2.27]; P < .001 and HR, 1.06 [95% CI, 1.01-1.10]; P = .02). Left ventricular ejection fraction (LVEF) (per 1%) was not associated with all-cause mortality (HR, 0.99 [95% CI, 0.97-1.02]; P = .47), cardiovascular mortality (HR, 0.97 [95% CI, 0.94-1.00]; P = .05), or arrhythmic outcomes (HR, 0.99 [95% CI, 0.97-1.01]; P = .34). Lower risks for heart failure events (HR, 0.97 [95% CI, 0.95-0.98]; P = .002) and MACE (HR, 0.98 [95% CI, 0.96-0.99]; P < .001) were observed with higher LVEF. Higher native T1 relaxation times (per 10 ms) were associated with arrhythmic events (HR, 1.07 [95% CI, 1.01-1.14]; P = .04) and MACE (HR, 1.06 [95% CI, 1.01-1.11]; P = .03). Global longitudinal strain (GLS) (per 1%) was not associated with heart failure events (HR, 1.06 [95% CI, 0.95-1.18]; P = .15) or MACE (HR, 1.03 [95% CI, 0.94-1.14]; P = .43). Limited data precluded definitive analysis for native T1 relaxation times, GLS, and extracellular volume fraction (ECV) with respect to mortality outcomes. The presence and extent of LGE were associated with various adverse clinical outcomes, whereas LVEF was not significantly associated with mortality and arrhythmic end points in NIDCM. Risk stratification using native T1 relaxation times, extracellular volume fraction, and global longitudinal strain requires further evaluation.

Assessing the Role of Primary Heart Failure Etiology on Cardiac Transplant Outcomes.

There are diverse indications for heart transplantation (HTx), often categorized into ischemic (ICM) and nonischemic (NICM) cardiomyopathy. Although there is extensive research comparing the outcomes for these disease processes following certain therapeutic interventions, there are limited data on how recipient etiology impacts post-HTx survival. Our investigation seeks to identify this relationship. We conducted a retrospective analysis using adult HTx patients from the United Network for Organ Sharing database between 2000 and 2021. Patients with a combined heart-lung transplant or previous HTx were excluded. ICM included coronary artery disease (CAD) and ischemic dilated cardiomyopathy. NICM included nonischemic dilated (NIDCM), hypertrophic (HCM), and restrictive (RCM) cardiomyopathy. Overall survival was analyzed using Kaplan-Meier curves, log-rank tests, and multivariable Cox regression models. A total of 42268 patients were included in our study. Recipients with ICM were older and more likely to be males, obese, diabetics, and smokers. We found that patients with ICM had an increased incidence of transplant CAD (OR=1.23, p<0.001) and risk of mortality (hazard ratio [HR]=1.22, p<0.001) compared to NICM. When NICM was expanded, RCM had a similar hazard risk compared to ICM (HR=1.03, p=0.650), whereas both NIDCM (HR=0.81, p<0.001) and HCM (HR=0.70, p<0.001) had improved survival. Our study provides evidence to suggest that ICM has decreased survival when compared to NICM. When NICM was expanded, RCM was found to have an increased mortality risk similar to ICM, whereas NIDCM and HCM both had superior outcomes. The clinical implication of this investigation will allow clinicians to better understand the prognosis of certain patient groups.

Characteristics and Outcome of Patients with or without Previous Implantable Cardioverter Defibrillator Interventions Undergoing Ablation for Ventricular Tachycardia.

Background: Catheter ablation (CA) is a well-established treatment in patients with ventricular tachycardia and appropriate implantable cardioverter defibrillator (ICD) therapies. Methods: We enrolled 57 consecutive carriers of ICD undergoing CA for electrical storm (ES). Our aim was to investigate differences in clinical, device-related, and electroanatomic features among patients who had history of appropriate ICD interventions before the ES compared to those who had not. The primary endpoint was a composite of death from any cause and recurrences of sustained VT, ventricular fibrillation, appropriate ICD therapy, or ES. Results: During a median follow up of 39 months, 28 patients (49%) met the primary endpoint. Those with previous ICD interventions had a higher prevalence of late potentials and a greater unipolar low-voltage area at electroanatomic mapping. Patients who met the primary endpoint had a higher prevalence of ATP/shock episodes preceding the ES event. At Cox regression analysis, non-ischemic dilated cardiomyopathy (NIDCM), QRS duration, and previous ATP and/or shock before the ES were associated with arrhythmic recurrences and/or death. At multivariate analysis, NIDCM and previous shock were associated with arrhythmic recurrences and/or death. Conclusions: A history of recurrent ICD therapies predicts worse outcomes when CA is needed because of ES. Although more studies are needed to definitively address this question, our data speak in support of an early referral for CA of ES.

Left Atrium Reverse Remodeling in Fusion CRT Pacing: Implications in Cardiac Resynchronization Response and Atrial Fibrillation Incidence.

Background: When compared to biventricular pacing, fusion CRT pacing was linked to a decreased incidence of atrial fibrillation (AF). There is a gap in the knowledge regarding exclusive fusion CRT without interference with RV pacing, and all the current data are based on populations of patients with intermittent fusion pacing. Purpose: To assess left atrium remodeling and AF incidence in a real-life population of permanent fusion CRT-P. Methods: Retrospective data were analyzed from a cohort of patients with exclusive fusion CRT-P. Device interrogation, exercise testing, transthoracic echocardiography (TE), and customized medication optimization were all part of the six-monthly individual follow-up. Results: Study population: 73 patients (38 males) with non-ischemic dilated cardiomyopathy aged 63.7 ± 9.3 y.o. Baseline characteristic: QRS 159.8 ± 18.2 ms; EF 27.9 ± 5.1%; mitral regurgitation was severe in 38% of patients, moderate in 47% of patients, and mild in 15% of patients; 43% had type III diastolic dysfunction (DD), 49% had type II DD, 8% had type I DD. Average follow-up was 6.4 years ± 27 months: 93% of patients were responders (including 31% super-responders); EF increased to 40.4 ± 8.5%; mitral regurgitation decreased in 69% of patients; diastolic profile improved in 64% of patients. Paroxysmal and persistent AF incidence was 11%, with only 2% of patients developing permanent AF. Regarding LA volume, statistically significant LA reverse remodeling was observed. Conclusions: Exclusive fusion CRT-P was associated with important LA reverse remodeling and a low incidence of AF.