Structural Cardiac Interventions in Patients With Heart Failure: JACC Scientific Statement.

Pathologic left ventricular remodeling and valvular heart disease may contribute to the clinical presentation and outcomes of patients presenting with heart failure, and limit the effectiveness of guideline-directed medical therapy. Although surgical interventions including surgical ventricular restoration techniques and valve repair or replacement are effective therapies, there is growing evidence that transcatheter interventions may be options for patients with persistent symptoms of heart failure despite optimal medical therapy, where surgical options may be limited. This scientific statement will review the current available and investigational percutaneous strategies for the management of structural contributors to heart failure: dilated left ventricular cardiomyopathies and valvular heart disease.

[Analysis of pediatric heart transplantation supported by extracorporeal membrane oxygenation].

Objective: To summarize the clinical characteristics of patients with end-stage heart failure who receive heart transplant under extracorporeal membrane oxygenation (ECMO) support. Methods: The clinical data of 12 pediatric patients who received heart transplant with ECMO support in the Seventh Medical Center of Chinese People's Liberation Army General Hospital and Guangdong Provincial People's Hospital, from January 2019 to December 2023 was collected. The data included sex, age, weight, diagnosis, pre-ECMO lactate level, left ventricular ejection fraction (LVEF), vasoactive-inotropic score (VIS), and preoperative ECMO running time. Surgical data included cold ischemia time of the donor heart, cardiopulmonary bypass time, intraoperative use of immunosuppressant, postoperative use of ECMO, duration of postoperative ECMO, rate of successful weaning from ECMO, and survival discharge rate. The paired t-test was performed to compare cardiac function indices before and after left ventricular decompression. Results: The 12 patients ranged in age from 1.1 to 15.8 years, and weighted from 8 to 63 kg. Ten children were diagnosed with dilated cardiomyopathy, one with myocardial underdensification, and one with a novel heterozygous mutation of the SCN5A gene causing overlap syndrome complicated by fatal arrhythmia. Before ECMO, the lactate ranged from 0.6 to>15.0 mmol/L, the LVEF from 6.5% to 43%, and VIS from 3 to 108. Four patients underwent left ventricular decompression supported by preoperative ECMO, and their pulse pressure was significantly increased after decompression ((17.8±2.1) vs. (9.8±1.5) mmHg, 1 mmHg=0.133 kPa, t=11.31, P=0.001), while there was no apparent change in LVEF ((26.8±4.4)% vs. (24.9±4.9)%, t=1.75, P=0.178). A total of 7 children received a second run of ECMO after surgery and 3 of them successfully weaned off ECMO and survived to discharge. In the entire cohort, 10 were successfully weaned from ECMO and 8 survived to discharge. Conclusions: For children with end-stage heart failure supported by ECMO, left ventricular decompression can significantly improve pulse pressure. These patients will eventually require heart transplantation.

In vivo rescue of genetic dilated cardiomyopathy by systemic delivery of nexilin.

BACKGROUND: Dilated cardiomyopathy (DCM) is one of the most common causes of heart failure. Multiple identified mutations in nexilin (NEXN) have been suggested to be linked with severe DCM. However, the exact association between multiple mutations of Nexn and DCM remains unclear. Moreover, it is critical for the development of precise and effective therapeutics in treatments of DCM. RESULTS: In our study, Nexn global knockout mice and mice carrying human equivalent G645del mutation are studied using functional gene rescue assays. AAV-mediated gene delivery is conducted through systemic intravenous injections at the neonatal stage. Heart tissues are analyzed by immunoblots, and functions are assessed by echocardiography. Here, we identify functional components of Nexilin and demonstrate that exogenous introduction could rescue the cardiac function and extend the lifespan of Nexn knockout mouse models. Similar therapeutic effects are also obtained in G645del mice, providing a promising intervention for future clinical therapeutics. CONCLUSIONS: In summary, we demonstrated that a single injection of AAV-Nexn was capable to restore the functions of cardiomyocytes and extended the lifespan of Nexn knockout and G645del mice. Our study represented a long-term gene replacement therapy for DCM that potentially covers all forms of loss-of-function mutations in NEXN.

Prognostic relevance of global work index and global constructive work in patients with non-ischemic dilated cardiomyopathy.

Myocardial work (MW) derived from pressure-strain loops is a novel non-invasive tool to assess left ventricular (LV) function, incorporating global longitudinal strain (GLS) by speckle tracking echocardiography and non-invasively assessed blood pressure. Studies on the role of MW in dilated cardiomyopathy (DCM) are still limited. Therefore, the aim of this study was to evaluate the potential value of MW for predicting adverse outcomes in patients with DCM. 116 consecutive patients with DCM who underwent heart catheterization were retrospectively recruited from June 2009 to July 2014. 34 patients (30%) met the composite endpoints for major adverse cardiac events (MACE) of cardiac transplantation, need for implantable cardioverter-defibrillator (ICD) therapy, heart failure hospitalization and all-cause mortality. Patients with DCM were followed up for a mean of 5.1 years (IQR: 2.2-9.1 years). Global work index (GWI) and global constructive work (GCW) were not only independent predictors but also provided incremental predictive values (Integrated discrimination improvement [IDI] > 0) of MACE in multivariate Cox models. Furthermore, Patients with GWI < 788 mm Hg% (HR 5.46, 95%CI 1.66-17.92, p = 0.005) and GCW < 1,238 mm Hg% (HR 4.46, 95%CI 1.53-12.98, p = 0.006) had higher risks of MACE. GWI and GCW assessed by strain imaging echocardiography may have an additional value beyond LV-EF and GLS for predicting adverse outcomes in DCM.

Impact of DCM-Causing Genetic Background on Long-Term Response to Cardiac Resynchronization Therapy.

BACKGROUND: Patients with nonischemic dilated cardiomyopathy (DCM), severe left ventricular (LV) dysfunction, and complete left bundle branch block benefit from cardiac resynchronization therapy (CRT). However, a large heterogeneity of response to CRT is described. Several predictors of response to CRT have been identified, but the role of the underlying genetic background is still poorly explored. OBJECTIVES: In the present study, the authors sought to define differences in LV remodeling and outcome prediction after CRT when stratifying patients according to the presence or absence of DCM-causing genetic background. METHODS: From our center, 74 patients with DCM subjected to CRT and available genetic testing were retrospectively enrolled. Carriers of causative monogenic variants in validated DCM-causing genes, and/or with documented family history of DCM, were classified as affected by genetically determined disease (GEN+DCM) (n = 25). Alternatively, by idiopathic dilated cardiomyopathy (idDCM) (n = 49). The primary outcome was long-term LV remodeling and prevalence of super response to CRT (evaluated at 24-48 months after CRT); the secondary outcome was heart failure-related death/heart transplant/LV assist device. RESULTS: GEN+DCM and idDCM patients were homogeneous at baseline with the exception of QRS duration, longer in idDCM. The median follow-up was 55 months. Long-term LV reverse remodeling and the prevalence of super response were significantly higher in the idDCM group (27% in idDCM vs 5% in GEN+DCM; P = 0.025). The heart failure-related death/heart transplant/LV assist device outcome occurred more frequently in patients with GEN+DCM (53% vs 24% in idDCM; P = 0.028). CONCLUSIONS: Genotyping contributes to the risk stratification of patients with DCM undergoing CRT implantation in terms of LV remodeling and outcomes.

Arrhythmia-Induced Cardiomyopathy: JACC State-of-the-Art Review.

Arrhythmias frequently accompany heart failure and left ventricular dysfunction. Tachycardias, atrial fibrillation, and premature ventricular contractions can induce a reversible form of dilated cardiomyopathy (CM) known as arrhythmia-induced CM (AiCM). The intriguing question is why certain individuals are more susceptible to AiCM, despite similar arrhythmia burdens. The primary challenge is determining the extent of arrhythmias' contribution to left ventricular systolic dysfunction. AiCM should be considered in patients with a mean heart rate of >100 beats/min, atrial fibrillation, or a PVC burden of >10%. Confirmation of AiCM occurs when CM reverses upon eliminating the responsible arrhythmia. Therapy choice depends on the specific arrhythmia, patient comorbidities, and preferences. After left ventricular function is restored, ongoing follow-up is essential if an abnormal myocardial substrate persists. Accurate diagnosis and treatment of AiCM have the potential to enhance patients' quality of life, improve clinical outcomes, and reduce hospital admissions and overall health care costs.

Left ventricular assist device temporary explantation as a strategy for infection control in a pediatric patient.

We report a case of temporary Berlin Heart EXCOR® explantation in a pediatric patient with idiopathic dilated cardiomyopathy who suffered an uncontrollable inflow cannulation site infection while on bridge-to-transplantation. Despite failure to thrive and catheter-related infections, once free of the device, the patient was cured of infection using systemic antibiotics and surgical debridement. The patient underwent EXCOR® reimplantation after four months, and is awaiting heart transplantation in stable condition. A life-threatening ventricular assist device-related infection may require device explantation under conditions that may not fulfill conventional explantation criteria despite risks. Temporary explantation can be an effective strategy if isolated systolic dysfunction is managed carefully.

Use of cardiac contractility modulation combined with left bundle branch pacing CRT-P in a female with a 22-year history of non-ischemic dilated cardiomyopathy: A case report.

Cardiac contractility modulation (CCM) is a novel device-based therapy used to treat patients with heart failure with reduced ejection fraction (HFrEF). In both randomized clinical trials and real-life studies, CCM has been shown to improve exercise tolerance and quality of life, reverse left ventricular remodeling, and reduce hospitalization in patients with HFrEF. In this case report, we describe for the first time the use of CCM combined with left bundle branch pacing (LBBP) cardiac resynchronization therapy pacemaker (CRT-P) implantation therapy in a female with a 22-year history of non-ischemic dilated cardiomyopathy. With the optimal medical therapy and cardiac resynchronization therapy (CRT) strategies, the patient's quality of life initially recovered to some extent, but began to deteriorate in the past year. Additionally, heart transplantation was not considered due to economic reasons and late stage systolic heart failure. This is the first case of CCM implantation in Fujian Province and the first report of a combined CCM and left bundle branch pacing CRT-P implantation strategy in a patient with non-ischemic etiology dilated cardiomyopathy in China.

Proteomic Profiling of Dilated Cardiomyopathy Plasma Samples ─ Searching for Biomarkers with Potential to Predict the Outcome of Therapy.

Determination of the prognosis and treatment outcomes of dilated cardiomyopathy is a serious problem due to the lack of valid specific protein markers. Using in-depth proteome discovery analysis, we compared 49 plasma samples from patients suffering from dilated cardiomyopathy with plasma samples from their healthy counterparts. In total, we identified 97 proteins exhibiting statistically significant dysregulation in diseased plasma samples. The functional enrichment analysis of differentially expressed proteins uncovered dysregulation in biological processes like inflammatory response, wound healing, complement cascade, blood coagulation, and lipid metabolism in dilated cardiomyopathy patients. The same proteome approach was employed in order to find protein markers whose expression differs between the patients well-responding to therapy and nonresponders. In this case, 45 plasma proteins revealed statistically significant different expression between these two groups. Of them, fructose-1,6-bisphosphate aldolase seems to be a promising biomarker candidate because it accumulates in plasma samples obtained from patients with insufficient treatment response and with worse or fatal outcome. Data are available via ProteomeXchange with the identifier PXD046288.

Imagenetics for Precision Medicine in Dilated Cardiomyopathy.

Dilated cardiomyopathy (DCM) is a common heart muscle disorder of nonischemic etiology associated with heart failure development and the risk of malignant ventricular arrhythmias and sudden cardiac death. A tailored approach to risk stratification and prevention of sudden cardiac death is required in genetic DCM given its variable presentation and phenotypic severity. Currently, advances in cardiogenetics have shed light on disease mechanisms, the complex genetic architecture of DCM, polygenic contributors to disease susceptibility and the role of environmental triggers. Parallel advances in imaging have also enhanced disease recognition and the identification of the wide spectrum of phenotypes falling under the DCM umbrella. Genotype-phenotype associations have been also established for specific subtypes of DCM, such as DSP (desmoplakin) or FLNC (filamin-C) cardiomyopathy but overall, they remain elusive and not readily identifiable. Also, despite the accumulated knowledge on disease mechanisms, certain aspects remain still unclear, such as which patients with DCM are at risk for disease progression or remission after treatment. Imagenetics, that is, the combination of imaging and genetics, is expected to further advance research in the field and contribute to precision medicine in DCM management and treatment. In the present article, we review the existing literature in the field, summarize the established knowledge and emerging data on the value of genetics and imaging in establishing genotype-phenotype associations in DCM and in clinical decision making for DCM patients.

Clinical Trajectories and Long-Term Outcomes of Alcoholic Versus Other Forms of Dilated Cardiomyopathy.

BACKGROUND: Alcoholic cardiomyopathy (ACM) is a form of dilated cardiomyopathy (DCM) occurring secondary to long-standing heavy alcohol use and is associated with poor outcomes, but the cause-specific risks are insufficiently understood. METHOD: Between 1997 and 2018, we identified all patients with a first diagnosis of ACM or DCM. The cumulative incidence of different causes of hospitalisation and mortality in the two groups was calculated using the Fine-Gray and Kaplan-Meier methods. RESULTS: A Total of 1,237 patients with ACM (mean age 56.3±10.1 years, 89% men) and 17,211 individuals with DCM (mean age 63.6±13.8 years, 71% men) were identified. Diabetes (10% vs 15%), hypertension (22% vs 31%), and stroke (8% vs 10%) were less common in ACM than DCM, whereas obstructive lung disease (15% vs 12%) and liver disease (17% vs 2%) were more prevalent (p<0.05). Cumulative 5-year mortality was 49% in ACM vs 33% in DCM, p<0.0001, multivariable adjusted hazards ratio 2.11 (95% confidence interval 1.97-2.26). The distribution of causes of death was similar in ACM and DCM, with the predominance of cardiovascular causes in both groups (42% in ACM vs 44% in DCM). 5-year cumulative incidence of heart failure hospitalisations (48% vs 54%) and any somatic cause (59% vs 65%) were also similar in ACM vs DCM. At 1 year, the use of beta blockers (55% vs 80%) and implantable cardioverter defibrillators (3% vs 14%) were significantly less often used in ACM vs DCM. CONCLUSIONS: Patients with ACM had similar cardiovascular risks and hospitalisation patterns as other forms of DCM, but lower use of guideline-directed cardiovascular therapies and greater mortality.

[Development and clinical value of programmed ventricular stimulation in coronary artery disease and dilated cardiomyopathy]. / Entwicklung und Bedeutung der programmierten Ventrikelstimulation bei der koronaren Herzerkrankung und dilatativen Kardiomyopathie.

Programmed ventricular stimulation (PVS), a clinical tool introduced in the early 1980s, aims to prove the electrical vulnerability of the heart and, independent of spontaneous arrhythmia variability, to trigger arrhythmias under controlled conditions. A specific response is the inducibility of monomorphic sustained ventricular tachycardia. This depends on the underlying heart disease, e.g., only for coronary artery disease but not for nonischemic diseases. The value of pharmacologic arrhythmia control as serial electrical testing is uncertain. Up to now there seems to be no prognostic value of PVS concerning sudden cardiac death. PVS is used as a tool to monitor the results of ventricular tachycardia (VT)-catheter ablation in patients who were primarily inducible.

CRISPR Activation Reverses Haploinsufficiency and Functional Deficits Caused by TTN Truncation Variants.

BACKGROUND: TTN truncation variants (TTNtvs) are the most common genetic lesion identified in individuals with dilated cardiomyopathy, a disease with high morbidity and mortality rates. TTNtvs reduce normal TTN (titin) protein levels, produce truncated proteins, and impair sarcomere content and function. Therapeutics targeting TTNtvs have been elusive because of the immense size of TTN, the rarity of specific TTNtvs, and incomplete knowledge of TTNtv pathogenicity. METHODS: We adapted CRISPR activation using dCas9-VPR to functionally interrogate TTNtv pathogenicity and develop a therapeutic in human cardiomyocytes and 3-dimensional cardiac microtissues engineered from induced pluripotent stem cell models harboring a dilated cardiomyopathy-associated TTNtv. We performed guide RNA screening with custom TTN reporter assays, agarose gel electrophoresis to quantify TTN protein levels and isoforms, and RNA sequencing to identify molecular consequences of TTN activation. Cardiomyocyte epigenetic assays were also used to nominate DNA regulatory elements to enable cardiomyocyte-specific TTN activation. RESULTS: CRISPR activation of TTN using single guide RNAs targeting either the TTN promoter or regulatory elements in spatial proximity to the TTN promoter through 3-dimensional chromatin interactions rescued TTN protein deficits disturbed by TTNtvs. Increasing TTN protein levels normalized sarcomere content and contractile function despite increasing truncated TTN protein. In addition to TTN transcripts, CRISPR activation also increased levels of myofibril assembly-related and sarcomere-related transcripts. CONCLUSIONS: TTN CRISPR activation rescued TTNtv-related functional deficits despite increasing truncated TTN levels, which provides evidence to support haploinsufficiency as a relevant genetic mechanism underlying heterozygous TTNtvs. CRISPR activation could be developed as a therapeutic to treat a large proportion of TTNtvs.

Differences in underlying cardiac substrate among S-ICD recipients and its impact on long-term device-related outcomes: Real-world insights from the iSUSI registry.

BACKGROUND: Outcome comparisons among subcutaneous implantable cardioverter-defibrillator (S-ICD) recipients with nonischemic cardiomyopathies are scarce. OBJECTIVE: The aim of this study was to evaluate differences in device-related outcomes among S-ICD recipients with different structural substrates. METHODS: Patients enrolled in the i-SUSI (International SUbcutaneouS Implantable cardioverter defibrillator registry) project were grouped according to the underlying substrate (ischemic vs nonischemic) and subgrouped into dilated cardiomyopathy, hypertrophic cardiomyopathy, Brugada syndrome (BrS), arrhythmogenic right ventricular cardiomyopathy (ARVC). The main outcome of our study was to compare the rates of appropriate and inappropriate shocks and device-related complications. RESULTS: Among 1698 patients, the most common underlying substrate was ischemic (31.7%), followed by dilated cardiomyopathy (20.5%), BrS (10.8%), hypertrophic cardiomyopathy (8.5%), and ARVC (4.4%). S-ICD for primary prevention was more common in the nonischemic cohort (70.9% vs 65.4%; P = .037). Over a median (interquartile range) follow-up of 26.5 (12.6-42.8) months, no differences were observed in appropriate shocks between ischemic and nonischemic patients (4.8%/y vs 3.9%/y; log-rank, P = .282). ARVC (9.0%/y; hazard ratio [HR] 2.492; P = .001) and BrS (1.8%/y; HR 0.396; P = .008) constituted the groups with the highest and lowest rates of appropriate shocks, respectively. Device-related complications did not differ between groups (ischemic: 6.4%/y vs nonischemic: 6.1%/y; log-rank, P = .666), nor among underlying substrates (log-rank, P = .089). Nonischemic patients experienced higher rates of inappropriate shocks than did ischemic S-ICD recipients (4.4%/y vs 3.0%/y; log-rank, P = .043), with patients with ARVC (9.9%/y; P = .001) having the highest risk, even after controlling for confounders (adjusted HR 2.243; confidence interval 1.338-4.267; P = .002). CONCLUSION: Most S-ICD recipients were primary prevention nonischemic cardiomyopathy patients. Among those, patients with ARVC tend to receive the most frequent appropriate and inappropriate shocks and patients with BrS the least frequent appropriate shocks.

Genetics of Dilated Cardiomyopathy.

Dilated cardiomyopathy (DCM) is defined as dilation and/or reduced function of one or both ventricles and remains a common disease worldwide. An estimated 40% of cases of familial DCM have an identifiable genetic cause. Accordingly, there is a fast-growing interest in the field of molecular genetics as it pertains to DCM. Many gene mutations have been identified that contribute to phenotypically significant cardiomyopathy. DCM genes can affect a variety of cardiomyocyte functions, and particular genes whose function affects the cell-cell junction and cytoskeleton are associated with increased risk of arrhythmias and sudden cardiac death. Through advancements in next-generation sequencing and cardiac imaging, identification of genetic DCM has improved over the past couple decades, and precision medicine is now at the forefront of treatment for these patients and their families. In addition to standard treatment of heart failure and prevention of arrhythmias and sudden cardiac death, patients with genetic cardiomyopathy stand to benefit from gene mechanism-specific therapies.

Incremental prognostic value of left atrial and biventricular feature tracking in dilated cardiomyopathy: a long-term study.

BACKGROUND: Despite the use of cardiovascular magnetic resonance (CMR) feature tracking (FT) imaging to detect myocardial deformation, the optimal strain index in dilated cardiomyopathy (DCM) is unclear. This study aimed to determine whether atrial and biventricular strains can provide the greatest or joint incremental prognostic value in patients with DCM over a long follow-up period. METHODS: Four hundred-twelve DCM patients were included retrospectively. Comprehensive clinical evaluation and imaging investigations were obtained, including measurements of CMR-FT derived left atrial (LA) reservoir, conduit, booster strain (εs, εe, εa); left ventricular (LV) and right ventricular (RV) global longitudinal, radial, circumferential strain (GLS, GRS, GCS). All patients were followed up for major adverse cardiac events (MACE) including all-cause mortality, heart transplantation, and implantable cardioverter defibrillator discharge. The predictors of MACE were examined with univariable and multivariable Cox regression analysis. Subsequently, nested Cox regression models were built to evaluate the incremental prognostic value of strain parameters. The incremental predictive power of strain parameters was assessed by Omnibus tests, and the model performance and discrimination were evaluated by Harrell C-index and integrated discrimination improvement (IDI) analysis. Patient survival was illustrated by Kaplan-Meier curves and differences were evaluated by log-rank test. RESULTS: During a median follow-up of 5.0 years, MACE were identified in 149 (36%) patients. LAεe, LVGLS, and RVGLS were the most predictive strain parameters for MACE (AUC: 0.854, 0.733, 0.733, respectively). Cox regression models showed that the predictive value of LAεe was independent from and incremental to LVGLS, RVGLS, and baseline variables (HR 0.74, 95% CI 0.68-0.81, P < 0.001). In reclassification analysis, the addition of LAεe provided the best discrimination of the model (χ2 223.34, P < 0.001; C-index 0.833; IDI 0.090, P < 0.001) compared with LVGLS and RVGLS models. Moreover, LAεe with a cutoff of 5.3% further discriminated the survival probability in subgroups of patients with positive LGE or reduced LVEF (all log-rank P < 0.001). CONCLUSION: LAεe provided the best prognostic value over biventricular strains and added incremental value to conventional clinical predictors for patients with DCM.