Left Ventricular Cardiomyopathy Research Articles

Cardiac Manifestations in Inherited Metabolic Diseases.

Inherited metabolic diseases (IMDs) stem from genetic defects affecting enzyme function within specific metabolic pathways, collectively constituting rare conditions with an incidence of less than 1/100,000 births. While IMDs typically manifest with multisystemic symptoms, cardiac manifestations are common, notably hypertrophic cardiomyopathy. Additionally, they can lead to dilated or restrictive cardiomyopathy, as well as noncompacted left ventricular cardiomyopathy. Rhythm disturbances such as atrioventricular conduction abnormalities, Wolff-Parkinson-White syndrome, and ventricular arrhythmias, along with valvular pathologies and ischemic coronary issues, are also prevalent. This study aims to provide a narrative review of IMDs associated with cardiac involvement, delineating the specific cardiac manifestations of each disorder alongside systemic symptoms pivotal for diagnosis.

Translation of Electrocardiography and Genetics in Arrhythmogenic Left Ventricular Cardiomyopathy

Translational cardiology combines different techniques in order to get a correct diagnosis (precision medicine). In a rare disease called arrhythmogenic left ventricular cardiomyopathy caused by non-desmosonal gene mutations 12-lead ECG and results of genetics were combined and analyzed. In a few gene mutations ECG findings were highly specific and predicts gene mutation, like desmoplakin, phospholamban, desmoglein-2, desmocollin-2, TMEM43, lamin A/C, and probably filamin C mutation. With the help of simple 12-lead ECG technique a precise prediction of specific gene mutation can be made.

Impact of functional gene groups on outcomes after ablation of ventricular tachycardia in patients with inherited left ventricular cardiomyopathy: an international multicentre study

Abstract Background Advances in genetic testing has enabled identification of pathogenic variants of different functional gene groups associated with non-dilated left ventricular cardiomyopathy (NDLCM)/dilated cardiomyopathy (DCM) and ventricular tachycardia (VT). However, there is limited data on the impact of functional groups on VT ablation outcome. Aim We aimed to assess the impact of likely pathogenic/pathogenic variants (LP/Pv) of different functional gene groups on heart failure (HF) outcomes and VT recurrence in patients with NDLCM/DCM after VT ablation. Methods Patients with NDLCM/DCM who underwent genetic testing (next-generation sequencing) and were referred for VT ablation were enrolled at 6 participating centers. Patients were followed for VT recurrence, HF-related adverse outcomes (death, left ventricular assist device [LVAD], or heart transplantation due to HF), and all-cause mortality. Results A total of 239 patients (age 55±14yrs; male n=193; LVEF 40±12%; amiodarone at admission n=103; ICD n=180) were included. LP/Pv were identified in 128 patients (54%), predominantly found in genes encoding sarcomeric (n=36/128, [28%]; titin n=20, myosin binding protein C n=12), followed by nuclear membrane (n=27/128, [22%]; lamin A/C; n=26), desmosomal (n=23/128, [18%]; desmoplakin n=11, plakophilin n=9), cytoskeleton (n=12/128, [9%]; filamin C n=8), and sarcoplasmic reticulum proteins (n=12/128, [9%]; phospholamban n=10). Variants of unknown significance (n=32) were grouped with patients who tested negative. Acute complete ablation success, defined as non-VT inducibility of any sustained monomorphic VT, was achieved in 113 patients (47%), 63 (56%) with LP/Pv. During a median follow-up of 32 months, 108 patients (45%) had VT recurrence, 41 (17%) had HF-related adverse outcomes (death with/without LVAD in 34, LVAD in 2, heart transplantation in 5) and 47 (20%) died. Patients with LP/Pv were more likely to have VT recurrence, HF-related adverse outcomes and had a higher mortality compared to those without (VT, 68 [53%] vs. 40 [36%]; HF-related adverse outcomes, 30 [23%] vs. 11 [10%]; mortality, 30 [23%] vs. 17 [15%]; log-rank, P<0.01 for all). As compared to patients without LP/Pv, those with LP/Pv in genes encoding nuclear membrane or sarcomeric proteins had significantly worse (P<0.01 for both) and those with LP/Pv in genes encoding desmosomal proteins had similar HF and VT recurrence outcomes (Figure). Of interest, patients with LP/Pv in genes encoding cytoskeleton proteins had favorable HF-related adverse outcomes, but worse VT recurrence (P=0.02) compared to those without LP/Pv (Figure). Conclusion In patients with NDLCM/DCM and VT, the impact of LP/Pv on HF and VT-recurrence outcomes after ablation differs across functional groups. Integrating genetic testing in the comprehensive evaluation of patients with NDLCM/DCM undergoing VT ablation may facilitate personalized ablation strategies and early consideration of alternative HF treatments.

Epicardial catheter ablation of ventricular tachycardia in patients of acm - from a university hospital report in switzerland

Abstract Background Arrhythmogenic left ventricular cardiomyopathy (ALVC) as a subtype of arrhythmogenic cardiomyopathy (ACM) is increasingly being recognized. Cardiac magnetic resonance (CMR) has emerged as the primary imaging modality for the diagnosis of ACM. In patients with right-dominant ACM (ARVC) and recurrent sustained ventricular tachycardia (VT), endocardial +/-epicardial ablation yields good clinical outcomes in the long-term. However, studies on VT ablation in ACM with LV involvement are scarce. Purpose We sought to investigate clinical outcomes of VT ablation in ACM patients with LV involvement. Methods The study included patients from the Zurich ACM Registry who met 2020 "Padua Criteria" for ACM and underwent VT ablation between January 2018 and July 2023. Epicardial ablation was performed in patients with recurrent sustained VT despite endocardial ablation, those lacking and endocardial substrate or if the ECG of the VT / substrate on CMR was suggestive of an epicardial origin. Catheter ablation was guided by activation/entrainment mapping for mappable VT, and pace mapping/voltage mapping during sinus rhythm for unmappable VT. Consecutive follow-up of all patients was performed according to our protocol. Results Twenty-one ACM patients underwent n=24 VT ablation procedures. Of those 20 patients, 6 patients (30%) had LV involvement on CMR. Eight (33%) patients underwent epicardial +/- endocardial ablation. Among patients receiving epicardial ablation, 3 patients (38%) had LV involvement. These three underwent a single ablation procedure, which was epicardial only. Total follow-up was 30 months (range 4-43). Three-month sustained VT/VF recurrence rates were 12% in the ACM group with LV involvement vs 25% in ACM without LV involvement. All patients with sustained VT/VF recurrence underwent repeat ablation via an epicardial approach within 3 months and were free of sustained VT/VF thereafter during a median follow-up of 12 months. One-year recurrence rate did not differ between ACM patients with LV involvement vs. without LV involvement (7.7% vs 8.3%, P＝0.117). Seven out of eight epicardial ablations achieved freedom from VT/VF after one-year follow-up. One ARVC patient with previous endocardial ablation had recurrent VT one month after epicardial ablation, which was free of VT after Flecainide combined with beta-blocker. No significant differences were found in the use of beta-blockers and antiarrhythmic drugs between both groups (ACM with LV involvement vs. without LV involvement) at baseline and during one-year follow-up. Conclusions Single or adjuvant epicardial substrate ablation of VT in arrhythmogenic cardiomyopathy is promising in terms of postprocedural VT free survival, especially in patients with left ventricular involvement demonstrated by CMR.Figure 1Figure 2

EXPLORING THE 12 LEAD ECG CHARACTERISTIC OF PAEDIATRIC AND YOUNG ADULT CARRIERS OF DESMOPLAKIN GENE VARIANTS

Abstract Background and Aim The DSP gene (locus. 6p24.3) encodes desmoplakin, a quintessential desmosomal protein for cellular adhesion, particularly within cardiac tissues. DSP gene variants can cause dilated cardiomyopathy, non–dilated left ventricular cardiomyopathy (NDLVC) and arrhythmogenic righ ventricular cardiomyopathy (ARVC), cardiac conditions known to trigger malignant ventricular arrhythmias and cause sudden cardiac death in young individuals. Nevertheless, the electrocardiographic (ECG) patterns in children carrying DSP variants are underexplored. Methods A retrospective analysis was conducted involving paediatric DSP gene variant carriers (</=18 years), followed at Great Ormond Street Hospital from 2006 to 2023. Their 12–lead ECGs were characterised and compared with those of an age and gender–matched healthy control group (χ2, p–value<0.05). Results 25 DSP carriers (64% females; 12.6±4 years) were identified [including 4 (16%) with an overt cardiomyopathy phenotype] and compared to 25 healthy matched controls (12.7±4.3years). Compared to the control group, DSP carriers exhibited a higher prevalence of low QRS voltages (72% vs 44%, p= 0.041), QRS notching (72% vs 26%, p= 0,014) and flattened T waves (72% vs 52%, p= 0,026). All 4 patients with an overt cardiomyopathy phenotype had widespread low QRS voltages and QRS fractionation, as well as flattened/inverted T waves, particularly in the inferior and lateral leads. Conclusion Predominant ECG features observed in paediatric patients with DSP gene variants included low QRS voltages, QRS notching, and flat or inverted T waves. Our findings suggest that ECG features may precede the development of an overt cardiomyopathy phenotype in children with DSP variants, but further studies with larger cohorts are needed to confirm this and to determine their prognostic significance.

DIAGNOSTIC CRITERIA FOR NON–DILATED LEFT VENTRICULAR CARDIOMYOPATHY WITH PROGNOSTIC SIGNIFICANCE

Abstract Background Non–dilated left ventricular cardiomyopathy (NDLVC) is a novel diagnostic entity defined as non–ischemic LV scarring or fatty replacement regardless of the presence of global or regional wall motion abnormalities, or isolated global LV hypokinesia without scarring. While the absence of LV dilation and systolic dysfunction are implicit, no cut–offs were proposed. Methods All patients undergoing cardiac magnetic resonance (CMR) examination at a tertiary referral center from 2012 to 2022 and meeting the definition of NDLVC were evaluated. The primary endpoint was a composite of cardiac death, sustained ventricular tachycardia (VT) or ventricular fibrillation, appropriate defibrillator intervention; the secondary endpoint included also non–sustained VT. Results The cohort included 262 patients, with 176 men (67%) and a median age of 55 years (interquartile range 44–64 years). Patients without moderate (n=243, 93%) or severe LV dilation (n=249, 95%) had a longer survival free from both endpoints. The 50% LVEF threshold identified patients with different outcomes, whereas the 55% and 60% cut–offs did not. LVEF ≥50% and no severe LV dilation predicted a better outcome independent of percent LGE in the LV, the number of LV segments with LGE, LV fibro–fatty replacement, or right ventricular involvement. LVEF ≥50% and no severe LV dilation retained an independent prognostic value even in patients with LV LGE (80% of the whole cohort). Conclusions Excluding severe LV dilation (LVEDVi >129 mL/m2 in men and >116 mL/m2 in women) and LV dysfunction (LVEF <50%) could enhance the prognostic utility of the NDLVC definition.

Description of the Two-Dimensional Layer-Specific Strain Echocardiography Phenotype of Arrhythmogenic Left Ventricular Cardiomyopathy

Arrhythmogenic left ventricular cardiomyopathy (ALVC) is characterized by fibrofatty myocardial replacement demonstrated on cardiac magnetic resonance by late gadolinium enhancement (LGE) mainly involving the subepicardium. The aims of this study were to describe the layer-specific strain (LSS) echocardiography phenotype of ALVC and to compare it with LGE features. All consecutive ALVC pathogenic genetic variant carriers and noncarrier relatives were separated into four prespecified groups (overt ALVC [group 1], isolated LGE [group 2], pathogenic genetic variant carrier without ALVC phenotype [group 3], and no genetic variant carrier [group 4]) and studied accordingly using cardiac magnetic resonance and LSS echocardiography. Eighty-five individuals were included. Endocardial global longitudinal strain (GLS)-epicardial GLS (GLSepi) gradient was altered predominantly in group 1, illustrating transmural strain alteration in overt ALVC (3.8±1.1 in group 1, 4.3±2.2 in group 2, 5.2±1.2 in group 3, and 5.4±1.6 in group 4; P=.0017), whereas GLSepi was impaired predominantly in group 2 (endocardial GLS and GLSepi were 15.0±4.1% and 11.2±3.3%, respectively, in group 1; 20.5±2.8% and 16.2±5.5% in group 2; 23.4±3.3% and 18.2±2.7% in group 3; and 24.6±2.8% and 19.2±1.9% in group 4; P<.0001 for all). GLSepi was able to detect subepicardial LGE in genetic variant carriers without overt ALVC with an area under curve of 0.84 (95% CI, 0.73-0.95). However, segmental epicardial and endocardial strain behaved similarly and showed comparable diagnostic values for segmental LGE detection (areas under the curve, 0.72; [95% CI, 0.69-0.76] and 0.73 [95% CI, 0.70-0.76], respectively, P=.40). LSS alteration in ALVC progresses from the epicardium to the endocardium along with disease severity. Irrespective of LSS analysis, which did not provide incremental diagnostic value for the detection and localization of LGE, strain echocardiography was shown to be a potential surrogate marker of LGE, including in apparently healthy individuals with isolated LV fibrosis.

Європейські рекомендації 2023 року щодо лікування кардіоміопатій та впровадження їх у практику в Україні

In this article we analyzed the main positions of the recommendations of the European Society of Cardiology regarding the treatment of cardiomyopathies and presented the actual issues of implementing recommendations into clinical practice in Ukraine. The diagnostic flowchat of a patient with suspected cardiomyopathy is presented. Five phenotypes of cardiomyopathies are presented with current definition. New fenotype of non-dilated left ventricular cardiomyopathy is presented. The role of various imaging methods in diagnosis of cardiomyopathy phenotype is considered. The role of methods of genetic testing and magnetic resonance imaging of the heart with contrast is determined. The attention is focused on the need to differentiate the etiology of phenotypes and phenocopies of cardiomyopathies for pathogenetic treatment. Methods of assessing the risk of sudden cardiac death in cardiomyopathies and methods of secondary and primary prevention are discussed. Calculators for the risk of sudden death in cardiomyopathies and indications for implantation of a cardioverter-defibrillator are given. The management of patients with atrial fibrillation in various cardiomyopathies is determined. The issue of treatment of heart failure in patients with different phenotypes and ethiology of cardiomyopathies is discussed. Attention is focused on the role of «cardiomyopathy teams» in cardiological centers. An experience of echocardiographic diagnostics of cardiomyopathies, genetic testing, usage of magnetic resonance imaging in cardiomyopathies is presented.

The new 2023 ESC guidelines for the management of cardiomyopathies: a guiding path for cardiologist decisions.

In the ESC 2023 guidelines, cardiomyopathies are conservatively defined as 'myocardial disorders in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease, and congenital heart disease sufficient to cause the observed myocardial abnormality'. They are morpho-functionally classified as hypertrophic, dilated, restrictive, and arrhythmogenic right ventricular cardiomyopathy with the addition of the left ventricular non-dilated cardiomyopathy that describes intermediate phenotypes not fulfilling standard disease definitions despite the presence of myocardial disease on cardiac imaging or tissue analysis. The new ESC guidelines provide 'a guide to the diagnostic approach to cardiomyopathies, highlight general evaluation and management issues, and signpost the reader to the relevant evidence base for the recommendations'. The recommendations and suggestions included in the document provide the tools to build up pathways tailored to specific cardiomyopathy (phenotype and cause) and define therapeutic indications, including target therapies where possible. The impact is on clinical cardiology, where disease-specific care paths can be assisted by the guidelines, and on genetics, both clinics and testing, where deep phenotyping and participated multi-disciplinary evaluation provide a unique tool for validating the pathogenicity of variants. The role of endomyocardial biopsy remains underexploited and confined to particular forms of restrictive cardiomyopathy, myocarditis, and amyloidosis. New research and development will be needed to cover the gaps between science and clinics. Finally, the opening up to disciplines such as bioinformatics, bioengineering, mathematics, and physics will support clinical cardiologists in the best governance of the novel artificial intelligence-assisted resources.

Molecular genetic screening after non-ischaemic sudden cardiac arrest and no overt cardiomyopathy in real life: A major tool for the aetiological diagnostic work-up

BackgroundWith the development of advanced sequencing techniques, genetic testing has emerged as a valuable tool for the work-up of non-ischaemic sudden cardiac arrest (SCA). AimsTo evaluate the effectiveness of genetic testing in patients with unexplained SCA, according to clinical phenotype. MethodsAll patients who underwent molecular genetic testing for non-ischaemic SCA with no left ventricular cardiomyopathy between 2012 and 2021 in two French university hospitals were included. ResultsOf 66 patients (mean age 36.7±11.9years, 54.5% men), 21 (31.8%; 95% confidence interval 22.4–45.3%) carried a genetic variant: eight (12.1%) had a pathogenic or likely pathogenic (P/LP) variant and 13 (19.7%) had a variant of uncertain significance (VUS). Among 37 patients (56.1%) with no phenotypic clues, genetic testing identified a P/LP variant in five (13.5%), mainly in RYR2 (n=3) and SCN5A (n=2), and a VUS in nine (24.3%). None of the nine patients with phenotypic evidence of channelopathies had P/LP variants, but two had VUS in RYR2 and NKX2.5. Among the 20 patients with suspected arrhythmogenic cardiomyopathy, three P/LP variants (15.0%) and two VUS (10.0%) were found in DSC2, PKP2, SCN5A and DSG2, TRPM4, respectively. Genetic testing was performed sooner after cardiac arrest (P<0.001) and results were obtained more rapidly (P=0.02) after versus before 2016. ConclusionThis study highlights the utility of molecular genetic testing with a genetic variant of interest identified in one-third of patients with unexplained SCA. Genetic testing was beneficial even in patients without phenotypic clues, with one-fourth of patients carrying a P/LP variant that could have direct implications.

Arrhythmogenic Left Ventricular Cardiomyopathy: From Diagnosis to Risk Management.

Left ventricular arrhythmogenic cardiomyopathy (ALVC) is a rare and poorly characterized cardiomyopathy that has recently been reclassified in the group of non-dilated left ventricular cardiomyopathies. This review aims to summarize the background, diagnosis, and sudden cardiac death risk in patients presenting this cardiomyopathy. Although there is currently a lack of data on this condition, arrhythmogenic left ventricular dysplasia can be considered a specific disease of the left ventricle (LV). We have collected the latest evidence about the management and the risks associated with this cardiomyopathy. Left ventricular arrhythmogenic cardiomyopathy is still poorly characterized. ALVC is characterized by fibrofatty replacement in the left ventricular myocardium, with variable phenotypic expression. Diagnosis is based on a multiparametric approach, including cardiac magnetic resonance (CMR) and genetic testing, and is important for sudden cardiac death (SCD) risk stratification and management. Recent guidelines have improved the management of left ventricular arrhythmogenic cardiomyopathy. Further studies are necessary to improve knowledge of this cardiomyopathy.

Ser194Leu DSG2 mutation, associated with arrhythmogenic left ventricular cardiomyopathy and ventricular tachycardia.

Arrhythmogenic cardiomyopathy (AC) is an inherited cardiomyopathy characterized by fibro-fatty replacement of cardiomyocytes, leading to life-threatening ventricular arrhythmia and heart failure. Pathogenic variants of desmoglein2 gene (DSG2) have been reported as genetic etiologies of AC. In contrast, many reported DSG2 variants are benign or variants of uncertain significance. Correct genetic variant classification is crucial for determining the best medical therapy for the patient and family members. Pathogenicity of the DSG2 Ser194Leu variant that was identified by whole exome sequencing in a patient, who presented with ventricular tachycardia and was diagnosed with AC, was investigated by electron microscopy and immunohistochemical staining of endomyocardial biopsy sample. Electron microscopy demonstrated a widened gap in the adhering junction and a less well-organized intercalated disk region in the mutated cardiomyocytes compared to the control. Immunohistochemical staining in the proband diagnosed with AC showed reduced expression of desmoglein 2 and connexin 43 and intercalated disc distortion. Reduced expression of DSG2 and Connexin 43 were observed in cellular cytoplasm and gap junctions. Additionally, we detected perinuclear accumulation of DSG2 and Connexin 43 in the proband sample. Ser194Leu is a missense pathogenic mutation of DSG2 gene associated with arrhythmogenic left ventricular cardiomyopathy.

Non-dilated left ventricular cardiomyopathy vs. dilated cardiomyopathy: clinical background and outcomes.

Non-dilated left ventricular cardiomyopathy (NDLVC) was proposed as a new category of cardiomyopathy that included patients with non-left ventricular (LV) dilatation, LV wall motion abnormality, or LV scar. However, the clinical background and event rates of NDLVC were unclear. The aim of this study was to examine the characteristics and event rates of patients with NDLVC and reduced LV ejection fraction (NDLVC-REF) in comparison with those with dilated cardiomyopathy (DCM). We retrospectively included 363 patients with newly diagnosed non-ischaemic cardiomyopathy and reduced LV ejection fraction (<50%) between December 2004 and January 2018. Patients who did not have LV dilatation (LV dimension index of ≦31mm/m2 in men and ≦34mm/m2 in women) were categorized as NDLVC-REF (n=80, 22.2%), and the remaining patients were categorized as DCM. Cardiac events were defined as sudden cardiac death and rehospitalization for heart failure. Patients with NDLVC-REF had a higher prevalence of atrial fibrillation and a higher LV ejection fraction than those with DCM at baseline. LV ejection fraction was higher and LV end-diastolic diameter was smaller in patients with NDLVC-REF than in those with DCM at all time points after diagnosis. During the median follow-up period of 68.8months (interquartile range: 33.0-93.7months), 44 patients experienced cardiac events. The Kaplan-Meier curves showed no significant differences in the probability of cardiac events among NDLVC-REF and DCM patients (P=0.349). However, patients with NDLVC-REF and LV dilatation after diagnosis (14%) had a higher risk of cardiac events than those with NDLVC-REF without LV dilatation (P=0.049). There was no significant difference in the incidence of cardiac events between NDLVC-REF and DCM. Among NDLVC-REF patients, 18% of patients who showed LV dilatation after diagnosis had poor outcomes. Therefore, both NDLVC-REF and DCM patients may require equivalent attention to follow-up and regular assessment of LV function.

“Inherited cardiovascular disease mindset” can identify concealed inherited conditions at cardio-oncology evaluation: An opportunistic screening.

IntroductionBaseline cardiovascular (CV) risk stratification is recommended in all cancer patients. Integrating all clinical information (personal/family history, ECG and echocardiogram) can properly identify high-risk patients. We aimed to evaluate the concealed inherited CV conditions detected in mandatory CV screening performed at a Cardio-Oncology Unit. Methodsretrospective study of all consecutive cancer patients referred to the Cardio-Oncology Unit for CV evaluation (2020−2023). Inherited CV conditions diagnosis and genetic testing was performed according to guidelines. Results1984 cancer patients underwent CV screening. Sanger sequencing was indicated in 1 patient, excluding the genetic family disease. NGS sequencing was performed in 11 cancer patients with normal left ventricular ejection fraction (LVEF): 2 due to aortic syndrome evaluation (identifying 1 vascular Ehrler-Danlos syndrome due to COL3A1 p.Arg242Ter), 4 channelopathies (2 Long QT syndrome and 2 Brugada's), 4 hypertrophic cardiomyopathies and 1 non-dilated left ventricular cardiomyopathy (NDLVC). Among the 12 patients with reduced LVEF, one was diagnosed with NDLVC, and chemotherapy-induced dilated cardiomyopathy was only ascribable in 3 of them. ConclusionIntegrating clinical information at mandatory baseline CV toxicity risk cardio-oncology evaluation, can identify high-risk cancer patients with concealed inherited conditions. Keeping an “inherited cardiovascular disease-oriented mindset” to implement opportunist screenings is encouraged.

Pyridoxamine Limits Cardiac Dysfunction in a Rat Model of Doxorubicin-Induced Cardiotoxicity.

The use of doxorubicin (DOX) chemotherapy is restricted due to dose-dependent cardiotoxicity. Pyridoxamine (PM) is a vitamin B6 derivative with favorable effects on diverse cardiovascular diseases, suggesting a cardioprotective effect on DOX-induced cardiotoxicity. The cardioprotective nature of PM was investigated in a rat model of DOX-induced cardiotoxicity. Six-week-old female Sprague Dawley rats were treated intravenously with 2 mg/kg DOX or saline (CTRL) weekly for eight weeks. Two other groups received PM via the drinking water next to DOX (DOX+PM) or saline (CTRL+PM). Echocardiography, strain analysis, and hemodynamic measurements were performed to evaluate cardiac function. Fibrotic remodeling, myocardial inflammation, oxidative stress, apoptosis, and ferroptosis were evaluated by various in vitro techniques. PM significantly attenuated DOX-induced left ventricular (LV) dilated cardiomyopathy and limited TGF-β1-related LV fibrotic remodeling and macrophage-driven myocardial inflammation. PM protected against DOX-induced ferroptosis, as evidenced by restored DOX-induced disturbance of redox balance, improved cytosolic and mitochondrial iron regulation, and reduced mitochondrial damage at the gene level. In conclusion, PM attenuated the development of cardiac damage after DOX treatment by reducing myocardial fibrosis, inflammation, and mitochondrial damage and by restoring redox and iron regulation at the gene level, suggesting that PM may be a novel cardioprotective strategy for DOX-induced cardiomyopathy.

Concealed Inherited Cardiomyopathies Detected in Cardio-Oncology Screening.

Basal cardiovascular risk assessment in cardio-oncology is essential. Integrating clinical information, ECG and transthoracic echocardiogram can identify concealed inherited cardiomyopathies (ICMPs) with potential added risk of cardiotoxicity. We aimed to evaluate the impact of our Cardio-Oncology Unit design in detecting concealed ICMPs. We carried out a retrospective study of all consecutive breast cancer patients referred to the Cardio-Oncology Unit for cardiac evaluation (2020-2022). ICMPs diagnosis was provided according to ESC guidelines and underwent genetic testing. ICMPs prevalence in this cohort was compared to the highest and lowest frequency reported in the general population. Among 591 breast cancer patients, we identified eight patients with ICMPs: one arrhythmogenic cardiomyopathy (ACM), three familial non-ischemic dilated cardiomyopathy (DCM), three hypertrophic cardiomyopathy (HCM) and one left ventricular non-compaction cardiomyopathy (LVNC), which has now been reclassified as non-dilated left ventricular cardiomyopathy. The number of ICMPs identified was within the expected range (neither overdiagnosed nor overlooked): ACM 0.0017 vs. 0.0002-0.001 (p 0.01-0.593); DCM 0.0051 vs. 0.002-0.0051 (p 0.094-0.676); HCM 0.005 vs. 0.0002-0.002 (p < 0.001-0.099); LVCN 0.0017 vs. 0.00014-0.013 (p 0.011-0.015). Genetic testing identified a pathogenic FLNC variant and two pathogenic TTN variants. Opportunistic screening of ICMPs during basal cardiovascular risk assessment can identify high-risk cancer patients who benefit from personalized medicine and enables extension of prevention strategies to all available relatives at concealed high cardiovascular risk.

What can a cryptogenic stroke hide in a young patient?

Abstract Introduction Left ventricular hypertrabeculation is a recently described ventricular phenotype characterized by the alternation of excessive trabeculations with deep intertrabecular recesses that communicate with the left ventricular cavity but not with the coronary circulation. Case presentation We report the case of a young patient, recently diagnosed with ischemic stroke, in whom the cardiological assessment revealed the coexistence of left ventricular hypertrabeculation and dilated cardiomyopathy, which pathologies associated with a high risk of embolic events. The treatment administered followed the therapy for chronic heart failure, control of rhythm disorders that might occur, and the prevention of embolic accidents. Conclusions The particularity of the case is represented by atypical onset through a complication of the disease in a cardiovascular paucisymptomatic patient. Multimodal imaging corroborated with clinical and anamnestic elements had an essential role in the diagnosis.

Longitudinal echocardiographic parameters before and after pacemaker placement in congenital complete heart block

BackgroundCongenital complete heart block (CCHB) is seen in 1:15,000–1:20,000 live births, with risk of left ventricular (LV) dysfunction or dilated cardiomyopathy in 7%–23% of subjects. ObjectiveThe purpose of this study was to investigate serial changes in LV size and systolic function in paced CCHB subjects to examine the effect of time from pacemaker on echocardiographic parameters. MethodsSingle-center retrospective cohort analysis of paced CCHB subjects was performed. Echocardiographic data were collected before and after pacemaker placement. Linear mixed effect regression of left ventricular end-diastolic dimension (LVEDD) z-score, left ventricular shortening fraction (LVSF), and left ventricular ejection fraction (LVEF) was performed, with slopes compared before and after pacemaker placement. ResultsOf 114 CCHB subjects, 52 had echocardiographic data before and after pacemaker placement. Median age at CCHB diagnosis was 0.6 [interquartile range 0.0–3.5] years; age at pacemaker placement 3.4 [0.5–9.0] years; and pacing duration 10.8 [5.2–13.7] years. Estimated LVEDD z-score was 1.4 at pacemaker placement and decreased –0.08 per year (95% confidence interval [CI] –0.12 to –0.04; P = .002) to 0.2 (95% CI –0.3 to +0.3) 15 years postplacement. Estimated LVSF decreased –1.1% per year (95% CI –1.7% to –0.6%; P <.001) from 6 months prepacemaker placement to 34% (95% CI 32%–37%) 4 years postplacement. There was no significant change in LVSF between 4 and 15 years postplacement. Estimated LVEF did not change significantly after pacemaker placement, with estimated LVEF 59% (95% CI 55%–62%) 15 years postplacement. ConclusionIn 52 paced CCHB subjects, estimated LVEDD z-score decreased significantly after pacemaker placement, and estimated LVSF and LVEF remained within normal limits at 15 years postpacemaker placement.

Influence of left ventricular ejection fraction, type of mutation and sex on malignant ventricular arrhythmias in dsp and flnc mutations

Abstract Introduction Pathogenic mutations in FLNC and DSP are a common cause of arrhythmogenic left ventricular cardiomyopathy and "arrhythmic dilated cardiomyopathy". We aimed to study demographic and clinical differences amongst these carriers. Purpose 1. To study the prevalence of malignant ventricular arrhythmias in DSP and FLNC mutation carriers in the studies and reports published in the literature. 2. To analyse the effect of age, left ventricular ejection fraction (LVEF), and sex on ventricular arrhythmias in both groups. Methods A systematic review of the human studies published in Medline and EMBASE until September 2022 was carried out. "Desmoplakin Mutations", "Filamin Mutations", "Arrhythmogenic Cardiomyopathy" and "Dilated Cardiomyopathy" were the keywords included in the search queries. Studies, family reports, and registries reporting on individual data of pathogenic or likely pathogenic mutation carriers were selected for analysis. Results Twenty-four articles published between 2002 and 2020 were selected from a total of 430 entries. 171 DSP carriers (from 16 studies) and 169 FLNC carriers (from 7 studies) were included in the analysis. Mean age was similar in both groups: 39.45±19.23 years in DSP vs 42.02±16.27 in the FLNC group (p:0.201). The proportion of females was higher among DSP carriers than that found among FLNC carriers: 101 (59%) vs 76 (45%), p: 0.012. Non-missense mutations were more frequent in both groups: 98 DSP carriers (57%) and 157 FLNC carriers (97%). LVEF was slightly more depressed amongst FLNC carriers: 47.75±14.94% vs 52.37±14.64%, p:0.014. A total of 81 major arrhythmic events (sudden death, ventricular fibrillation, sustained ventricular tachycardia were reported. The LVEF of the male patients that had suffered a major event was similar in both groups (39.13±18.20% in DSP vs 39.03±12.24% in FLNC, p:0.987). On the contrary, LVEF was significantly lower in female carriers of DSP mutations (32.33±15.65% in DSP vs 47.60±15.88% in FLNC, p:0.050). Male carriers show a worse prognosis than their female counterparts (log-rank 0.005) (Figure). The difference was not significant after adjusting for LVEF and type of mutation (missense vs non-missense). LVEF (HR 0.94 per percentage unit (0.91-0.96), p &amp;lt;0.001) and non-missense mutations (HR 0.21 (0.07-0.66), p:0.008) were inversely associated with adverse outcomes in DSP carriers in a multivariate analysis. LVEF was also associated with a better outcome in FLNC carriers (HR 0.97 (0.95-0.99), p: 0.019. Conclusion Moderate systolic dysfunction is a risk factor for malignant arrhythmias amongst DSP and FLNC mutation carriers. Female FLNC carriers with mild systolic dysfunction are at risk for sustained ventricular arrhythmias. Missense DSP mutations are associated with poor arrhythmic prognosis.Sex differences in survival

Abstract 15689: Ablation for Atrial Fibrillation in Patients With Rare Pathogenic Variants in Cardiomyopathy and Arrhythmia Genes

Introduction: Patients with rare, pathogenic cardiomyopathy (CM) and arrhythmia variants can present with atrial fibrillation (AF), with or without overt ventricular involvement. The efficacy of AF ablation in these patients is unknown. Research Questions/Hypothesis: To test the hypotheses that: 1) patients with a pathogenic variant in any CM or arrhythmia gene have a higher risk of recurrence following AF ablation, and 2) patients with a pathogenic variant associated with a specific gene group (arrhythmogenic left ventricular CM [ALVC], arrhythmogenic right ventricular CM [ARVC], dilated CM [DCM], hypertrophic CM [HCM], or a channelopathy) have a higher risk of recurrence. Methods: We performed a prospective observational cohort study in participants referred for AF catheter ablation who underwent whole exome sequencing. Our primary outcome was AF recurrence, defined as &gt;30 seconds of AF, atrial flutter, or atrial tachycardia that occurred at least 90 days after AF ablation. Results: Among 1,366 participants, 109 (8.0%) had a pathogenic or likely-pathogenic (P/LP) variant in a CM or arrhythmia gene. In multivariable analysis, presence of a P/LP variant in any gene was not significantly associated with recurrence (HR 1.15 (0.84-1.60), p=0.53, Figure 1A ). When analyzed according to gene group, P/LP variants in the ALVC gene group, predominantly LMNA , were associated with increased recurrence (N=10; HR 3.75 (1.84-7.63), p&lt;0.001), compared to those in the ARVC gene group (N=6; HR 1.97 (0.62-6.27), p=0.25), DCM gene group (N=50; HR 0.98 (0.59-1.63), p=0.94), HCM gene group (N=33; HR 1.28 (0.76-2.17), p=0.35), and channelopathy gene group (N=17; HR 0.58 (0.21-1.56), p=0.28), as shown in Figure 1B, 1C . Conclusions: Our results support the continued use of AF ablation for most patients with rare pathogenic CM or arrhythmia variants, including TTN . However, patients with ALVC variants, such as in LMNA , may be at a significantly higher risk for arrhythmia recurrence.