Introduction and objectives: Arrhythmogenic cardiomyopathy (ACM) is a hereditary heart disease defined by the progressive replacement of the ventricular myocardium with fibroadipose tissue, which can act as a substrate for arrhythmias, sudden death, or even give rise to heart failure (HF). Sudden death is frequently the first manifestation of the disease, particularly among young patients. The aim of this study is to describe a new pathogenic variant in the PKP2 gene. Methods: A descriptive observational study that included eight initially non-interrelated families with a diagnosis of ACM undergoing follow-up at our HF and Familial Cardiomyopathies Unit, who were carriers of the NM_004572.3:c.775_776insG; p.(Glu259Glyfs*77) variant in the PKP2 gene. The genetic testing employed next-generation sequencing for the index cases and the Sanger method for the targeted study with family members. We compiled personal and family histories, demographic and clinical characteristics, data from the additional tests at the time of diagnosis, and arrhythmic events at diagnosis and during follow-up. Results: We included 47 subjects, of whom 8 were index cases (17%). Among the evaluated family members, 16 (34%) were carriers of the genetic variant, 3 of whom also had a diagnosis of ACM. The majority were women (26 patients; 55.3%), with a mean age on diagnosis of 48.9 ± 18.6 years and a median follow-up of 39 [24–59] months. Worthy of note are the high incidences of arrhythmic events as the form of presentation and in follow-up (21.5% and 20.9%, respectively), and the onset of HF in 25% of the sample. The most frequent ventricular involvements were right (four patients, 16.7%) and biventricular (four patients, 16.7%); we found no statistical differences in any of the variables analysed. Conclusions: This variant is a pathogenic variant of gene PKP2 that has not previously been described and is not present in the control groups associated with ACM. It has incomplete penetrance, a highly variable phenotypic expressivity, and was identified in eight families of our geographical area in Malaga (Andalusia, Spain), suggesting a founder effect in this area and describe the clinical and risk characteristics.

Background: Lipoprotein(a) [Lp(a)] is a causal and independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and is largely genetically determined. However, recent studies indicate significant intra-individual variability, particularly among patients with intermediate Lp(a) levels (30–50 mg/dL). Yet, data on long-term variability are limited, and acute coronary syndrome (ACS) may further influence Lp(a) levels, raising questions regarding the optimal timing of assessment after ACS. Methods: We studied 235 ACS patients across two follow-up cohorts. Baseline Lp(a) was measured 24 h before hospital discharge. Cohort A had follow-up measurements at 4 months and 8 months; Cohort B had them at 5 years. Clinically meaningful intra-individual variability was defined as ≥20 mg/dL or ≥25% change. Results: 57.9% of patients exhibited clinically significant Lp(a) variability. Changes in risk category occurred in 15.3% of patients in the baseline high-risk group, 60.6% of patients in the intermediate-risk group, and 5.5% of patients in the baseline low-risk group. In the multivariable analysis, incomplete revascularization was an independent predictor of high Lp(a) variability (odds ratio (OR) 2.22; 95% confidence interval (CI) 1.14–4.31; p = 0.02) while female sex and age-adjusted menopause showed a trend (OR 1.92; 95% CI 0.93–4.00; p = 0.08 and OR 11.18; 95% CI 0.79–157.58; p = 0.07, respectively) without reaching statistical significance. The median absolute changes from baseline to 4-month and from baseline to 5-year follow-up were 7.9 mg/dL (interquartile range (IQR) 3.0–18.9) and 10.7 mg/dL (IQR 3.0–21.7), respectively. Concordance between 4- and 8-month Lp(a) measurements was excellent. Conclusions: Early post-ACS intra-individual variability in Lp(a) is common, mainly affecting risk reclassification in intermediate-risk patients. In those patients, early, targeted, repeat Lp(a) measurement may improve cardiovascular risk stratification, whereas mid- to long-term reassessment appears unnecessary.

Background: Lipoprotein(a) [Lp(a)] is a casual and independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and is largely genetically determined. However, recent studies indicate significant intra-individual variability, particularly among patients with intermediate Lp(a) levels (30–50 mg/dL). Yet, data on long-term variability are limited, and acute coronary syndrome (ACS) may further influence Lp(a) levels, questioning the optimal timing of assessment after ACS. Methods: We studied 235 ACS patients across two follow-up cohorts. Baseline Lp(a) was measured 24 hours before hospital discharge. Cohort A had follow-up measurements at 4 months, and 8 months; Cohort B at 5 years. Clinically meaningful intra-individual variability was defined as ≥20 mg/dL or ≥25% change. Results: A total of 57.9% patients exhibited clinically significant Lp(a) variability. Changes in risk category occurred in 15.3% of patients in the baseline high-risk group, 60.6% of patients in the intermediate-risk group, and 5.5% of patients in the baseline low-risk group. At multivariable analysis incomplete revascularization was an independent predictor of high Lp(a) variability (OR 2.22; 95% CI 1.14-4.31; p 0.02) while female sex, and age-adjusted menopause showed a trend (OR 1.92; 95% CI 0.93-4.00; p 0.08 and OR 11.18; 95% CI 0.79-157.58; p 0.07, respectively) without reaching formal statistical significance. The median absolute changes from baseline to 4-month and from baseline to 5-years follow-up were 7.9 mg/dL (IQR 3.0-18.9) and 10.7 mg/dL (IQR 3.0-21.7), respectively. Concordance between 4- and 8-month Lp(a) measurements was excellent. Conclusions: Early post-ACS intra-individual variability in Lp(a) is common, mainly affecting risk reclassification in intermediate-risk patients. In those patients, early targeted repeat Lp(a) measurement may improve cardiovascular risk stratification, whereas mid- to long-term reassessment appears unnecessary.

Introduction and objectives: arrhythmogenic cardiomyopathy (ACM) is a hereditary heart disease defined by the progressive replacement of the ventricular myocardium with fibroadipose tissue, which can act as a substrate for arrhythmias, sudden death, or even give rise to heart failure (HF). Sudden death is frequently the first manifestation of the disease, particularly among young patients. The aim of this study is to describe a new pathogenic variant in the PKP2 gene. Methods: A descriptive observational study that included 8 initially non-interrelated families with a diagnosis of ACM undergoing follow-up at our HF and Familial Cardiomyopathies Unit, who were carriers of the NM_004572.3:c.775_776insG; p. (Glu259Glyfs*77) variant in PKP2 gene. The genetic testing employed next-generation sequencing for the index cases, and the Sanger method for the targeted study with family members. We compiled personal and family histories, demographic and clinical characteristics, data from the additional tests at the time of diagnosis, and arrhythmic events at diagnosis and during follow-up. Results: We included 47 subjects, of whom 8 were index cases (17%). Among the evaluated family members, 16 (34%) were carriers of the genetic variant, 3 of whom also had a diagnosis of ACM. The majority were women (26 patients; 55.3%), with a mean age on diagnosis of 48.9 ± 18.6 years, and a median follow-up of 39 [24-59] months. Worthy of note are the high incidence of arrhythmic events as the form of presentation and in follow-up (21.5% and 20.9% respectively), and the onset of HF in 25% of the sample. The most frequent ventricular involvements were right (4 patients 16.7%) and biventricular (4 patients 16.7%); we found no statistical differences in any of the variables analysed. Conclusions: This variant is a pathogenic variant of gene PKP2 that has not previously been described and is not present in the control groups associated with ACM. It has incomplete penetrance, a highly variable phenotypic expressivity, and was identified in 8 families of our geographical area in Malaga (Andalusia, Spain), where we can establish a founder effect and describe the clinical and risk characteristics.

Background/Objectives: Variants in genes classically associated with skeletal myopathies may be identified in patients with cardiomyopathy without clinically manifest skeletal muscle disease. We aimed to characterize the clinical, imaging, familial, and genetic features of this population. Methods: We conducted a single-center retrospective study of 33 patients with cardiomyopathy and no clinically manifest skeletal myopathy, comprising 31 laboratory-selected patients and two affected relatives from a previously published ACTA1 family. Clinical, familial, imaging, and genetic data were analyzed, incorporating available disease-specific variant classifications. Results: Median age at the beginning of cardiac follow-up was 47 years (range 16–77), and 42.4% were male. Dilated cardiomyopathy was the most frequent phenotype (22/33, 66.7%), followed by hypertrophic cardiomyopathy (8/33, 24.2%) and non-dilated left ventricular cardiomyopathy (3/33, 9.1%). ANO5 was the most frequently represented ascertainment gene (12/33, 36.4%). Among patients with complete data, 74.1% had no major conventional cardiovascular risk factors or significant coronary artery disease. Family history of cardiomyopathy was present in 43.8%, and 21 patients had additional genetic findings. Cardiac magnetic resonance was performed in 23 patients; late gadolinium enhancement was present in nine (39.1%), exclusively with non-ischemic patterns. Conclusions: The cohort describes heterogeneous cardiac presentations in patients carrying variants in skeletal-myopathy-associated genes without clinically manifest skeletal myopathy. These observations support further investigation of potential skeletal–cardiac phenotypic overlap and remain hypothesis-generating without establishing variant-level cardiac causality.