Arrhythmogenic right ventricular cardiomyopathies (ARVC): Diagnostic challenges from imaging to genetics.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary cardiomyopathy, predominantly affecting young males, regardless of ethnicity or race. Due to its variable penetrance, females usually have milder and less malignant phenotypes and it may be diagnosed in older individuals. Accordingly, some affected individuals may remain asymptomatic, while in others sudden cardiac death represents the inaugural symptom. Exercise-related palpitations and syncope are red-flag symptoms in otherwise healthy adolescents and young adults and should be fully investigated, considering ARVC as a potential diagnosis. Clinicians should adopt a cardiomyopathy-oriented mindset which is focused on recognizing suspicious electrocardiogram, structural abnormalities and family history of sudden cardiac death. Complete baseline-investigations should be performed in all individuals in whom ARVC is suspected, regardless of their symptoms. These include multi-modality imaging (echocardiogram, cardiac magnetic resonance imaging), electrocardiogram monitors and maximal exercise tolerance tests. Genetic testing should be regarded as the final piece of the puzzle and offered in individuals with a high pre-test probability. A clinically actionable result allows for predictive family testing and pre-implantation diagnosis. Importantly, it should be offered only with appropriate pre and post-test counselling. Both clinicians and patients should understand that not identifying a disease-causing variant does not exclude ARVC. Finally, three clinical cases illustrating the potential caveats in diagnosing ARVC are discussed.

Low foetal heart rate, a potentially ominous finding: case report.

Background: Congenital long QT syndrome (LQTS) type 1 is characterized by abnormally prolonged ventricular repolarization caused by inherited defects in cardiac potassium channels. Patients are predisposed to ventricular arrhythmias and even sudden cardiac death. In some cases, foetal sinus bradycardia is the only sign, making prenatal diagnosis challenging. Physicians should be aware of this subtle presentation of LQTS. Early diagnosis and proactive treatment are crucial for preventing unexpected cardiac events. Case summary: A healthy and asymptomatic 25-year-old pregnant woman was referred to our institute for cardiac evaluation after persistent foetal sinus bradycardia was detected during repeated ultrasounds, despite the absence of any foetal morphological or functional cardiac anomalies. After a thorough assessment, the mother was diagnosed with LQTS type 1, as confirmed by molecular genetic testing. Appropriate management, including maternal medication and increased surveillance, was initiated. The infant was delivered safely, and his electrocardiogram revealed a significantly prolonged QTc interval. Genetic testing confirmed the maternally inherited variant in KCNQ1 gene, and beta-blocker therapy was started. No arrhythmic events were noted. Discussion: Detection and careful stratification of foetal heart rate (FHR) is crucial in every pregnancy. Foetal bradycardia can be caused by both maternal and foetal factors. Persistent low FHR should raise a high suspicion for LQTS. The condition may also present with atrioventricular blocks, torsades de pointes, or sudden intrauterine foetal demise. Accurate and early diagnosis of LQTS is essential for implementing appropriate management strategies, which include vigilant monitoring, effective medical treatment, careful planning of delivery, and post-natal care.

How to Conduct Clinical Research in Cardiovascular Imaging: A Primer for Clinical Cardiologists and Researchers. A Statement of the European Association of Cardiovascular Imaging (EACVI) of the ESC.

This statement from the European Association of Cardiovascular Imaging (EACVI) of the ESC aims to address the fundamental principles that guide clinical research in the field of cardiovascular imaging. It provides clinical researchers, cardiology fellows, and Ph.D. students with a condensed, updated, and practical reference document to support them in designing, implementing, and conducting imaging protocols for clinical trials. Although the present article cannot replace formal research training and mentoring, it is recommended reading for any professional interested in becoming acquainted with or participating in clinical trials involving cardiovascular imaging.

Fabry disease phenotyping in women from the complete Romanian cohort - time for early diagnostic awareness.

Fabry disease (FD) is an X-linked rare disorder caused by mutations in the GLA gene. Women with FD have been less enrolled in studies and less treated compared with men. The aim of the present study is to describe the complete phenotype of the women cohort with FD diagnosed and evaluated in Romania and compare it to the male population. This study included all consecutive patients diagnosed with FD referred to the Expert Center for Rare Genetic Cardiovascular Diseases between 2014-2023 which included 73 consecutive Romanian FD patients: 41 women (56.2%) and 32 men (43.8%) from 33 unrelated families. Women with FD were diagnosed later and had a later symptom onset. Comparing with men, women were less often symptomatic, but with similar symptom severity. They had similar ophthalmologic and ENT involvement, but less angiokeratomas. Both women and men had similar heart failure symptoms, which were usually mild to moderate, with no difference between the age of developing of the heart failure symptoms. There were also similar rates of acroparesthesia and stroke between sexes, but women presented less renal involvement, with less requirement for renal transplant. This study demonstrates that women with Fabry disease are not just carriers of the disease, they can present symptoms as severe as men, and they have less or later access to pathogenic therapy. Further studies with more female participations are needed to better understand the burden of Fabry disease in women.

Complex management of Fabry cardiomyopathy: a case report on the use of alcohol septal ablation and chaperone therapy.

Background: Cardiac involvement in Fabry disease (FD) usually manifests as a concentric left ventricular hypertrophy with rare cases developing left ventricular outflow tract obstruction (LVOTO), symptoms varying from fatigue and exercise associated dyspnoea to angina or arrhythmias. Case summary: We present the case of a 54-year-old man with cardiovascular risk factors and aggravated exertional dyspnoea in the past year, in whom the echocardiography showed hypertrophic obstructive cardiomyopathy (HOCM). Cardiac magnetic resonance was used as differential diagnosis tool between sarcomeric HOCM and other phenocopies, suggesting a cardiac involvement of FD. Final diagnosis was formulated based on genetic testing and enzymatic activity of α-galactosidase. Left ventricular outflow tract obstruction was addressed by alcohol septal ablation successfully both in short term as well as at 1-year follow-up. Discussion: The present case illustrates the complex clinical pathway of a patient with HOCM due to FD, where multimodality imaging was instrumental from differential diagnosis to therapeutic choices, which addressed both the pathogenic background and the organ involvement. Although at the moment the number of patients with of FD cardiomyopathy undergoing LVOTO reduction therapies is scarce, current recommendations should be extended to also include these patients.

Pregnancy in women with dilated cardiomyopathy genetic variants.

INTRODUCTION AND OBJECTIVES: Limited information is available on the safety of pregnancy in patients with genetic dilated cardiomyopathy (DCM) and in carriers of DCM-causing genetic variants without the DCM phenotype. We assessed cardiac, obstetric, and fetal or neonatal outcomes in this group of patients. METHODS: We studied 48 women carrying pathogenic or likely pathogenic DCM-associated variants (30 with DCM and 18 without DCM) who had 83 pregnancies. Adverse cardiac events were defined as heart failure (HF), sustained ventricular tachycardia, ventricular assist device implantation, heart transplant, and/or maternal cardiac death during pregnancy, or labor and delivery, and up to the sixth postpartum month. RESULTS: A total of 15 patients, all with DCM (31% of the total cohort and 50% of women with DCM) experienced adverse cardiac events. Obstetric and fetal or neonatal complications were observed in 14% of pregnancies (10 in DCM patients and 2 in genetic carriers). We analyzed the 30 women who had been evaluated before their first pregnancy (12 with overt DCM and 18 without the phenotype). Five of the 12 (42%) women with DCM had adverse cardiac events despite showing NYHA class I or II before pregnancy. Most of these women had a history of cardiac events before pregnancy (80%). Among the 18 women without phenotype, 3 (17%) developed DCM toward the end of pregnancy. CONCLUSIONS: Cardiac complications during pregnancy and postpartum were common in patients with genetic DCM and were primarily related to HF. Despite apparently good tolerance of pregnancy in unaffected genetic carriers, pregnancy may act as a trigger for DCM onset in a subset of these women.

Genetic Characterization of Dilated Cardiomyopathy in Romanian Adult Patients.

Dilated cardiomyopathy (DCM) represents a group of disorders affecting the structure and function of the heart muscle, leading to a high risk of heart failure and sudden cardiac death (SCD). DCM frequently involves an underlying genetic etiology. Genetic testing is valuable for risk stratification, treatment decisions, and family screening. Romanian population data on the genetic etiology of DCM are lacking. We aimed to investigate the genetic causes for DCM among Romanian adult patients at tertiary referral centers across the country. Clinical and genetic investigations were performed on adult patients presenting to tertiary hospitals in Romania. The genetic investigations used next-generation sequencing panels of disease-associated DCM genes. A total of 122 patients with DCM underwent genetic testing. The mean age at DCM diagnosis was 41.6 ± 12.4 years. The genetic investigations identified pathogenic or likely pathogenic variants in 50.8% of participants, while 25.4% had variants of unknown significance. Disease-causing variants in 15 genes were identified in people with DCM, with 31 previously unreported variants. Variants in TTN, LMNA, and DSP explained 75% of genetic causes for DCM. In total, 52.4% of patients had a family history of DCM/SCD. Left ventricular ejection fraction of <35% was observed in 41.9% of patients with disease-causing variants and 55% with negative or uncertain findings. Further genotype-phenotype correlations were explored in this study population. The substantial percentage (50.8%) of disease-causing variants identified in patients with DCM acknowledges the importance of genetic investigations. This study highlights the genetic landscape in genes associated with DCM in the Romanian population.

Proposed diagnostic criteria for arrhythmogenic cardiomyopathy: European Task Force consensus report.

Arrhythmogenic cardiomyopathy (ACM) is a heart muscle disease characterized by prominent "non-ischemic" myocardial scarring predisposing to ventricular electrical instability. Diagnostic criteria for the original phenotype, arrhythmogenic right ventricular cardiomyopathy (ARVC), were first proposed in 1994 and revised in 2010 by an international Task Force (TF). A 2019 International Expert report appraised these previous criteria, finding good accuracy for diagnosis of ARVC but a lack of sensitivity for identification of the expanding phenotypic disease spectrum, which includes left-sided variants, i.e., biventricular (ABVC) and arrhythmogenic left ventricular cardiomyopathy (ALVC). The ARVC phenotype together with these left-sided variants are now more appropriately named ACM. The lack of diagnostic criteria for the left ventricular (LV) phenotype has resulted in clinical under-recognition of ACM patients over the 4 decades since the disease discovery. In 2020, the "Padua criteria" were proposed for both right- and left-sided ACM phenotypes. The presently proposed criteria represent a refinement of the 2020 Padua criteria and have been developed by an expert European TF to improve the diagnosis of ACM with upgraded and internationally recognized criteria. The growing recognition of the diagnostic role of CMR has led to the incorporation of myocardial tissue characterization findings for detection of myocardial scar using the late­gadolinium enhancement (LGE) technique to more fully characterize right, biventricular and left disease variants, whether genetic or acquired (phenocopies), and to exclude other "non-scarring" myocardial disease. The "ring-like' pattern of myocardial LGE/scar is now a recognized diagnostic hallmark of ALVC. Additional diagnostic criteria regarding LV depolarization and repolarization ECG abnormalities and ventricular arrhythmias of LV origin are also provided. These proposed upgrading of diagnostic criteria represents a working framework to improve management of ACM patients.

Sex-specific difference in cardiac function in patients with systemic sclerosis: association with cardiovascular outcomes.

BACKGROUND: Cardiovascular involvement is one of the leading causes of mortality in systemic sclerosis (SSc) and is reported to be higher in men as compared with women. However, the cause of this difference is largely unknown. The objective of this study was to assess sex differences in echocardiographic characteristics, including left ventricular global longitudinal strain (LV GLS), as a potential explanation of sex differences in outcomes. METHODS: A total of 746 patients with SSc from four centres, including 628 (84%, 54±13 years) women and 118 (16%, 55±15 years) men, were evaluated with standard and advanced echocardiographic examinations. The independent association of the echocardiographic parameters with the combined endpoint of cardiovascular events-hospitalisation/death was evaluated. RESULTS: Men and women with SSc showed significant differences in disease characteristics and cardiac function. After adjusting for the most important clinical characteristics, while LV ejection fraction and diastolic function were not significantly different anymore, men still presented with more impaired LV GLS as compared with women (-19% (IQR -20% to -17%) vs -21% (IQR: -22% to -19%), p<0.001). After a median follow-up of 48 months (IQR: 26-80), the combined endpoint occurred in 182 patients. Men with SSc experienced higher cumulative rates of cardiovascular events-hospitalisation/mortality (χ2=8.648; Log-rank=0.003), and sex differences were maintained after adjusting for clinical confounders, but neutralised when matching the groups for LV GLS. CONCLUSION: In patients with SSc, male sex is associated with worse cardiovascular outcomes even after adjusting for important clinical characteristics. LV GLS was more impaired in men as compared with women and potentially explains the sex difference in cardiovascular outcomes.

Intrafamilial Phenotypical Variability Linked to PRKAG2 Mutation-Family Case Report and Review of the Literature.

PRKAG2 syndrome (PS) is a rare, early-onset autosomal dominant phenocopy of sarcomeric hypertrophic cardiomyopathy (HCM), that mainly presents with ventricular pre-excitation, cardiac hypertrophy and progressive conduction system degeneration. Its natural course, treatment and prognosis are significantly different from sarcomeric HCM. The clinical phenotypes of PRKAG2 syndrome often overlap with HCM due to sarcomere protein mutations, causing this condition to be frequently misdiagnosed. The syndrome is caused by mutations in the gene encoding for the γ2 regulatory subunit (PRKAG2) of 5' Adenosine Monophosphate-Activated Protein Kinase (AMPK), an enzyme that modulates glucose uptake and glycolysis. PRKAG2 mutations (OMIM#602743) are responsible for structural changes of AMPK, leading to an impaired myocyte glucidic uptake, and finally causing storage cardiomyopathy. We describe the clinical and investigative findings in a family with several affected members (NM_016203.4:c.905G>A or p.(Arg302Gln), heterozygous), highlighting the various phenotypes even in the same family, and the utility of genetic testing in diagnosing PS. The particularity of this family case is represented by the fact that the index patient was diagnosed at age 16 with cardiac hypertrophy and ventricular pre-excitation while his mother, by age 42, only had Wolff−Parkinson−White syndrome, without left ventricle hypertrophy. Both the grandmother and the great-grandmother underwent pacemaker implantation at a young age because of conduction abnormalities. Making the distinction between PS and sarcomeric HCM is actionable, given the early-onset of the disease, the numerous life-threatening consequences and the high rate of conduction disorders. In patients who exhibit cardiac hypertrophy coexisting with ventricular pre-excitation, genetic screening for PRKAG2 mutations should be considered.

EACVI survey on the multi-modality imaging assessment of the right heart.

AIMS: The European Association of Cardiovascular Imaging (EACVI) Scientific Initiatives Committee performed a global survey to evaluate the use of different cardiac imaging modalities for the evaluation of the right heart. METHODS AND RESULTS: Delegates from 250 EACVI registered centres were invited to participate in a survey which was also advertised on the EACVI bulletin and on social media. One hundred and thirty-eight respondents from 46 countries across the world responded to the survey. Most respondents worked in tertiary centres (79%) and echocardiography was reported as the commonest imaging modality used to assess the right ventricle (RV). The majority of survey participants (78%) included RV size and function in >90% of their echocardiographic reports. The RV basal diameter obtained from the apical four-chamber view and the tricuspid annular plane systolic excursion were the commonest parameters used for the echocardiographic assessment of RV size and function as reported by 82 and 97% respondents, respectively. Survey participants reported arrhythmogenic cardiomyopathy as the commonest condition (88%) where cardiac magentic resonance (CMR) imaging was used for right heart assessment. Only 52% respondents included RV volumetric and ejection fraction assessments routinely in their CMR reports, while 30% of respondents included these parameters only when RV pathology was suspected. Finally, 73% of the respondents reported pulmonary hypertension as the commonest condition where right heart catheterization was performed. CONCLUSION: Echocardiography remains the most frequently used imaging modality for the evaluation of the right heart, while the use of other imaging techniques, most notably CMR, is increasing.

The Impact of Kidney Biopsy for Fabry Nephropathy Evaluation on Patients' Management and Long-Term Outcomes: Experience of a Single Center.

BACKGROUND: Fabry disease (FD) is a rare lysosomal storage disease causing progressive loss of target organ function. All renal cell types are involved from the early stages, even before clinical signs can be detected. FD-specific therapies can stop/mitigate disease progression. Thus, it is important to validate early markers of renal lesions so that they can be adopted as criteria for timely treatment initiation. MATERIALS AND METHODS: We retrospectively analyzed and extensively evaluated 21 FD case patients; this evaluation included a kidney biopsy. We looked for the influence of pathological findings on the management of FD patients. In addition, we investigated the association between general and FD-specific features and long-term patients' outcomes. We defined a combined endpoint as being at least one of the following: 50% decrease of estimated glomerular filtration rate (eGFR) from baseline, kidney failure (KF), end-stage kidney disease (ESKD), or death and mortality. RESULTS: Our cohort of 21 FD patients (11 males and 10 females) was stratified according to the presence of the combined endpoint: group 1 (n = 15) included patients without the combined endpoint, while group 2 (n = 6) patients reached the combined endpoint outcome. Patients from group 2 presented lower mean baseline eGFR (72.2 ± 38.7 mL/min/1.73 m2 vs. 82.5 ± 26.4 mL/min/1.73 m2) without statistical significance (p = 0.44), but significantly (p = 0.22) higher median baseline proteinuria (2.7 g/24 h vs. 0.4 g/24 h). Specific lysosomal deposits were identified in all patients. Segmental sclerosis was present in all patients with the combined endpoint and in only 33% of patients without the combined endpoint (p = 0.009). Global sclerosis and interstitial fibrosis were present in both groups, with no significant differences. A total of 15 out of the 16 treatment-naïve patients (7 males and 9 females) started FD-specific therapy after kidney biopsy. Treatment was initiated in all male FD patients and in 8 female patients. In 2 females, pathological findings in kidney biopsy offered important reasons to start FD treatment, although specific criteria of the Romanian protocol for prescription of FD-specific therapy were still not fulfilled. Cox univariate analysis showed that every increase in 24 h proteinuria with 1 g is associated with a 65% risk of developing the combined endpoint (HR = 1.65; 95%CI: 1.05-2.58; p = 0.02), and that the presence of segmental sclerosis increased the risk of developing the combined endpoint by 51.3 times (HR = 51.3; 95% CI: 95% CI: 1.67-103.5; p = 0.01). Kaplan-Meier analysis showed that the cumulative risk of developing the combined endpoint was higher in patients in whom segmental sclerosis (100% vs. 0%, log-rank test, p = 0.03) was present. CONCLUSIONS: Histological evaluation is an important tool for the detection of early kidney involvement and provides additional support to the early initiation of FD-specific therapy. Presence of segmental sclerosis can predict the long-term outcomes of kidney disease deterioration and mortality and may be used as an early indicator of disease progression. Additionally, in the absence of other criteria according to current guidelines, specific FD renal lesions as revealed by kidney biopsy might become a distinct criterion to initiate FD therapy.

Cardiovascular Disease in Primary Sjögren's Syndrome: Raising Clinicians' Awareness.

In the ever evolving landscape of systemic immune mediated diseases, an increased awareness regarding the associated cardiovascular system impairment has been noted in recent years. Even though primary Sjögren's Syndrome (pSS) is one of the most frequent autoimmune diseases affecting middle-aged individuals, the cardiovascular profile of this specific population is far less studied, at least compared to other autoimmune diseases. Traditional cardiovascular risk factors and disease specific risk factors are inextricably intertwined in this particular case. Therefore, the cardiovascular risk profile in pSS is a multifaceted issue, sometimes difficult to assess. Furthermore, in the era of multimodality imaging, the diagnosis of subclinical myocardial and vascular damage is possible, with recent data pointing that the prevalence of such involvement is higher in pSS than in the general population. Nevertheless, when approaching patients with pSS in terms of cardiovascular diseases, clinicians are often faced with the difficult task of translating data from the literature into their everyday practice. The present review aims to synthesize the existing evidence on pSS associated cardiovascular changes in a clinically relevant manner.

Electrocardiographic and Echocardiographic Predictors of Atrial Fibrillation in Patients With Hypertrophic Cardiomyopathy.

Background: Patients with hypertrophic cardiomyopathy (HCM) have an increased prevalence of atrial fibrillation (AF) compared to the general population, and left atrium (LA) remodeling is strongly correlated with the risk of AF. This prospective, monocentric study aimed to assess the role of LA electrocardiographic and echocardiographic (structural and functional) parameters in predicting the risk for incident AF in patients with HCM. Methods and Results: The study population consisted of 126 HCM patients in sinus rhythm (52.6 ± 16.2 years, 54 men), 118 of them without documented AF. During a median follow-up of 56 (7-124) months, 39 (30.9%) developed a new episode of AF. Multivariable analysis showed that LA booster pump function (assessed by ASr, HR = 4.24, CI = 1.84-9.75, and p = 0.038) and electrical dispersion (assessed by P wave dispersion - Pd, HR = 1.044, CI = 1.029-1.058, and p = 0.001), and not structural parameters (LA diameter, LA volume) were independent predictors of incident AF. Seventy-two patients had a LA diameter < 45 mm, and 16 of them (22.2%) had an AF episode during follow-up. In this subgroup, only Pd emerged as an independent predictor for incident AF (HR = 1.105, CI = 1.059-1.154, and p = 0.002), with good accuracy (AUC = 0.89). Conclusion: Left atrium booster pump function (ASr) and electrical dispersion (Pd) are related to the risk of incident AF in HCM patients. These parameters can provide further stratification of the risk for AF in this setting, including in patients considered at lower risk for AF based on the conventional assessment of LA size.