Standard Therapy in Cardiac Amyloidosis: What is Known, What is "Gray".

Amyloidosis is a systemic disease due to the accumulation of misfolded amyloid fibrils that damage the heart and worsen the prognosis. Heart failure (HF), a condition frequently linked with an advanced stage of this disease, is the most prevalent clinical manifestation that leads to its diagnosis. However, due to the growing awareness of the occurrence of cardiac amyloidosis (CA), it is now possible to perform an early diagnosis and have a positive impact on its natural course. This study aims to highlight the most compelling issues concerning patients' clinical management with HF and CA.

Screening for cardiac amyloidosis in patients with tenosynovial red flags: A collaboration between family medicine and cardiology.

BACKGROUND: Amyloid deposition in tenosynovial structures precedes cardiac involvement up to 20 years. Therefore, a cardiological screening in patients with a history of tenosynovial manifestations of cardiac amyloidosis (CA) could lead to an increased number of early diagnoses. METHODS: Patients with tenosynovial manifestations of CA (carpal tunnel syndrome, atraumatic biceps tendon rupture, lumbar spinal stenosis) have been identified by general practitioners and evaluated in a Referral Center for CA. Patients with a high suspicion of CA underwent the CA diagnostic pathway. RESULTS: Among 50 General Practitioners (GP) contacted, 10 (20%) agreed to participate in the study for a total of 5615 patients ≥60 years. One hundred forty-five patients met the inclusion criteria, 2 of them already had a diagnosis of CA, and 57 agreed to undergo a cardiological evaluation (electrocardiography, echocardiography, NTproBNP assay). The median age was 73 [67-80] years and 31 (54%) were women. Eight patients were suggested to start the CA diagnostic pathway, five of them underwent a complete diagnostic evaluation for CA, three refused to complete the diagnostic exams and no new diagnoses were made. CONCLUSION: A screening program for CA in patients with tenosynovial manifestations identified by general practitioners is feasible, but may not yield a high rate of new diagnosis. In this study, we identified two patients who already had a diagnosis of CA, and among patients at high risk for CA, 37% refused to complete the diagnostic pathway. Increased awareness of CA among patients might increase participation and diagnostic yield in screening studies. Further validation of this protocol is needed to evaluate its diagnostic performance.

Natural history and clinical outcomes of patients with hypertrophic cardiomyopathy from thin filament mutations.

Hypertrophic cardiomyopathy (HCM) due to thick filament variants is more common; however, HCM due to thin filament variants (HCM-Thin) may be associated with a more malignant phenotype with an increased risk of sudden cardiac death. The aim of this study was to review all the published cases of HCM-Thin to better understand the natural history and clinical outcomes of this disease. A literature review of HCM-Thin identified 21 studies with a total of 177 patients that were suitable for analysis. There were three outcomes of interest, which included a heart failure composite, a ventricular arrhythmia composite and a heart failure and arrhythmia composite outcome. Kaplan-Meier (KM) survival analyses for freedom from each of the abovementioned composite outcomes were completed for the entire cohort and stratified by age of onset and sarcomeric variant. The heart failure composite occurred in 24 (13.6%) patients, the ventricular arrhythmia composite occurred in 30 patients (16.9%) and the combined heart failure and arrhythmia composite occurred in 50 patients (28.2%). In regard to left ventricular ejection fraction (LVEF), the majority of patients were preserved (LVEF > 50%) compared with mildly reduced (LVEF 41%-50%) and reduced (LVEF ≤ 40%) (respectively 26.6% vs. 0.6% vs. 3.4%). The median maximal left ventricular wall thickness (LVWT) was 19.0 mm [interquartile range (IQR) 5.3]. Only 10.7% of the cohort had evidence of left ventricular outflow tract (LVOT) obstruction. Those with paediatric-onset HCM had earlier onset and were at higher risk for each endpoint than their adult counterparts. When stratified by genetic variant, patients with TNNI3 and TPM1 were at a higher risk of the heart failure composite endpoint and the combined heart failure and arrhythmia composite endpoint in comparison with those with the other genetic variants. HCM-Thin is associated with significant morbidity and mortality, with a high arrhythmia burden despite low rates of cardiac obstruction and mild hypertrophy. The paediatric onset of disease and certain sarcomeric variants appear to be associated with a worse prognosis than their adult-onset and other sarcomeric variant counterparts. HCM-Thin seems to have a distinct phenotype, which may require a different management approach.

Effects of ranolazine on the arrhythmic substrate in hypertrophic cardiomyopathy.

Introduction: Hypertrophic cardiomyopathy (HCM) is a leading cause of lethal arrhythmias in the young. Although the arrhythmic substrate has been hypothesised to be amenable to late Na+ block with ranolazine, the specific mechanisms are not fully understood. Therefore, this study aimed to investigate the substrate mechanisms of safety and antiarrhythmic efficacy of ranolazine in HCM. Methods: Computational models of human tissue and ventricles were used to simulate the electrophysiological behaviour of diseased HCM myocardium for variable degrees of repolarisation impairment, validated against in vitro and clinical recordings. S1-S2 pacing protocols were used to quantify arrhythmic risk in scenarios of (i) untreated HCM-remodelled myocardium and (ii) myocardium treated with 3µM, 6µM and 10µM ranolazine, for variable repolarisation heterogeneity sizes and pacing rates. ECGs were derived from biventricular simulations to identify ECG biomarkers linked to antiarrhythmic effects. Results: 10µM ranolazine given to models manifesting ventricular tachycardia (VT) at baseline led to a 40% reduction in number of VT episodes on pooled analysis of >40,000 re-entry inducibility simulations. Antiarrhythmic efficacy and safety were dependent on the degree of repolarisation impairment, with optimal benefit in models with maximum JTc interval <370 ms. Ranolazine increased risk of VT only in models with severe-extreme repolarisation impairment. Conclusion: Ranolazine efficacy and safety may be critically dependent upon the degree of repolarisation impairment in HCM. For moderate repolarisation impairment, reductions in refractoriness heterogeneity by ranolazine may prevent conduction blocks and re-entry. With severe-extreme disease substrates, reductions of the refractory period can increase re-entry sustainability.

Determinants of health status in older patients with transthyretin cardiac amyloidosis: a prospective cohort study.

BACKGROUND: Whether, and to what extent, frailty and other geriatric domains are linked to health status in patients with transthyretin cardiac amyloidosis (ATTR-CA) is unknown. AIMS: To determine the association of frailty with health status [defined by the Kansas City Cardiomyopathy Questionnaire (KCCQ)] in patients with ATTR-CA. METHODS: Consecutive ATTR-CA patients undergoing cardiovascular assessment at a tertiary care clinic from September 2021 to September 2023 were invited to participate. KCCQ, frailty and social environment were recorded. Frailty was assessed using the modified Frailty Index (mFI), mapping 11 variables from the Canadian Study of Health and Aging (frailty ≥0.36). RESULTS: Of 168 screened ATTR-CA patients, 138 [83% men, median age of 79 (75-84) years] were enrolled in the study. Median KCCQ was 66 (50-75). wtATTR-CA was the most prevalent form (N = 113, 81.9%). The most frequent cardiac variant was Ile68Leu (17/25 individuals with vATTR-CA). Twenty (14.5%) patients were considered frail, and prevalence of overt disability was 6.5%. At multivariable linear regression analysis, factors associated with worsening KCCQ were age at evaluation, the mFI, NYHA Class, and NAC Score. Gender, ATTR-CA type, phenotype, and LVEF were not associated with health status. DISCUSSION: In older patients diagnosed with ATTR-CA, frailty, symptoms, and disease severity were associated with KCCQ. CONCLUSIONS: Functional status is a determinant of quality of life and health status in older individuals with a main diagnosis of ATTR-CA. Future research may provide more in-depth knowledge on the association of frailty in patients with ATTR-CA with respect to quality of life and prognosis.

Terapia génica para la insuficiencia cardiaca y las miocardiopatías / Gene therapy for heart failure and cardiomyopathies

Las estrategias de terapia génica incluyen diversos enfoques, como la sustitución y la edición de genes. La sustitución proporciona una copia funcional de un gen alterado y la edición permite corregir una mutación genética preexistente. La terapia génica ya está aprobada para trastornos genéticos como la amaurosis congénita de Leber y la atrofia muscular espinal, y actualmente se estudia su uso en cardiología. En esta revisión se resume el mecanismo de las distintas estrategias de terapia génica, los sistemas de administración disponibles, los principales riesgos relacionados con la terapia génica, los ensayos clínicos en curso y los objetivos futuros, con especial atención a las miocardiopatías.(AU)

Gene therapy strategies encompass a range of approaches, including gene replacement and gene editing. Gene replacement involves providing a functional copy of a modified gene, while gene editing allows for the correction of existing genetic mutations. Gene therapy has already received approval for treating genetic disorders like Leber's congenital amaurosis and spinal muscular atrophy. Currently, research is being conducted to explore its potential use in cardiology. This review aims to summarize the mechanisms behind different gene therapy strategies, the available delivery systems, the primary risks associated with gene therapy, ongoing clinical trials, and future targets, with a particular emphasis on cardiomyopathies.(AU)