Cinzia Zuchi

Background: Fabry disease (FD) is a rare inborn error of metabolism in which absent or deficient activity of α-galactosidase A leads to lysosomal dysfunction and globotriaosylceramide accumulation in different organs, including the heart. FD is characterized by a broad clinical spectrum, but Fabry cardiomyopathy represents the leading cause of morbidity and mortality. Electrocardiogram (ECG), echocardiography, and cardiac magnetic resonance (CMR) imaging are the cornerstones to suspect and diagnose cardiac involvement and to monitor it. Cardiac biomarkers such as troponin and N-terminal pro-B-type natriuretic peptide are also used to ascertain the degree of cardiac involvement. However, definitive data are lacking on how to plan the follow-up of patients with or without cardiac involvement, when to initiate specific therapy, and when to switch from one treatment to another. Current proposals suggest initiating treatment when there is evidence of left ventricular hypertrophy but before fibrosis develops. Main body: Ten experts on FD met in Milan on March 8, 2024. The panel of experts was selected based on their expertise and contribution to the literature on FD. The group deliberated on appropriate parameters for cardiac assessment at diagnosis and during follow-up. The panel discussed developing a multiparametric cardiac assessment system (including ECG, laboratory biomarkers, echocardiographic and CMR parameters) to be used in clinical practice to guide management and monitor treatment response. The authors defined the requirements of such a system and advocate for the research needed to build and validate it. The experts also proposed a multiparametric clinical pathway for cardiac assessment, treatment initiation, and follow-up, designed to support routine clinical decisions. This was intended as general guidance, acknowledging that clinicians should tailor management to the individual patient’s specific characteristics - a principle of particular importance in rare diseases such as FD, where organ involvement and treatment response can differ substantially among individuals. Conclusion: Since cardiovascular disease is a leading cause of death in FD, an agreed staging system for evaluating cardiac progression is urgently needed. Further research should be carried out to confirm the criteria of a cardiac assessment system, evaluate its prognostic and predictive validity, and ensure its reliability and reproducibility.

Systemic sclerosis (SSc) and amyloidosis are rare, complex conditions that impair the function of multiple organs, each with distinct pathogenic mechanisms: autoimmunity for SSc and misfolded protein deposition for amyloidosis. We present the first documented case of a 57-year-old woman with coexisting SSc and systemic AL amyloidosis with multi-organ involvement, in which treatment for amyloidosis led to a notable improvement in SSc symptoms. The patient presented experiencing fatigue, exertional dyspnea, epigastric pain and syncopal episodes in the summer of 2023. Investigations revealed mild increase in left ventricle thickness, elevated NT-proBNP and troponin with negative coronary angiography. She was subsequently diagnosed with SSc with multi-organ involvement and systemic AL amyloidosis confirmed by biopsy. Treatment with a modified Dara-CyBorD protocol led to improvement in SSc symptoms, especially in terms of dyspnea and skin involvement. This is the first reported case of SSc coexisting with systemic AL amyloidosis. The patient responded well to therapy for amyloidosis, suggesting potential overlapping treatment benefits. A multidisciplinary approach was essential, and further studies are needed to explore therapeutic interactions between these two rare diseases.

Background: Left atrial (LA) volume is a marker of cardiac remodeling and prognosis in heart failure (HF) with reduced ejection fraction (EF), but LA function is rarely measured or characterized. We investigated determinants and prognostic impact of LA reservoir function in patients with HF with reduced EF. Methods and Results: In 405 patients with stable HF with reduced EF (EF, ≤40%) in sinus rhythm, we assessed LA reservoir function by both LA total EF (by phasic volume changes) and peak atrial longitudinal strain (PALS; by speckle tracking echocardiography); LA functional index was also calculated. During follow-up (median, 30 months; Q1–Q3, 13–52), 139 patients (34%) reached the composite end point (all-cause death/HF hospitalization). Median PALS was 15.5% (interquartile range, 11.2–20.6). By univariable analysis, all LA function parameters significantly predicted outcome ( P P =0.030). Adding PALS to a base model, including age, sex, LA volume, EF, E/E′ ratio, and global longitudinal strain, provided incremental predictive value (continuous net reclassification improvement, 0.449; P =0.0009). Conclusions: In HF with reduced EF, assessment of LA reservoir function by PALS allows powerful prognostication, independently of LA volume and left ventricular longitudinal contraction.

Background—: In heart failure (HF) with reduced ejection fraction, right ventricular (RV) impairment, as defined by reduced tricuspid annular plane systolic excursion, is a predictor of poor outcome. However, peak longitudinal strain of RV free wall (RVFWS) has been recently proposed as a more accurate and sensitive tool to evaluate RV function. Accordingly, we investigated whether RVFWS could help refine prognosis of patients with HF with reduced ejection fraction in whom tricuspid annular plane systolic excursion is still preserved. Methods and Results—: A total of 200 patients with HF with reduced ejection fraction (age, 66±11 years; ejection fraction, 30±7%) with preserved tricuspid annular plane systolic excursion (>16 mm) underwent RV function assessment using speckle-tracking echocardiography to measure peak RVFWS. After a median follow-up period of 28 months, 62 (31%) patients reached the primary composite end point of all-cause death/HF rehospitalization. Median RVFWS was −19.3% (interquartile range, −23.3% to −15.0%). By lasso-penalized Cox-hazard model, RVFWS was an independent predictor of outcome, along with Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure-HF score, Echo-HF score, and severe mitral regurgitation. The best cutoff value of RVFWS for prediction of outcome was −15.3% (area under the curve, 0.68; P P P <0.001), with 68% of nonevents correctly reclassified. Conclusions—: In patients with HF with reduced ejection fraction with preserved tricuspid annular plane systolic excursion, RV free-wall strain provides incremental prognostic information and improved risk stratification.

Myocardial reflectivity, as assessed by calibrated integrated backscatter (cIB) analysis, is a non-invasive surrogate for the amount of left ventricular (LV) fibrosis. The aim of this study was to assess the myocardial reflectivity pattern in patients with heart failure and preserved ejection fraction (HFpEF), and to evaluate its relationship with longitudinal systolic deformation of LV by 2D-speckle tracking echocardiography, and degree of diastolic dysfunction. Transthoracic echocardiography, myocardial Doppler-derived systolic (Sm) and early diastolic velocity (E′), global longitudinal strain (GLS), and tissue characterization by cIB, were obtained in 86 subjects, 46 with HFpEF, and 40 controls. GLS was significantly impaired in HFpEF patients (−15.4 ± 3.5 % vs −21.5 ± 2.9 % in controls; P < 0.0001). Increased myocardial reflectivity, as evidenced by less negative values of cIB, was also found in HFpEF compared to controls (−21.2 ± 4.4 dB vs −25.3 ± 3.9 dB, P < 0.0001). In HFpEF patients, myocardial reflectivity was positively related to GLS (r = 0.68, P < 0.0001), E/E′ ratio (r = 0.38, P = 0.009), and Tau (r = 0.43, P = 0.002), and inversely related to E′ velocity (r = −0.46, P = 0.0012). These associations remained significant after adjustment for age, preload and afterload indices. Patients with HFpEF show changes of LV structure consistent with enhanced fibrosis—as evidenced by increased myocardial reflectivity- which parallel the degree of diastolic dysfunction, and of longitudinal systolic dysfunction.