Huixia Lu

Introduction: Heart failure with reduced ejection fraction (HFrEF) is one of the main subtypes of heart failure (HF). Model for end-stage liver disease excluding international normalized ratio (MELD-XI) score and late gadolinium enhancement (LGE) assessed by cardiac magnetic resonance (CMR) each independently predict adverse prognosis in HF patients. Methods: This retrospective study enrolled adult HFrEF patients admitted to Qilu Hospital of Shandong University between September 2018 and January 2023. The primary endpoint was defined as a composite endpoint of rehospitalization for HF and all-cause mortality. Multivariate Cox regression model was established to evaluate the effects of LGE and MELD-XI score on the primary endpoint. We also evaluate the incremental prognostic value of adding the MELD-XI score to the model. Results: A total of 246 HFrEF patients were included and 55 patients reached the primary endpoint during follow-up. In the adjusted Cox regression model, for each standard deviation increase in LGE and MELD-XI score, the hazard ratios (HRs) for primary endpoint were 1.52 (95% CI: 1.23–1.88) and 1.60 (95% CI: 1.31–1.94), respectively. Adding MELD-XI score into model improved its incremental prognostic performance [ Δ C-Statistic: 0.052 (95% CI: 0.001–0.092), p = 0.039; Continuous NRI: 0.399 (95% CI: 0.077–0.532), p = 0.027; IDI: 0.094 (95% CI: 0.018–0.174), p = 0.010]. Conclusions: Both CMR-assessed LGE and MELD-XI score were associated with adverse outcomes in patients with HFrEF. Combining these two indicators provided complementary prognostic information for HFrEF patients.

Recent VICTOR study and the VICTORY pooled analysis demonstrate that vericiguat shows significant therapeutic value in a broader population of relatively stable heart failure with reduced ejection fraction (HFrEF) patients. However, the efficacy and safety of vericiguat in HFrEF patients receiving guideline-directed medical therapy (GDMT) who present with asymptomatic hypotension (systolic blood pressure (SBP) ≤ 100 mmHg) remain unclear and require further investigation. This multicenter observational cohort study enrolled 164 patients with HFrEF and asymptomatic hypotension (SBP ≤ 100 mmHg), who voluntarily decide whether to receive vericiguat treatment. Propensity score matching (1:2) was employed to address non-random treatment allocation. The primary outcome was the first occurrence of a ≥ 30% reduction in N-terminal pro-B-type natriuretic peptide(NT-proBNP) from baseline at any assessment time point during follow-up. Kaplan-Meier (K-M) analysis and multivariable Cox regression models were applied to assess outcomes. A total of 61 vericiguat-treated patients and 36 controls completed the study. The incidence of significant NT-proBNP reduction in the vericiguat group was 68.8%, significantly higher than the 47.2% in the control group. Kaplan-Meier analysis demonstrated a significantly higher cumulative incidence of NT-proBNP reduction in the vericiguat group than in the control group (hazard ratio (HR) = 2.54, 95% confidence interval (CI): 1.42-4.55, P < 0.001). Multivariate Cox regression confirmed vericiguat as an independent predictor of significant NT-proBNP reduction (Model 3: HR = 2.34, 95% CI: 1.30-4.21, P = 0.004). In patients with HFrEF receiving GDMT with concomitant asymptomatic hypotension (SBP ≤ 100 mmHg), vericiguat treatment is significantly associated with a ≥ 30% reduction in NT-proBNP levels during follow-up. In terms of safety in this study, the small number of adverse events and the absence of major safety signals only suggest no statistically significant differences in safety between the two groups. Further large-scale studies with adequate statistical power are required to better evaluate the safety of vericiguat.

As a mechanosensitive channel, PIEZO1 translates mechanical stretching of cardiomyocytes into Ca ²⁺ signaling, underpinning the Frank-Starling law. This mechanism contributes to compensatory responses in heart failure. However, the relationship between PIEZO1 mutations and the development of cardiomyopathy remains unclear. Acute heart failure complicated with severe myocardial iron deposition was identified in the 31-year-old male proband of PIEZO1 ^D669Y variant. However, PIEZO1 gain-of-function (GOF) mutation D674Y mice and cardiomyocyte-specific Piezo1 overexpression disrupted cardiac function besides iron overload. Using single-cell RNA sequencing, we observed suppression of lipid metabolism pathways in cardiomyocytes with the PIEZO1 GOF mutation, with forkhead box O3 (FOXO3) as a key mediator in lipid metabolism pathways. Specifically, the PIEZO1 GOF mutation increased Ca ²⁺ levels, leading to calcium- and calmodulin-dependent protein kinase II (CaMKII) activation and subsequent FOXO3 down-regulation. Together, we demonstrate that PIEZO1 GOF mutation contributes to cardiomyopathy by disrupting myocardial lipid metabolism. This study challenges the current clinical focus on iron-related mechanisms in cardiomyopathy and supports PIEZO1 as a potential candidate for future genetic screening for cardiomyopathy.

Background: As an extremely rare genetic disorder, limb-girdle muscular dystrophy type 2Y (LGMD2Y) is associated with progressive muscle weakness and potential cardiac involvement. Despite being less common compared with other muscular dystrophies, cardiac manifestations in LGMD2Y can lead to severe heart failure (HF). The diagnosis and management of cardiac involvement are crucial for improving outcomes in these patients. Case summary: In this study, the case of a 23-year-old woman who has suffered from progressive muscle weakness since age 13 and was initially diagnosed with metabolic myopathy was presented. Four months before admission, she developed symptoms of HF, like chest oppression and leg oedema. Echocardiography showed a left ventricular ejection fraction (LVEF) of 26% and LV dilation. Genetic testing identified a missense variant in torsin A interacting protein 1 (TOR1AIP1) (OMIM #614512), which confirmed LGMD2Y. During hospitalisation for acute HF, she was treated with intravenous diuretic, nesiritide, levosimendan and guideline-directed medical therapy (GDMT). After 2 years of follow-up, her LVEF increased to 41%, and her N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels stabilized, with no hospital readmissions for HF exacerbations. Discussion: It is essential to investigate the aetiology of HF, as even rare causes can be identified. Early diagnosis and tailored management, including GDMT for HF, are critical for improving patient outcomes. Additionally, this case highlights the importance of close cardiac monitoring in LGMD subtypes prone to cardiomyopathy.