Heart failure (HF) is a clinical syndrome that can present as an acute or chronic condition resulting from various cardiovascular (CV) diseases. It poses a significant global health burden and affects individuals regardless of biological sex. HF can be caused by various differing etiologies exhibiting different rates of disease progression and mortality. Treatment of HF is often approached using a one-size-fits-all strategy that overlooks sex and gender differences, relying solely on left ventricular ejection fraction as the clinical parameter. This is due to a lack of evidence and subsequent missing deepened understanding of nuances of disease manifestation, course, and outcome. Biological sex (defined as biological aspects of having female or male body) and gender (society norms and roles of women and men) are known to substantially influence prognosis, age of disease onset, as well as severity in CV disease and subsequent HF. However, varying quality and availability of supporting evidence and subsequently unmet diagnostic and therapeutic needs exist for general HF and cardiomyopathy (CM) management. This review aims to elucidate the influence of sex and gender on the development and treatment of HF and CM as a basis for advancing personalized diagnosis and treatment strategies.

BACKGROUND:Amyloid transthyretin cardiomyopathy (ATTR-CM) results from extracellular deposition of misfolded transthyretin (TTR), causing progressive heart failure. Naturally-occurring antibodies (nAbs) targeting misfolded proteins exist in neurodegenerative disease, but their presence in ATTR-CM is unknown. The objective of this study is to determine whether nAbs against TTR (nAbsTTR) exist in humans and whether they are influenced by disease or its treatment. METHODS:Serum from healthy donors, umbilical cord blood (UCB), and patients with ATTR-CM - both untreated and receiving TTR-stabilizing therapy - was analyzed for nAbsTTR using immunoassays, blotting, and binding studies. Functional activity was evaluated in a fibril formation assay. RESULTS:nAbsTTR binding both native and amyloid TTR (ATTR) with high affinity (KD 30 nM/7 nM) were detected in healthy serum and UCB. NAbsTTR levels were significantly altered in ATTR-CM compared to controls: nAbsTTR (IgG) were higher while nAbsTTR (IgM) were lower. nAbsTTR of both subtypes significantly increased by 22% (p ≤ 0.05) in patients receiving TTR-stabilizing therapy. In vitro, nAbsTTR suppressed TTR fibril aggregation. CONCLUSIONS:Naturally-occurring TTR-targeting antibodies are present from birth, modulated by disease and therapy, and inhibit fibril formation. These findings reveal an unrecognized immune mechanism with potential relevance for ATTR-CM pathogenesis and treatment.

The efficacy of transthyretin stabilisation in cardiac transthyretin amyloidosis (ATTR-CM) has been demonstrated in a clinical trial setting, but little is known about treatment decision-making in the real world. Particularly, initiating or discontinuing specific therapy is challenging in early and advanced disease. We evaluated current decision pathways for tafamidis in ATTR-CM. This multicentre retrospective study included consecutive patients from 15 tertiary centres in Germany in whom ATTR-CM was newly diagnosed between January and June 2024, as well as patients, in whom tafamidis treatment was discontinued during this period. Out of 516 patients with newly established ATTR-CM included in the present analysis, tafamidis was initiated in 414 (80

Aims:Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed cause of heart failure. With a male:female ratio of approximately 10:1, current evidence including diagnostic criteria is largely based on male-dominant collectives. Sex-specific differences may contribute to delayed diagnosis in women. This study investigates these differences in a real-world setting. Methods and results:In this retrospective single-centre cohort study, all patients at West German Amyloidosis Center diagnosed with ATTR-CM between 2018 and 2024 were analysed. Clinical, echocardiographic, and laboratory parameters as well as outcomes under transthyretin stabilizer therapy at 6 and 12 months were evaluated. Among 240 patients, 34 (14.2%) were women. Compared to men, women had lower interventricular septal diameter, left ventricular mass, and stroke volume, but higher ejection fraction. Troponin I levels were lower and renal function was worse in women. Diagnostic delay was significantly longer in women (median 750 vs. 86 days, P = 0.022). Despite therapy, sex-specific echocardiographic differences persisted, and functional capacity remained lower in women, although NYHA functional class was comparable. Conclusion:Transthyretin amyloid cardiomyopathy presents with persistent sex-specific differences that may contribute to diagnostic delay in women. Current diagnostic thresholds may not adequately reflect female disease patterns, underscoring the need for sex-adapted diagnostic criteria to improve early detection and management.

BACKGROUND:Mavacamten has revolutionised the treatment of hypertrophic obstructive cardiomyopathy (HOCM) but requires frequent follow-up. Routine ECG may offer an accessible tool to indicate response to therapy. This study evaluates ECG-based indices of left ventricular hypertrophy (LVH) in patients with HOCM receiving mavacamten therapy. METHODS:In this retrospective study, after screening of 62 consecutive patients with HOCM treated at a German tertiary referral centre from August 2023 to February 2025, 31 patients (42% female, mean age 61±12 years) were included. During the first 12 weeks of myosin inhibitor treatment, echocardiographic parameters, laboratory values, symptoms and ECG LVH indices were assessed. RESULTS:Mavacamten reduced the mean left ventricular outflow tract obstruction (LVOTO) during Valsalva from 103 mm Hg (73-145) to 32 mm Hg (19-60), (p<0.001). All ECG LVH indices significantly decreased with treatment (Sokolow-Lyon Index: 2.56±0.97 mm vs 2.04±0.75 mm, p<0.001; Cornell criteria: 1.23 mm (0.92-2.21) vs 0.92 mm (0.75-1.75), p=0.001; Peguero-Lo Presti criteria: 2.39 mm (1.62-3.22) vs 1.61 mm (1.12-2.01), p<0.001; all pre vs post mavacamten). Notably, an increase in the Sokolow-Lyon Index and Peguero-Lo Presti criteria correlated with worsening LVOTO (area under the curve 0.72 and 0.88, respectively). Sensitivity and specificity of ECG LVH indices for detecting LVOTO progression during therapy were 100% and 88.6%, respectively. CONCLUSION:A combinatory ECG-based approach using the Sokolow-Lyon Index and Peguero-Lo Presti criteria may serve as an accessible tool for monitoring LVOTO progression in patients with HOCM on mavacamten. Prospective validation is warranted.

AIMS AND BACKGROUND:Cardiac amyloidosis leads to functional cardiac impairment and heart failure. Transthyretin amyloid cardiomyopathy (ATTR-CM) is the most common form. After initial suspicion, diagnosis involves imaging techniques, biopsy and genetic tests, prompting transthyretin stabilizer therapy to slow disease progression. The study aims to assess delays in diagnosis in ATTR-CM patients. METHODS:Patients with ATTR-CM receiving transthyretin stabilizer therapy at the West German Amyloidosis Center (01/2018-12/2023) were included. Clinical, laboratory, and imaging data were analysed. Diagnostic timelines were compared across two periods (2018-2020 and 2021-2023). RESULTS:After screening 254 patients, 154 were included in the analysis. ATTRwt was the most common form (96.8%). The median age was 80 (76-83) years, 87% were male and 46.6% were NYHA class ≥III. Time to diagnosis decreased from 398 to 277 days in the second period (P < 0.001). The median duration from diagnosis to stabilizer therapy was 84 (44-160) days, reducing from 111 (55-237) days in the first period to 57 (36-102) days in the second period (P < 0.001). Patients diagnosed in the first period had lower LVEF (P < 0.001) and more advanced NAC stages (P = 0.004). More women were diagnosed in the second period (P = 0.010). CONCLUSION:ATTR-CM is associated with diagnostic delays from initial suspicion to therapy initiation. While diagnostic and treatment timelines have improved, enhanced awareness, supraregional networks, specialized centres and focused education are essential to improve diagnosis and outcomes. Increasing awareness has led to patients being diagnosed at earlier disease stages, underscoring the potential to positively impact patient prognosis.

Aims: The optimal strategy to identify transthyretin-type cardiac amyloidosis (ATTR-CA) in patients with aortic stenosis (AS) is still unclear. This study aimed to investigate if targeted screening for ATTR-CA in patients with severe AS and amyloid red flags is associated with higher detection rates. Methods: The study prospectively enrolled patients ≥65 years with severe AS. Patients who fulfilled ≥1 major (carpal tunnel syndrome (CTS), ruptured biceps tendon, spinal stenosis, N-terminal pro B-type natriuretic peptide ≥1000 pg/mL, cardiac troponin >99th percentile) or ≥2 minor criteria (diastolic dysfunction ≥2 grade/lateral e’ <10 cm/s, atrial fibrillation, atrioventricular conduction disease/pacemaker) received bone scintigraphy and biochemical analysis for light chain amyloidosis. Hypertensive patients (>140/90 mmHg) and those with interventricular septal thickness (IVSd) ≤13 mm were excluded. Results: Overall, 264 patients were screened, of whom 85 were included in the analysis. Tracer uptake Perugini grade ≥1 was detected in nine patients (11%). An endomyocardial biopsy was additionally performed in four of nine patients, yielding a prevalence of 7% (n = 6). All patients with dual AS-ATTR were male. Syncope was more commonly reported in AS-ATTR patients (50% vs. 6%, p = 0.010), who also tended to have more severe hypertrophy (IVSd of 18 vs. 16 mm, p = 0.075). Pericardial effusion and CTS were more common in patients with dual pathology (67% vs. 8%, p < 0.001, and 83% vs. 24%, p = 0.003, respectively). Conclusion: Targeted screening for ATTR-CA in patients with AS and amyloid red flags does not yield higher detection rates than those reported previously in all comers with AS.

(1) Background: The transcoronary ablation of septal hypertrophy (TASH) is an established therapy for hypertrophic obstructive cardiomyopathy (HOCM). Previous studies on this topic are characterised by a consistent male predominance and show a worse prognosis in females. (2) Methods: This study is a retrospective analysis of all TASH procedures conducted between 2006 and 2021 at a tertiary academic centre. A solution of 75 µm microspheres (Embozene®, Boston Scientific, Marlborough, MA, USA) was used as an embolising agent. The outcomes of interest were left ventricular outflow tract (LVOT) gradient reduction and symptom improvement among males vs. that among females. Secondarily, we analysed the sex-related differences in procedural safety outcomes and mortality. (3) Results: The study population consisted of 76 patients, with a median age of 61 years. Females comprised 57% of the cohort. We observed no sex-related differences in the baseline LVOT gradients at rest or under provocation (p = 0.560 and p = 0.208, respectively). Females were significantly older at the time of the procedure (p < 0.001), had lower tricuspid annular systolic excursion (TAPSE) (p = 0.009), presented a worse clinical status according to the NYHA functional classification (for NYHA ≥ 3, p < 0.001), and were more often on diuretics (p < 0.001). We did not observe sex-related differences in absolute gradient reduction at rest (p = 0.147) and under provocation (p = 0.709). There was a reduction in the NYHA class by a median value of 1 (p = 0.636) at follow-up for both sexes. Postprocedural access site complications were documented in four cases (two of which concerned females), and complete atrioventricular block was noted in five patients (three of which concerned females). The 10-year survival rates were comparable between the sexes (85% in females and 88% in males). The female sex was not associated with enhanced mortality according to multivariate analysis after adjusting for the confounding variables (HR 0.94; 95% CI 0.376–2.350; p = 0.895), but we observed age-related differences in long-term mortality (HR 1.035; 95% CI 1.007–1.063; p = 0.015). (4) Conclusions: TASH is safe and effective in both sexes, irrespective of their clinical differences. Women present at an advanced age and with more severe symptoms. An advanced age at the time of the intervention is an independent predictor of mortality.