In the phase 3 study SEQUOIA-HCM (NCT05186818), aficamten, a next-in-class cardiac myosin inhibitor, was safe and efficacious in participants with obstructive hypertrophic cardiomyopathy (oHCM). Using pharmacokinetics/pharmacodynamics (PKPD) modeling, we quantified the relationship between aficamten exposure and cardiodynamic measures of safety (left ventricular ejection fraction [LVEF]) and efficacy (post-Valsalva left ventricular outflow tract gradient [LVOT-G]), and used Clinical Trial Simulations (CTS) to predict cardiodynamics for a flexible dose regimen in a post-approval setting. PKPD relationships between aficamten average concentration over 24 h (Cavg,24) and LVEF or LVOT-G were well quantified. Within-subject variability for LVEF was low (CV = 7.6%), indicating that prior LVEF readings are highly predictive of future readings during stable therapy. A ~2% decrease in LVEF is expected per 100 ng/mL increase in Cavg,24. LVOT-G slope was ~10-fold steeper vs. LVEF, suggesting a relatively large therapeutic window. The commercial regimen allows for individualized flexible echocardiography-based dose titration (every 2-8 weeks) from 5 to 20 mg once daily and flexible maintenance dose monitoring. CTS demonstrated minimal differences in population progression of LVOT-G < 30 mmHg and LVEF < 50% between evaluated dose-titration frequencies (every 2, 4, 6, or 8 weeks) over the first 6 months of treatment, supporting a 2-8 week window for dose titration. With maintenance doses, the probability of maintaining LVOT-G < 30 mmHg (~60%) was high and the probability of occurrences of LVEF < 50% (~3%) was low. Therefore, this regimen should maintain safe and efficacious cardiodynamics while increasing convenience and access for patients with oHCM.

Aortic stenosis (AS) is the most common valvular heart disease in Western countries. Current clinical guidelines recommend intervention exclusively for severe AS, given its association with poor short-term prognosis. However, accumulating evidence over recent years suggests that even moderate AS may be associated with adverse outcomes, particularly in patients with heart failure with reduced ejection fraction (HFrEF). Consequently, an early aortic valve replacement (AVR) strategy could potentially improve survival and reduce heart-failure-related hospitalizations. Moreover, treating moderate AS in patients with HFrEF may reduce left ventricular afterload and improve haemodynamic status, thereby facilitating the initiation and/or up-titration of guideline-directed medical therapy (GDMT), especially when such therapy is poorly tolerated due to hypotension or other hypoperfusion-related factors. Nevertheless, the available evidence is derived predominantly from retrospective observational studies. The only published randomized controlled trial to date (the TAVR UNLOAD trial) failed to demonstrate a prognostic benefit of transcatheter aortic valve implantation (TAVI) in patients with moderate AS and HFrEF or heart failure with mildly reduced ejection fraction (HFmrEF). Two additional ongoing randomized trials may ultimately provide more definitive evidence. In summary, although the pathophysiological rationale is sound and the available data are encouraging, an early AVR strategy in moderate AS cannot currently be regarded as evidence-based.

Lipoprotein(a) [Lp(a)] is a causal and independent cardiovascular risk factor for atherosclerotic cardiovascular disease and calcific aortic valve stenosis, with elevated levels observed in approximately 20% of the general population. Plasma Lp(a) concentrations are predominantly determined by genetic factors, particularly polymorphisms of the LPA gene, which modulate apolipoprotein(a) [apo(a)] size and influence its hepatic synthesis. Structurally, Lp(a) consists of an LDL-like particle containing apolipoprotein B100, covalently bound to apo(a), conferring markedly enhanced atherogenic, pro-inflammatory, and prothrombotic properties compared with an LDL particle. In the absence of therapies specifically approved for Lp(a) reduction, current clinical management relies on an intensive approach to global cardiovascular risk reduction. ESC/EAS guidelines recommend aggressive lowering of LDL cholesterol, particularly through high-intensity statin therapy and, in patients at high or very high risk, the addition of ezetimibe and PCSK9 inhibitors, in order to mitigate the residual risk associated with elevated Lp(a) levels. Lipoprotein apheresis represents the only intervention capable of producing a substantial and immediate reduction in Lp(a); however, its use is limited to selected patients due to its invasive nature and limited availability. In parallel, innovative therapies targeting LPA gene silencing-such as antisense oligonucleotides and small interfering RNA-as well as oral agents inhibiting Lp(a) assembly, are in advanced stages of development. These approaches have demonstrated Lp(a) reductions of up to 80-90%, offering concrete prospects for a causal therapeutic strategy, pending the results of cardiovascular outcome trials.

In Japan, surgical repair for Stanford type A acute aortic dissection(AAAD)has been increasingly performed, accompanied by gradual improvement in early outcomes, While ascending or hemiarch replacement remains the mainstream strategy, late aneurysmal dilatation of the residual dissected aorta is still a concern, The frozen elephant trunk(FET)technique, which facilitates aortic remodeling, has been increasingly adopted in AAAD surgery, Since the introduction of a domestic integrated four-branched FET device in late 2022, expectations have risen for improved procedural safety and simplicity, We report our early institutional outcomes of total arch replacement(TAR)using the integrated four-branched FET, Methods:Among 211 AAAD cases treated between December 2022 and April 2025, 110 underwent TAR with FET, of which the first 50 consecutive cases using the integrated four-branched FET[FROZENIX 4 Branched(FZX4B)]were retrospectively analyzed, The primary endpoint was early postoperative outcome, including mortality and spinal cord ischemia(SCI), Secondary endpoints included midterm survival, freedom from aortic events, and morphologic changes in the descending aorta, Results:The median age was 65 years[interquartile range(IQR):56~74], and 29 patients(58%)were male, The median operative time was 372 minutes(IQR:315~506), and the hypothermic circulatory arrest time was 42 minutes(IQR:38~50), The distal anastomosis was performed in zone 3 in 84% of cases, The FZX4B diameter most used was 25 mm(60%), In-hospital mortality was 4%, SCI occurred in one patient(2%), Two patients(4%)required additional thoracic endovascular aortic repair(TEVAR)for FET stenosis, The median follow-up was 248 days(IQR:165~472), Overall survival was 93% at 1 year and 86% at 2 years, and freedom from aortic events was 87% and 81% at 1 and 2 years, respectively, The FET distal level was mainly at Th6(62%), The aortic diameter at the distal edge of the FET decreased from 30 mm(IQR:28~33)preoperatively to 27 mm(25~31)at 1 year(p<0.001), The FET tip diameter correlated with the preoperative outer diameter at the anastomotic site(r=0.66, p<0.001), Conclusions:Although FET-related stenosis should be recognized as a potential procedural risk, TAR using the integrated FET for AAAD achieved acceptable early outcomes, A larger comparative study with conventional repair is warranted to elucidate its statistical impact.

Stanford type A acute aortic dissection(AAAD)is a life-threatening cardiovascular emergency, Early surgical repair is essential to prevent fatal outcomes, According to the 2023 Annual Report of the Japanese Association for Thoracic Surgery, AAAD cases increased by 4.4% in 2022, with an in-hospital mortality of 10% for AAAD, Although surgical outcomes have improved with advances in cerebral protection techniques, patients with cerebral malperfusion remain at high risk of poor neurological outcomes and mortality, with postoperative death rates reported between 15~30%, Antegrade selective cerebral perfusion(ASCP)is the standard method for cerebral protection during circulatory arrest, However, in AAAD patients with carotid artery occlusion or severe stenosis, conventional ASCP may result in uneven cerebral perfusion, risking ischemia in the affected hemisphere, To address this, we introduced a two-roller pump technique, in which each carotid artery(affected and non-affected)is perfused independently using separate ASCP circuits, Cerebral perfusion was monitored with transcranial Doppler and regional cerebral oxygen saturation(rSO2), The common carotid artery(CCA)was exposed via median sternotomy without additional neck incision, and direct cannulation was performed to establish targeted perfusion, The two-roller pump technique allowed independent regulation of flow and pressure for each carotid artery, Intraoperative monitoring confirmed stable perfusion to all cerebral vessels, including the previously occluded CCA, The two-pump technique prevented uneven blood distribution, reduced cerebral ischemia time, and was associated with improved immediate neurological outcomes, It enables immediate, controlled reperfusion of the affected hemisphere, potentially improving neurological outcomes, and offers a practical option for urgent surgical management of severe cerebral malperfusion in AAAD.

Left ventricular noncompaction (LVNC) is a rare cardiomyopathy marked by excessive myocardial trabeculations and profound intertrabecular recesses, frequently identified incidentally, yet occasionally linked to significant cardiac dysfunction and adverse outcomes. It is uncommon for LVNC to coexist with other congenital cardiac anomalies, and the concurrent occurrence of LVNC, patent ductus arteriosus (PDA), and bicuspid aortic valve has not been previously reported. We report a 7-month-old female infant who exhibited exertional cyanosis and an episode of syncope in early infancy. Transthoracic echocardiography revealed that the left ventricle was not functioning correctly and that the aorta was too narrow. Therefore, a cardiac computed tomography angiography (CTA) was performed to gather further information. The CTA showed a significant PDA with flow in both directions, predominantly right-to-left shunting. This was caused by pulmonary arterial hypertension, which caused the pulmonary arteries (PAs) and descending thoracic aorta to have different levels of contrast opacification. There was significant dilation in all the heart's chambers and PAs. In addition, classic imaging features of LVNC were identified, including prominent trabeculations and deep intertrabecular recesses, with a noncompacted to compacted myocardial ratio > 3. The aortic valve had two cusps and thickened leaflets and raphes, which caused severe valvular stenosis. These three congenital defects probably worked together to cause early heart failure, pulmonary hypertension, and a high risk of death. This case exemplifies an extraordinarily rare congenital cardiac triad that manifests in infancy, emphasizing the critical importance of CTA in thorough anatomical and functional evaluation. Early identification of intricate associations is essential for risk stratification, multidisciplinary management, and prognostication in affected infants.

Paradoxical low-flow, low-gradient aortic stenosis (pLF-LG AS) represents a distinct phenotype of severe aortic stenosis characterized by a reduced aortic valve area with low transvalvular gradients despite preserved left ventricular ejection fraction and reduced forward flow. It is associated with concentric remodeling, impaired longitudinal systolic function, and diastolic dysfunction, resulting in reduced stroke volume and potential underestimation of disease severity. This state-of-the-art review synthesizes evidence from registries, observational studies, randomized trial subgroup analyses, guideline recommendations, and mechanistic investigations. Diagnosis requires an integrative multimodality approach combining Doppler echocardiography, low-dose dobutamine stress echocardiography, and computed tomography-based aortic valve calcium scoring to differentiate true-severe from pseudo-severe disease. In symptomatic patients with confirmed severe pLF-LG AS, aortic valve replacement is associated with improved survival, although the magnitude of clinical benefit remains variable. Transcatheter aortic valve implantation represents an effective treatment option in selected patients; however, phenotype-specific comparative data versus surgical valve replacement remain limited. Overall, pLF-LG AS requires accurate diagnostic confirmation and individualized, Heart Team-guided management to optimize clinical outcomes.