Emerging technologies for septal reduction therapy in hypertrophic cardiomyopathy

To the Editor: Hypertrophic cardiomyopathy (HCM), a genetic disorder characterized by asymmetric left ventricular hypertrophy, has an estimated prevalence of 0.5% in the general population. In patients with left ventricular outflow tract (LVOT) obstruction, the primary pathophysiological mechanism involves basal septal hypertrophy and systolic anterior motion (SAM) of the anterior mitral leaflet. Current invasive septal reduction therapies (SRT), including surgical septal myectomy (SSM) and alcohol septal ablation (ASA), aim to alleviate LVOT obstruction. Although SSM and ASA remain cornerstone treatments, emerging minimally invasive and image-guided techniques may reshape therapeutic paradigms. This article provides an overview of recent advances in the field, with a particular focus on innovations in interventional therapy. Pathophysiological characteristics and treatment of HCM: HCM is pathophysiologically characterized by several key features, including LVOT obstruction, mitral regurgitation, diastolic dysfunction, myocardial ischemia, arrhythmias, and autonomic dysfunction. Current pharmacological treatment includes mainly β-blockers and non-dihydropyridine calcium channel blockers (CCBs) for symptomatic relief. However, there is currently no conclusive evidence that these agents can modify disease progression. SRT has been identified as a treatment option for obstructive patients with HCM who are refractory to pharmacotherapy with a resting or provoked LVOT gradient (LVOTG) ≥50 mmHg and suitable septal anatomy. Its efficacy has been demonstrated in the relief of symptoms, the enhancement of quality of life, and the improvement of long-term outcomes. Mavacamten, a first-in-class cardiac myosin inhibitor, has demonstrated its clinical efficacy in randomized controlled trials. Recent clinical studies indicate that mavacamten alleviates symptom burden and reduces the dependency for SRT in HCM patients. The legacy and limitations of traditional SRT: SSM is widely regarded as the gold standard of treatment for SRT, with studies demonstrating that it provides sustained hemodynamic improvement. Nevertheless, the procedure is associated with significant risks, including bleeding, stroke, and prolonged recovery due to its dependence on median sternotomy and cardiopulmonary bypass, particularly in elderly patients or those with frailty. ASA, initially introduced in 1995, achieves controlled septal infarction through targeted ethanol infusion into the septal perforator artery.[1] Although demonstrating reduced invasiveness, ASA carries a higher risk of complete heart block, often requiring permanent pacemaker implantation. A meta-analysis encompassing 15,968 patients has demonstrated comparable 5-year survival rates between the two modalities; notably, ASA shows a higher reintervention rate and interindividual efficacy variation attributable to coronary anatomical heterogeneity. A comparative study was conducted to assess the effectiveness of ASA and SSM in reducing LVOTG and alleviating symptoms. The study found that both treatments were equally effective in this regard; however, SSM was found to be more efficacious in achieving hemodynamic improvement of pressure gradients.[2] Mechanisms and clinical evidence of emerging interventional techniques: Percutaneous endocardial radiofrequency ablation (PESA) is a procedure performed using radiofrequency energy that is delivered transcatheterally with the intention of ablating septal myocardium under the guidance of 3D electroanatomic mapping systems. This technique incorporates real-time intracardiac echocardiography to precisely guide catheter navigation and mitigate the risk of conduction system injury. As a minimally invasive intervention, PESA significantly reduces LVOTG, positioning it as an alternative for patients ineligible for SSM or ASA. Current studies confirm procedural efficacy; nevertheless, the limited sample sizes reported higher complication rates. Acute post-ablation septal edema may transiently exacerbate LVOT obstruction. A consensus-based procedural standardization for this intervention has yet to be established. Percutaneous intramyocardial septal radiofrequency ablation (PIMSRA), a procedure pioneered by Liu et al,[3] involves the insertion of a transapical radiofrequency needle under real-time echocardiography to directly ablate hypertrophic myocardium. By circumventing the conductive bundle, this technique reduces collateral damage, with a permanent pacemaker implantation rate significantly lower than ASA. PIMSRA has also been studied in conjunction with transcatheter aortic valve replacement in patients with concomitant aortic stenosis and demonstrating procedural feasibility. Post-procedural outcomes include sustained LVOTG reduction, decreased septal thickness, and improved symptoms. A 5-year follow-up study of 27 patients revealed that surgical intervention led to the alleviation of long-term symptoms without any adverse effects on left ventricular systolic function or an increased incidence of ventricular arrhythmias. This finding indicates that the long-term safety of PIMSRA is maintained postoperatively. Stereotactic body radiotherapy (SBRT) delivers high doses of radiation to the septum using image-guided linear accelerators. Early-phase studies report improved exercise tolerance and New York Heart Association (NYHA) classification despite a modest reduction in LVOTG (baseline: 88 mmHg vs. 52 mmHg post-SBRT). Despite the absence of acute complications, SBRT is reserved for inoperable patients due to concerns about delayed radiation-induced fibrosis and arrhythmogenicity, necessitating long-term surveillance. More research evidence is needed to confirm its long-term efficacy and safety. Transcoronary radiofrequency ablation (TCRFA) is a procedure that uses a guidewire-mounted radiofrequency electrode to ablate septal branches via coronary access. Preclinical canine studies demonstrated a >50% reduction in LVOTG, without arrhythmic complications. Preliminary human trials show comparable efficacy, yet procedural standardization remains elusive. TCRFA's adjustable energy delivery may bridge gaps between ASA and SSM, pending larger trials. Septal scoring along the midline endocardium (SESAME) mimics surgical myotomy through an electrosurgical technique, facilitating transcatheter valve implantation. SESAME has the potential to benefit patients who require SRT for obstructive HCM, as well as those with LVOT obstruction following heart valve replacement. Furthermore, it can help facilitate transcatheter valve implantation. Transapical beating-heart septal myectomy (TA-BSM), an off-pump approach, reduces LVOTG from 86 mmHg to 19 mmHg under real-time echocardiography but demands advanced surgical proficiency. This technique can be performed without the need for cardiopulmonary bypass or thoracotomy and is performed on a beating heart. This facilitates real-time evaluation of LVOT hemodynamics using echocardiography, which helps to minimize complications associated with cardiopulmonary bypass. Although TA-BSM is a more minimally invasive procedure than traditional surgical methods, the complexity of the operation and the technical expertise required of the operator are significantly higher than those of other interventions. Consequently, the procedure is best performed by a highly experienced cardiac surgical team. Validation phase technology: Pulsed field ablation (PFA) induces cardiomyocyte apoptosis through microsecond electric pulses while sparing the extracellular matrix and conduction tissues. Several methods have been employed in the study of endocardial PFA. One method used two identical solid-tip ablation catheters as positive and negative electrodes, respectively, positioned on either side of the septum.[4] An alternative approach involves securing the PFA catheter within the septal myocardium via rotational insertion, analogous to the technique employed for actively fixed pacing leads, followed by ablation. The challenges include the optimization of electrode configurations for anatomical variability and the mitigation of off-target effects, such as right bundle branch block. High-intensity focused ultrasound (HIFU) achieves noninvasive ablation of septal myocardium through extracorporeal ultrasound focusing. Initial canine studies achieved targeted necrosis but cardiac motion and blood flow attenuated energy delivery. Clinical translation requires strategies to modulate coronary flow during ablation. Transvenous intramyocardial cerclage radiofrequency ablation signifies a pioneering approach entailing the advancement of a specialized intraseptal radiofrequency ablation catheter through the coronary sinus and a septal vein into the ventricular septum. To achieve this, higher electrode temperatures and an irrigated ablation mode are used, resulting in the creation of a more substantial ablation volume within the septum. The results from ex vivo and in vivo porcine heart experiments demonstrated a reduction in septal thickness after ablation without significant atrioventricular conduction block. Other interventional treatments: Other interventional techniques, such as pacing therapy or the implantation of MitraClip™ (Abbott Laboratories, Abbott Park, IL, USA), a catheter-based percutaneous edge-to-edge repair technique to correct mitral regurgitation, are primarily used as strategies to address the various pathophysiological changes associated with HCM. Pacing therapy was introduced before PESA and has been used in the treatment of HCM. For elderly patients with high risk or patients with mild symptoms, sequential pacing is suitable. Conduction system pacing, including His bundle or left bundle branch pacing, has also been attempted in patients with HCM. Currently, the utilization of dual-chamber pacemakers (right atrium–right ventricle sequential pacing) in the management of obstructive HCM is less common, and its long-term efficacy remains uncertain. It is only considered for patients at high risk of developing cardiac conduction block after SSM or ASA. Furthermore, risk stratification and the use of implantable cardioverter-defibrillator can prevent sudden death in patients diagnosed with HCM. Cardiac resynchronization therapy is a safe and effective treatment option for patients with HCM and heart failure. Furthermore, MitraClip has been used to address SAM in patients with HCM, relieving LVOT obstruction and the enhancement of cardiac function. This technique is particularly appropriate for HCM patients with SAM, concomitant mitral valve disease, or severe mitral regurgitation, including cases of severe mitral regurgitation caused by ASA. Transcatheter mitral valve repair is principally intended to address mitral valve disease, with the relief of obstruction representing a secondary indication. Discussion and conclusion: Contemporary evidence substantiates that SRT, encompassing SSM and ASA, demonstrates significant survival benefits for patients with symptomatic obstructive HCM during extended follow-up. Although novel techniques, such as PESA and PIMSRA, have been shown to exhibit superior short-term efficacy profiles, their long-term clinical utility remains to be validated through multicenter randomized controlled trials assessing 5-year outcomes, including sudden cardiac death risk and progression to end-stage HCM. It is important to note that a lack of standardized procedural protocols is a feature of percutaneous ablation techniques, including PESA and TCRFA. The efficacy of the procedure is contingent upon the morphology of the septum and the expertise of the operator. Furthermore, there is an absence of systematic preventive strategies that have been formulated to mitigate complications in these interventions. Modalities in the preclinical stage, including PFA and HIFU, have demonstrated compelling proof-of-concept in animal models. However, human feasibility studies remain pending. The usage of advanced imaging techniques, such as cardiac MRI and strain echocardiography, has the potential to refine the selection of patients for intervention. In circumstances where midventricular obstruction is present, PIMSRA may emerge as a favored option. Conversely, in cases of apical hypertrophy, the implementation of hybrid therapeutic strategies may be more conducive to achieving optimal outcomes. The integration of SRT with conduction system pacing (e.g., conduction system pacing) or transcatheter mitral valve repair (e.g., MitraClip) has the potential to address the multifactorial HCM pathophysiology. The therapeutic landscape of SRT is undergoing a paradigm shift driven by three key factors: (1) technological innovation in catheter-based platforms, (2) growing clinical emphasis on minimally invasive approaches, and (3) emerging translational research bridging basic science and clinical application. From a mechanistic perspective, multimodal strategies combining pharmacological therapies, implantable devices, and precision-guided interventions are redefining therapeutic paradigms in the management of HCM. Accelerating clinical translation requires collaborative multicenter research, competency-based training protocols, and rigorously designed patient-centered trials to ensure the safe implementation of these innovations. Acknowledgements The authors thank LetPub (www.letpub.com) for its linguistic assistance during the preparation of this manuscript. Funding This work was supported by the Zhejiang Medical Association Clinical Medical Research Funds (No. 2024ZYC-Z14), Hangzhou Medicine and Health Science and Technology Funds (No. ZD20250246). Conflicts of interest None.