Evolving therapeutic approaches to aortic stenosis, tricuspid regurgitation, hypertrophic cardiomyopathy, and acute heart failure

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on valvular heart disease, heart failure, and cardiomyopathies contains the Fast Track Congress manuscript ‘Cardiac biomarkers and effects of aficamten in obstructive hypertrophic cardiomyopathy: the SEQUOIA-HCM trial’ by Caroline Coats from the University of Glasgow, and colleagues.1 The authors note that in spite of the clinical relevance of obstructive hypertrophic cardiomyopathy (HCM),2–8 the role of biomarker testing in its management is not well defined. This pre-specified analysis of SEQUOIA-HCM (NCT05186818) sought to define the associations between clinical characteristics and baseline concentrations of N-terminal probrain natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (hs-cTnI), and to evaluate the effect of treatment with aficamten on biomarker concentrations. Cardiac biomarkers were measured at baseline and serially throughout the study. Regression analyses determined predictors of baseline NT-proBNP and hs-cTnI concentrations and evaluated whether early changes in these biomarkers relate to later changes in left ventricular outflow tract gradient (LVOT-G), other echocardiographic measures, health status, and functional capacity. Baseline concentration of NT-proBNP was associated with LVOT-G and measures of diastolic function, while hs-cTnI was associated with left ventricular thickness. Within 8 weeks of treatment with aficamten, NT-proBNP was reduced by 79% (P < .001) and hs-cTnI by 41% (P < .001); both biomarkers reverted to baseline after washout. Reductions in NT-proBNP and hs-cTnI by 24 weeks were strongly associated with a lowering of LVOT-G, improvement in health status, and increased peak oxygen uptake. The authors note that NT-proBNP and hs-cTnI concentrations are associated with key variables in obstructive HCM. Serial measurement of NT-proBNP and hs-cTnI appears to reflect clinical response to aficamten therapy. The contribution is accompanied by an Editorial by Evangelos Giannitsis, Norbert Frey, and Hugo A. Katus from the University Hospital Heidelberg in Germany.9 The authors conclude that this important contribution indicates the power of the cardio-specific biomarkers NT-proBNP and hs-cTnI to monitor myosin inhibitor treatment in obstructive HCM and reveals that these two biomarkers provide distinct but complementary information on structural and functional changes of the diseased heart and exercise capacity in patients with obstructive cardiomyopathy. The treatment of acute heart failure (AHF) is challenging.10–15 The efficacy and safety of early sacubitril/valsartan (Sac/Val) initiation after AHF has not been demonstrated outside North America. In a Fast Track Congress article entitled ‘In-hospital initiation of angiotensin receptor–neprilysin inhibition in acute heart failure: the PREMIER trial’, Atsushi Tanaka from the Saga University in Japan, and colleagues aimed to evaluate the effect of in-hospital Sac/Val therapy initiation after an AHF episode on NT-proBNP level in Japanese patients.16 This was an investigator-initiated, multicentre, prospective, randomized, open-label, blinded-endpoint pragmatic trial. After haemodynamic stabilization within 7 days after hospitalization, eligible inpatients were allocated to switch from an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker to Sac/Val (Sac/Val group) or to continue angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (control group). The primary efficacy endpoint was the 8-week proportional change in geometric means of NT-proBNP levels. A total of 400 patients were equally randomized, and 376 (median age 75 years, 32% women, de novo heart failure rate 56%, and median left ventricular ejection fraction 37%) were analysed. The per cent changes in NT-proBNP level geometric means at Weeks 4/8 were −35%/−45% (Sac/Val group) and −18%/−32% (control group), and their group ratio (Sac/Val vs. control) was 0.80 (P = .008) at Week 4 and 0.81 (P = .012) at Week 8, respectively. In the pre-specified subgroup analyses, the effects of Sac/Val were confined to patients with a left ventricular ejection fraction <40% and were more evident in those in sinus rhythm and taking mineralocorticoid receptor antagonists. No adverse safety signal was evident. Tanaka and colleagues conclude that in-hospital Sac/Val therapy initiation in addition to contemporary recommended therapy triggered a greater NT-proBNP level reduction in Japanese patients hospitalized for AHF. These findings may expand the evidence on Sac/Val therapy in this clinical situation outside North America. The contribution is accompanied by an Editorial by Ankeet S. Bhatt from the Kaiser Permanente San Francisco Medical Center and Division of Research in San Francisco, CA, USA and Muthiah Vaduganathan from the Brigham and Women’s Hospital and Harvard Medical School in Boston, MA, USA.17 The authors note that all in all, we are no longer in an era where the treatment for worsening HF is limited to decongestion with conventional diuretic strategies alone; several components of chronic HF treatments can be safely implemented during or early after worsening HF. This benefit is punctuated by the findings from STRONG-HF, reporting that early intensive implementation of medical therapy during and immediately following worsening HF led to improvements in clinical outcomes within 180 days. However, pervasive implementation gaps remain, and discovery science in HF is rapidly evolving. Novel implementation studies are needed that prioritize in-hospital initiation during acute worsening episodes of care and prospectively evaluate medication adherence, quality of life, and clinical outcomes. Such programmes may utilize the unique access to multidisciplinary care teams that hospitalization provides, including empowering pharmacists and other providers to more actively nudge high-quality care. Doing so will ensure we can provide PREMIER care for our patients experiencing worsening HF. In the canonical pathway of intravenous iron metabolism, ferric carboxymaltose (FCM) is taken up by reticuloendothelial macrophages of the spleen and liver. Here, FCM is metabolized and iron liberated for export into the circulation by the iron exporter ferroportin (FPN). Upon export, this iron is loaded onto its plasma chaperone transferrin (Tf). This transferrin-bound iron is then consumed, primarily by the bone marrow for the production of red blood cells (RBCs). Once senescent, RBCs are subjected to breakdown by spleen reticuloendothelial macrophages, allowing this iron to be recycled. Iron may also be stored in hepatocytes, to be mobilized at times of increased iron demand. The heart acquires iron from FCM through a non-canonical pathway that is independent of reticuloendothelial macrophages. This is because FCM releases some of its iron directly into the circulation, resulting in the appearance of non-transferrin-bound iron (NTBI). Owing to abundant expression of the NTBI transporters, L-type and T-type calcium channels (L/TTCC) and divalent metal transporter 1 (DMT1), cardiac myocytes rapidly take up FCM-derived NTBI from the circulation. The iron that enters the cardiac myocytes in this manner joins the intracellular labile iron pool (LIP), which is the pool of reactive iron responsible for generating oxidative stress21 Intravenous iron therapies are playing a growing role in cardiovascular diseases.18–20 They contain iron–carbohydrate complexes, designed to ensure that iron becomes bioavailable via the intermediary of spleen and liver reticuloendothelial macrophages. How other tissues obtain and handle this iron remains unknown. In a Fast Track Clinical Research article entitled ‘Intravenous iron therapy results in rapid and sustained rise in myocardial iron content through a novel pathway’, Mayra Vera-Aviles from the University of Oxford in the UK, and colleagues address this question in the context of the heart.21 A prospective observational study was conducted in 12 patients receiving ferric carboxymaltose (FCM) for iron deficiency. Myocardial, spleen, and liver magnetic resonance relaxation times and plasma iron markers were collected longitudinally. To examine the handling of iron taken up by the myocardium, the intracellular labile iron pool (LIP) was imaged in FCM-treated mice and cells. In patients, myocardial relaxation time T1 dropped maximally 3 h post-FCM, remaining low 42 days later, while splenic T1 dropped maximally at 14 days, recovering by 42 days. In plasma, non-transferrin-bound iron (NTBI) peaked at 3 h, while ferritin peaked at 14 days. Changes in liver T1 diverged among patients. In mice, the myocardial LIP rose by 1 h and remained elevated 42 days after FCM. In cardiomyocytes, FCM exposure raised the LIP rapidly. This was prevented by inhibitors of the NTBI transporters T-type and L-type calcium channels and divalent metal transporter 1 (Figure 1). The authors conclude that intravenous iron therapy with FCM delivers iron to the myocardium rapidly through NTBI transporters, independently of reticuloendothelial macrophages. This iron remains labile for weeks, reflecting the myocardium’s limited iron storage capacity. These findings challenge current notions of how the heart obtains iron from these therapies and highlight the potential for long-term dosing to cause cumulative iron build-up in the heart. The contribution is accompanied by an Editorial by Stephan von Haehling and Ryosuke Sato from the Georg-August University in Goettingen, Germany and Stefan Anker from the Charité–University Medical Center Berlin in Germany.22 The authors note that some additional questions await answers. Are we able to reduce the amount of non-transferrin-bound iron following intravenous iron administration, and would we still see the clinical benefit? Do different iron preparations result in varying amounts of NTBI in the circulation? Do different iron preparations therefore accumulate different amounts of iron inside the myocardium? Finally, does this have any clinical consequences that require additional diagnostic steps such as follow-up magnetic resonance imaging? Until we have answers to these questions, we should exercise the best possible practice and treat iron deficiency effectively. Severe tricuspid regurgitation (TR) is associated with increased mortality rates, but the benefit of its correction and ideal timing are not clearly determined. In a Fast Track Congress article entitled ‘Benefit of isolated surgical valve repair or replacement for functional tricuspid regurgitation and long-term outcomes stratified by the TRI-SCORE’, Julien Dreyfus from the Centre Cardiologique du Nord in Saint-Denis, France, and colleagues aimed to identify patient subsets who might benefit from the surgery.23 In TRIGISTRY, an international cohort study of consecutive patients with severe isolated functional TR (33 centres, 10 countries), survival rates up to 10 years were compared between patients who underwent isolated tricuspid valve surgery (repair or replacement) and those conservatively managed, overall and according to TRI-SCORE category (low, ≤ 3; intermediate, 4–5; and high, ≥ 6). A total of 1217 patients were managed conservatively, and 551 underwent isolated tricuspid valve surgery (200 repairs and 351 replacements). TRI-SCORE distribution was 33% low, 32% intermediate, and 35% high. At 10 years, survival rates were similar between surgical and conservative management (41% vs. 36%; hazard ratio [HR] 0.97; P = .57). Surgery improved survival compared with conservative management in the low TRI-SCORE category (72% vs. 44%; HR 0.27; P < .0001), but not in the intermediate (36% vs. 37%; HR 1.17; P = .09) or high categories (20% vs. 24%; HR 1.06; P = .45). Both repair and replacement improved survival in the low TRI-SCORE category (84% and 61% vs. 44%; HR 0.11; P < .0001, and HR 0.65; P = .009). Repair showed benefit in the intermediate category (59% vs. 37%; HR 0.49; P < .0001) while replacement was possibly harmful (25% vs. 37%; HR 1.43; P = .0002). The authors conclude that higher survival rates were observed with repair than replacement, and benefit of intervention declined as TRI-SCORE increased, with no benefit of any type of surgery in the high TRI-SCORE category. These results emphasize the importance of timely intervention and patient selection to achieve the best outcomes and the need for randomized controlled trials. This manuscript is accompanied by an Editorial by Nikolaos Bonaros, Can Gollmann-Tepeköylü, and Michael Grimm from the University of Innsbruck, Austria.24 The authors highlight that we have three important messages to consider for the treatment of tricuspid valve disease: first, never forget the fact that severe TR is not a benign disease, even if the patient is oligosymptomatic; second, tricuspid surgery itself is not high risk if the right patients are operated on at the right time; and third, if the disease is too advanced, conservative treatment might be the best option for the patients. Cumulative incidence of all-cause death (upper panel) and heart failure hospitalization (lower panel) (intention-to-treat population)25 The question of when and how to treat truly asymptomatic patients with severe aortic stenosis (AS) and normal left ventricular systolic function is still subject to debate and ongoing research. In a Fast Track Congress article entitled ‘Aortic valve replacement vs. conservative treatment in asymptomatic severe aortic stenosis: long-term follow-up of the AVATAR trial’, Marko Banovic from the University of Belgrade in Serbia, and colleagues report the results of extended follow-up of the AVATAR trial.25 The AVATAR trial randomly assigned patients with severe, asymptomatic AS and left ventricular ejection fraction ≥50% to undergo either early surgical aortic valve replacement (AVR) or conservative treatment with a watchful waiting strategy. All patients had negative exercise stress testing. The primary hypothesis was that early AVR will reduce a primary composite endpoint comprising all-cause death, acute myocardial infarction, stroke, or unplanned hospitalization for heart failure, as compared with a conservative treatment strategy. A total of 157 low-risk patients (mean age 67 years, 57% men, mean Society of Thoracic Surgeons score 1.7%) were randomly allocated to either the early AVR group (n = 78) or the conservative treatment group (n = 79). In an intention-to-treat analysis, after a median follow-up of 63 months, the primary composite endpoint outcome event occurred in 18/78 patients (23%) in the early surgery group and in 37/79 patients (47%) in the conservative treatment group (HR early surgery vs. conservative treatment 0.42; P = .002). The Kaplan–Meier estimates for individual endpoints of all-cause death and heart failure hospitalization were significantly lower in the early surgery compared with the conservative group (HR 0.44; P = .012, for all-cause death and HR 0.21; P = .007, for heart failure hospitalizations) (Figure 2). The authors conclude that the extended follow-up of the AVATAR trial demonstrates better clinical outcomes with early surgical AVR in truly asymptomatic patients with severe AS and normal left ventricular ejection fraction compared with patients treated with conservative management on watchful waiting. The contribution is accompanied by an Editorial by Andreas Martinsson and Anders Jeppsson from the Sahlgrenska University Hospital in Gothenburg, Sweden.26 Martinsson and Jeppsson note that the triallists of the AVATAR trial should be commended for their work and for having managed to finalize their trial in such a challenging context. The trial expands our knowledge and has provided important insights for patients with asymptomatic severe aortic stenosis. Fortunately, we can anticipate further insights from ongoing trials, as several studies are currently enrolling patients. These future reports may help establish the optimal treatment strategy for this complicated patient cohort, potentially offering a more nuanced classification beyond the current dichotomy of asymptomatic and symptomatic patients. In a Viewpoint article entitled ‘Heart failure with preserved ejection fraction: underdiagnosed and undertreated in patients with tricuspid regurgitation’ Khawaja M. Talha from the University of Mississippi Medical Center in Jackson, MS, USA and colleagues remind us that while the clinical trials in patients with TR using novel percutaneous techniques have been encouraging, these trials did not systematically evaluate heart failure with preserved ejection fraction (HFpEF) at baseline.27 This has significant consequences: (i) we do not know what proportion of patients in the clinical trials had an important comorbidity; (ii) we do not know if effective diagnosis and treatment of HFpEF could reduce the need for TR intervention; (iii) if HFpEF is treated effectively prior to transcatheter TR intervention, would it improve the outcomes of the interventions considering the potential of less haemodynamic challenge to the valvular procedure? ; (iv) for patients intolerant to medical therapy, can transcatheter TR interventions help enable more effective medical HF treatment? ; (v) can transcatheter TR interventions prevent the development of clinical HFpEF? ; and (vi) can transcatheter TR interventions improve HFpEF outcomes? Mitigating these concerns can potentially have a major impact on patient-centred outcomes and procedural success, but have not been addressed in clinical trials evaluating TR interventions. The authors urge that, as best as possible, there should be a retrospective assessment of HFpEF in existing data from trials in patients with TR based on baseline history, examination, natriuretic peptide levels, and haemodynamic data from right heart catheterization. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘Is intravascular ultrasound needed to optimize drug-coated balloon angioplasty results?’, Fernando Alfonso from the Universidad Autónoma de Madrid in Spain and Bernardo Cortese from the Fondazione Ricerca e Innovazione Cardiovascolare in Milan, Italy comment on the recent publication ‘Intravascular ultrasound-guided drug-coated balloon angioplasty for femoropopliteal artery disease: a clinical trial’ by Young-Guk Ko from the Yonsei University College of Medicine in Seoul, Korea.28,29 Ko et al. respond in a separate comment.30 The editors hope that this issue of the European Heart Journal will be of interest to its readers. Dr. Crea reports speaker fees from Abbott, Amgen, Astra Zeneca, BMS, Chiesi, Daiichi Sankyo, Menarini outside the submitted work. With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.