Hot topics in valvular heart disease and dyslipedaemias

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This Focus Issue on valvular heart disease and dyslipidaemias starts with an ESC Guidelines entitled ‘2025 ESC/EACTS Guidelines for the management of valvular heart disease’ by Fabien Praz from the University of Bern, Switzerland, and colleagues.1 New evidence has accumulated since the publication of the 2021 Guidelines for the management of valvular heart disease, leading to the need for new recommendations and revision of existing recommendations mainly concerning the following topics: (i) the importance of shared and patient-centred decision-making by multidisciplinary expert Heart Teams working within a regional network; (ii) advanced imaging modalities—such as three-dimensional echocardiography, cardiac computed tomography, and cardiac magnetic resonance imaging; (iii) importance of correctly assessing the cause(s) and mechanism(s) of all valve diseases; (iv) the benefits of intervention for the treatment of severe aortic stenosis (AS) irrespective of symptoms, left ventricular ejection fraction, and flow reserve; (v) the criteria used for decision-making concerning the optimal modality of AS treatment; (vi) the indications for transcatheter aortic valve implantation in patients with bicuspid AS or severe aortic regurgitation at high surgical risk, based on anatomical suitability and a comprehensive Heart Team evaluation; (vii) guidance regarding the diagnostic steps and management of patients with multiple and mixed valvular heart disease; (viii) definitions of structural valve deterioration; (ix) the use of direct oral anticoagulants in patients with valvular heart disease; and (x) sex-specific issues in patients with valvular heart disease. Cardiovascular disease remains a major global health challenge, with dyslipidaemia being a key modifiable risk factor. While LDL cholesterol (LDL-C) is the primary target for lipid-lowering therapies, recent evidence highlights the importance of triglycerides, apolipoprotein B (apoB), and lipoprotein(a) [Lp(a)] for residual cardiovascular risk.2–11 In a State of the Art Review article entitled ‘The evolving landscape of targets for lipid lowering: from molecular mechanisms to translational implications’, Christie Ballantyne from Baylor College of Medicine in Houston, TX, USA, and colleagues aim to discuss current and novel targets/strategies for lipid lowering from a pharmacological and clinical perspective, focusing on the mechanism of action and expected benefits.12 Current lipid-lowering therapies target key enzymes and proteins involved in cholesterol and lipid metabolism. Statins inhibit HMG-CoA reductase, reducing cholesterol biosynthesis and increasing LDL receptor (LDLR) expression in the liver. Bempedoic acid inhibits ATP citrate lyase, the enzyme upstream of HMG-CoA reductase in the mevalonate pathway, offering an alternative to statins by selectively acting in the liver, minimizing muscle-related side effects. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (evolocumab, alirocumab, inclisiran, lerodalcibep, and enlicitide decanoate) prevent LDLR degradation, while ezetimibe limits intestinal cholesterol absorption. Emerging lipid-lowering targets include angiopoietin-like 3 protein (ANGPTL3) and apolipoprotein C-III (apoC-III). Inhibiting ANGPTL3 reduces both triglycerides and LDL-C independently of the LDLR. Inhibition of apoC-III unleashes lipoprotein lipase activity, promoting triglyceride-rich particle catabolism. Cholesteryl ester transfer protein inhibition increases the catabolism of apoB-containing lipoproteins. Ongoing research into strategies to reduce Lp(a), primarily but not exclusively through antisense therapies, aims to demonstrate the cardiovascular benefits of targeting this lipoprotein. In summary, the field of targets for lipid and lipoprotein lowering is constantly evolving and offers new strategies for patients resistant to current therapies or with specific lipid profile abnormalities. Atherosclerotic vascular disease remains a leading cause of morbidity and mortality, yet effective risk factor management offers the potential to significantly alter its trajectory and prevent cardiovascular (CV) events. Among modifiable risk factors, LDL-C has a pivotal role, with a well-established causal link to CV events. In a Great Debate article entitled ‘Great debate: fire-and-forget beats personalized lipid-lowering treatment’, Lale Tokgozoglu from Hacettepe University in Turkey, and colleagues discuss two opposing strategies that have been proposed for LDL-C lowering: the ‘fire-and-forget’ approach vs personalized prevention.13 The ‘fire-and-forget’ approach in LDL lowering refers to a treatment strategy where lipid lowering therapy is prescribed and the patient is expected to take it consistently with minimal need for ongoing adjustments based on regular lipid panel tests, with the aim to simplify management. The ‘fire-and-forget’ approach in LDL lowering was first recommended in the 2013 ACC/AHA guidelines on cholesterol treatment followed by the the NICE (National Institute for Health and Care Excellence) guidelines. This strategy is practical but has the shortcomings of lack of follow-up and not progressing to more aggressive therapies if not at goal. On the other hand, the European Guidelines advocate for a risk-based approach, utilizing SCORE2 to predict individual risk and establish treatment goals tailored to the total CV risk level. This approach allows for the customization of prevention strategies based on individual risk factors and responses to optimize management, leading to more targeted and effective interventions. Monitoring goal achievement can aid patient–physician communication and stimulate patients and physicians to attain guideline-recommended goals. Both approaches have been implemented in clinical settings, suggesting that there is no single, universally effective solution. In this Great Debate, top experts in the field discuss the Pro and Contra of the ‘fire-and-forget’ approach. Structured Graphical Abstract.14 Higher levels of Lp(a) drive increasing risk of atherosclerotic cardiovascular disease (ASCVD) in otherwise healthy individuals regardless of sex and race/ethnicity. In a Fast Track Congress article entitled ‘Lipoprotein(a) and recurrent atherosclerotic cardiovascular events: the US Family Heart Database’, Diane MacDougall from the Family Heart Foundation in Fernandina Beach, FL, USA, and colleagues aim to evaluate whether this is also true for recurrent ASCVD, and whether LDL-C-lowering therapy possibly mitigates such a relationship.14 In US medical claims between 2012 and 2022 for 340 million individuals, 273 770 had diagnosed ASCVD and Lp(a) measured in nmol/L. Lp(a) levels were higher in women vs men and in Black vs Hispanic and White individuals. During a median follow-up of 5.4 years, 15% of individuals experienced recurrent ASCVD. Increasing Lp(a) levels were associated with continuously increasing risk of recurrent ASCVD. Compared with individuals with Lp(a) <15 nmol/L, the adjusted hazard ratios (HRs) for recurrent ASCVD events were 1.04 for 15–79 nmol/L, 1.15 for 80–179 nmol/L, 1.29 for 180–299 nmol/L, and 1.45 for ≥300 nmol/L. Results were similar for individual ASCVD components, and in sex, race/ethnicity, baseline ASCVD, and diabetes subgroups; however, a high impact LDL-C-lowering therapy possibly mitigated the deleterious effect of Lp(a) ≥180 nmol/L, most pronounced in those on PCSK9 inhibitors (Figure 1). The authors conclude that in individuals with ASCVD, increasing Lp(a) levels are associated with continuously increasing risk of recurrent ASCVD events regardless of sex and race/ethnicity that may be partially mitigated by high impact LDL-C-lowering therapy. The manuscript is accompanied by an Editorial by Michelle O’Donoghue and Victorien Monguillon from Brigham and Women's Hospital in Boston, MA, USA.15 The authors highlight that the current study leverages a robust dataset to further expand our knowledge toward understanding the relationship between Lp(a) and CV risk across a large and diverse US population with established ASCVD. Although the measurement of Lp(a) is endorsed by several consensus groups, it remains infrequently measured in clinical practice. In part, this stems from uncertainty regarding optimal management of those patients who are found to have an elevated Lp(a) concentration. However, the results of clinical trials for novel therapeutics that markedly lower Lp(a) are on the near horizon, and therefore dedicated therapies may soon exist. In the interim, it remains critical to optimize risk factor management for those patients who are determined to have elevated Lp(a), as it is a valuable marker of risk and helps identify those with more active underlying atherogenesis who may otherwise be under-recognized because traditional risk factors may be absent. Until dedicated therapies become available, such patients will almost invariably benefit from more optimized traditional risk factor management that includes more intensive cholesterol management. There also remains interest in whether Lp(a) may additionally be useful for helping guide particular treatment strategies, such as the use of aspirin in primary prevention. Although there are still unanswered questions regarding the optimal management of persons with elevated Lp(a), this uncertainty should ultimately not contribute to the unwillingness of providers to routinely measure Lp(a) in clinical practice to help identify those who are at increased CV risk. Association of lipoprotein(a) levels with risk of Alzheimer's disease and vascular-related dementia in individuals from the Copenhagen General Population Study, the Copenhagen City Heart Study, and the UK Biobank.16 Dementia is a leading cause of death and disability that shares risk factors with ASCVD. High Lp(a) is a causal risk factor for ASCVD, while results for dementia are conflicting. In a Fast Track Congress article entitled ‘Lipoprotein(a) and risk of dementia: findings from three cohort studies’, Peter Thomas from Copenhagen University Hospital-Herlev and Gentofte in Denmark, and colleagues test the hypothesis that Lp(a) levels and/or isoform size are associated with the risk of Alzheimer's disease and vascular-related dementia.16 Lp(a) measurements were available in ∼540 000 individuals from the Copenhagen General Population Study, the Copenhagen City Heart Study, and the UK Biobank. Individuals were followed for up to 30 years, during which 6404 developed Alzheimer's disease and 7866 vascular-related dementia. The numbers of LPA kringle IV type 2 (KIV-2) repeats, which determines Lp(a) isoform size and correlates inversely with Lp(a) levels, were available in 117 029 individuals from the Copenhagen studies. Statistical analyses accounted for competing risk of death, important for studies of dementia occurring late in life. On continuous scales, Lp(a) levels were not associated with the risk of Alzheimer's disease or vascular-related dementia. When accounting for competing risk of death, absolute risks of vascular-related dementia increased with higher Lp(a) levels in the UK Biobank (P = .01), but not in the Copenhagen studies (P = .42). In the Copenhagen studies, the numbers of LPA KIV-2 repeats ≤5th vs > 50th percentiles were associated with a subdistribution HR for Alzheimer's disease of 1.25 (Figure 2). The authors conclude that low Lp(a) levels are not associated with the risk of Alzheimer's disease or vascular-related dementia. It cannot be excluded that very high Lp(a) levels or small isoform size increase the risk of dementia. The manuscript is accompanied by an Editorial by Florian Kronenberg from the Medical University of Innsbruck in Austria.17 The author notes that this landmark study provides the most compelling evidence to date for the link between Lp(a) and dementia. It shows that while low Lp(a) concentrations are not a risk factor for dementia, very high Lp(a) concentrations and certain genetic apo(a) isoforms can increase the risk, particularly for Alzheimer's disease. The rigorous methodology, large scale, and inclusion of genetic data set new standards for research in this field and provide important insights for clinical practice and future studies. In order to live in the here and now, the question arises of what can we do right now to minimize the risk of dementia. One of the authors of the new study mentioned in an earlier review ‘it is safe to say that what is good for the heart is good for the brain’. The Lancet Standing Commission clearly elaborated that many factors are involved in the development of dementia. Those are less education, hearing loss, hypertension, smoking, obesity, depression, physical inactivity, diabetes, excessive alcohol consumption, traumatic brain injury, air pollution, social isolation, untreated vision loss, and high LDL-C. Many of them are modifiable, but we do not act on them sufficiently even though we could kill two birds with one stone by acting for the heart and the brain with the same efforts. This might trigger an avalanche in the future considering the increasing age of our populations. There is increasing interest in transthyretin-associated cardiac amyloidosis (ATTR-CA).18–21 Concomitant AS and ATTR-CA is an increasingly recognized cause of structural heart failure. Aortic valve replacement (AVR) improves prognosis in this population, but the efficacy of ATTR-specific medication remains unclear. In a Clinical Research article entitled ‘Cardiac transthyretin amyloidosis treatment improves outcomes after aortic valve replacement for severe stenosis’, Christian Nitsche from the Medical University of Vienna in Austria, and colleagues aim to investigate the prognostic implications of ATTR-specific medication in patients with dual AS–CA.22 This is a multicentre, international, transatlantic registry of patients with a concomitant pathology of significant AS (moderate/severe) and ATTR-CA (ClinicalTrials.gov identifier: NCT06129331). The severity of AS was diagnosed by transthoracic echocardiography, and ATTR-CA by myocardial uptake on bone scintigraphy and/or positive endomyocardial biopsy in the absence of monoclonal proteins. Mortality (all-cause and CV) and hospitalization for heart failure (HHF) served as clinical endpoints. Outcomes were compared with a control cohort of confirmed lone AS receiving AVR matched for EuroSCORE II. Of 226 patients with dual pathology (mean age 85 years, 80% male) identified in 16 centres across 10 countries, AS was severe in 87% of patients, and moderate in 13%. Valve treatment strategies were transcatheter/surgical AVR in 72%/3.5%, balloon angioplasty in 1.3%, and conservative management in 23%; 32% of patients were prescribed, and 30% eventually received ATTR-specific medication (99% tafamidis) and were younger, with lower EuroSCORE II, a higher portion of moderate AS, but higher interventricular septum thickness and more severely impaired left ventricular function compared with patients without ATTR medication. After 3.6 years, 50% of patients had died and 26% experienced HHF. ATTR-specific medication was independently associated with lower all-cause (weighted HR 0.40) and CV mortality (weighted HR 0.47) but not HHF. Patients who received both ATTR-specific medication and AVR had the most favourable prognosis, comparable with a control cohort with lone AS undergoing AVR. The authors conclude that ATTR-specific treatment and AVR both result in significant survival benefit in dual pathology AS and ATTR-CA. The results should be interpreted in the context of the non-randomized study setting and differences in patient characteristics. The manuscript is accompanied by an Editorial by Sarah Cuddy from Brigham and Women's Hospital in Boston, MA, USA.23 The author highlights that in any observational cohort there will be biases and confounders that cannot be adjusted for; for example, are those initiated on ATTR therapy perceived as healthier? Ideally these results would be confirmed in a prospective, randomized trial, although such a study would be very challenging to execute. The authors made a strong effort to address this difficulty by employing inverse probability of treatment weighting (IPTW). The findings of the current study help alleviate concerns that incidentally detected ATTR-cardiomyopathy (CM) in AS is merely a confounder rather than a true prognostic factor. This study strengthens the case for systematic screening of older patients with AS for ATTR-CM and for thoughtfully considering ATTR-directed therapy in appropriate patients. Climate change is increasingly recognized as a public health issue, with the World Health Organization estimating an excess of 250 000 mortalities per year and ultimately accounting for 8 million deaths worldwide between 2030 and 2050, and increasing evidence for the role of environmental factors in cardiovascular morbidity and mortality. In a Clinical Research article entitled ‘Carbon emission analysis of aortic valve replacement: the environmental footprint of transcatheter vs surgical procedures’, David Blitzer from New York Presbyterian Hospital-Columbia University Irving Medical Center in New York, USA, and colleagues aim to quantify greenhouse gas emissions associated with surgical (SAVR) and transcatheter AVR (TAVR).24 The total carbon footprint from SAVR (n = 10) and TAVR (n = 10 operating room [OR]-TAVR, n = 10 cathlab [CATH]-TAVR) from March to September 2023 was calculated. Patients undergoing any other procedure at the time of SAVR or TAVR were excluded. A model for carbon footprints, measured in kilograms of CO2 equivalents (kg CO2e) was created following ISO14067 standards, based on primary data (materials, procedures, and energies, in the pre-operative, operative, and post-operative setting). Total life cycle carbon footprint for OR-TAVR, CATH-TAVR, and SAVR was 280–340 kg CO2e, 290–360 kg CO2e, and 620–750 kg CO2e, (P SAVR vs intensive and accounted for the portion of the carbon kg for of kg for of and kg for SAVR of (P SAVR vs Of the intensive of was a large to the carbon of OR-TAVR, of CATH-TAVR, and of the SAVR The authors conclude that the carbon footprint of SAVR is as high as those from or findings should be and guidelines into the The manuscript is accompanied by an Editorial by and from University of Medicine in and the Heart and Center in The authors that for in the is a strategy to reduce and This includes and a of and to and reduce to strategies include reducing the use of such as and for such as and and and reducing during of these such as and can contribute to reducing the environmental footprint of while reducing In a Clinical Research article entitled to predict valvular heart an from Hospital of University in and colleagues aim to to and predict future moderate or severe valvular heart regurgitation regurgitation and aortic regurgitation The were developed in a dataset of 000 000 and transthoracic from patients from The used a residual with a survival was in from a dataset from Medical Boston, USA, of patients with In the test the future significant and findings were confirmed in the test The authors conclude that this study developed to and predict and the in a and The could be to guide in patients at risk of future to and The manuscript is accompanied by an Editorial by from the General Hospital in Boston, MA, The author that the study by a significant and compelling in It a of in and the a critical in and personalized patient for The with the of and this as a for future The is also by a entitled on findings and major by from the University of also include the entitled analyses on and the risk of cardiovascular by and from the University of The that this of the European Heart will be of interest to its from the to and for help with of this