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Non-ischaemic cardiomyopathies are an important cause of heart failure (HF) and sudden death.1–6 This Focus Issue on heart failure and cardiomyopathies contains the State of the Art Review article ‘Restrictive cardiomyopathy: definition and diagnosis’ by the late Claudio Rapezzi, to whom the Issue is dedicated, and colleagues.7 The authors note that restrictive cardiomyopathy (RCM) is a heterogeneous group of diseases characterized by restrictive left ventricular pathophysiology, i.e. a rapid rise in ventricular pressure with only small increases in filling volume due to increased myocardial stiffness. More precisely, the defining feature of RCM is the co-existence of persistent restrictive pathophysiology, diastolic dysfunction, non-dilated ventricles, and atrial dilatation, regardless of ventricular wall thickness and systolic function. Beyond this shared haemodynamic hallmark, the phenotypic spectrum of RCM is wide. The disorders manifesting as RCM may be classified according to four main disease mechanisms: (i) interstitial fibrosis and intrinsic myocardial dysfunction; (ii) infiltration of extracellular spaces; (iii) accumulation of storage material within cardiomyocytes; or (iv) endomyocardial fibrosis. Many disorders do not show restrictive pathophysiology throughout their natural history, but only at an initial stage (with an evolution towards a hypokinetic and dilated phenotype) or at a terminal stage (often progressing from a hypertrophic phenotype). Furthermore, elements of both hypertrophic and restrictive phenotypes may co-exist in some patients, making the classification challenging. Restrictive pathophysiology can be demonstrated by cardiac catheterization or Doppler echocardiography. The specific conditions may usually be diagnosed based on clinical data, 12-lead electrocardiogram, echocardiography, nuclear medicine, or cardiovascular magnetic resonance (CMR), but further investigations may be needed, up to endomyocardial biopsy and genetic evaluation. The spectrum of therapies is also wide and heterogeneous, but disease-modifying treatments are available only for cardiac amyloidosis and, partially, for iron overload cardiomyopathy.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inheritable and progressive heart muscle disease characterized by high risk of ventricular tachyarrhythmias and sudden cardiac death, in addition to morphological abnormalities and eventually HF. The disease has autosomal dominant inheritance with variants in genes encoding for cardiac desmosomal proteins, and it exhibits variable penetrance and expressivity. ARVC diagnosis is made by combining multiple sources of information as described by the consensus-based revised 2010 Task Force Criteria.8–14 In a Fast Track Clinical Research article entitled ‘Highly malignant disease in childhood-onset arrhythmogenic right ventricular cardiomyopathy’, Marit Kristine Smedsrud from the Oslo University Hospital in Norway, and colleagues aimed to explore the incidence of severe cardiac events in paediatric ARVC patients and ARVC penetrance in paediatric relatives.15 Consecutive ARVC paediatric patients and genotype-positive relatives ≤18 years of age were followed with electrocardiographic, structural, and arrhythmic characteristics according to the 2010 revised Task Force Criteria. Penetrance of ARVC disease was defined as fulfilling definite ARVC criteria. Severe cardiac events were defined as cardiac death, heart transplantation (HTx), or severe ventricular arrhythmias. Childhood-onset disease was defined as meeting definite ARVC criteria at ≤12 years of age. Among 62 individuals (mean age 9.8 years, 11 probands), 20 (32%) fulfilled the definite ARVC diagnosis, of which 8 (40%) had childhood-onset disease. Severe cardiac events by last follow-up occurred in 14 (23%) and half occurred in patients ≤12 years of age. Among the eight patients with childhood-onset disease, five had biventricular involvement needing HTx and three had severe arrhythmic events. Among the 51 relatives, 3 (6%) met definite ARVC criteria at the time of genetic diagnosis, increasing to 9 (18%) at the end of follow-up.
The authors conclude that in a paediatric ARVC cohort, there is a high incidence of severe cardiac events and half of them occur in children ≤12 years of age. The ARVC penetrance in genotype-positive paediatric relatives is ∼20%. These findings of a high malignant phenotype in childhood-onset ARVC indicate a need for ARVC family screening at a younger age than currently recommended. The contribution is accompanied by an Editorial by Juan Pablo Kaski from the University College London in the UK.16 Kaski highlights that the next question is whether early identification can result in improved outcomes for this group of patients. As we move into an era of exciting new therapeutic opportunities in the field of cardiomyopathies, it is ever more important to ensure that children are at the forefront and adequately represented, both in natural history studies and in clinical trials. Systematic studies in childhood of disease expression and progression are a major first step towards this goal.
In a Clinical Research article entitled ‘Polygenic risk score for ACE-inhibitor-associated cough based on the discovery of new genetic loci’, Jonas Ghouse from the Copenhagen University Hospital in Denmark, and colleagues search for sequence variants associated with angiotensin-converting enzyme inhibitor (ACEi) discontinuation and test their relationship with ACEi-associated adverse drug reactions (ADRs).17 A genome-wide association study (GWAS) on ACEi discontinuation was conducted, including 33 959 ACEi discontinuers and 44 041 controls. Cases were defined as persons who switched from an ACEi treatment to an angiotensin receptor blocker. Controls were defined as persons who continued ACEi treatment for at least 1 year. To test for association with specific ACEi-associated ADRs, any genome-wide significant (P <5 × 10–8) ACEi discontinuation variant was tested for association with ACEi-associated cough and angioedema. A polygenetic risk score (PRS) based on ACEi discontinuation GWAS data was constructed and tested for association with ACEi-associated cough and angioedema in two population-based samples. In total, seven genetic genome-wide loci were identified, of which six were previously unreported. The strongest association with ACEi discontinuation was at 20q13.3 [odds ratio (OR) 1.21]. Five of seven lead variants were associated with ACEi-associated cough, whereas none was associated with ACEi-associated angioedema. The ACEi discontinuation PRS was associated with ACEi-associated cough in a dose–response manner but not with ACEi-associated angioedema. ACEi discontinuation was genetically correlated with important causes for cough, including gastro-oesophageal reflux disease, allergic rhinitis, hay fever, and asthma, which indicates partly shared genetics underpinning between these traits.
The authors conclude that this study shows the advantage of using prescription patterns to discover genetic links with ADRs. In total, they have identified seven genetic loci associated with ACEi discontinuation. The contribution is accompanied by an Editorial by Juan Tamargo from the Universidad Complutense in Madrid, Spain and colleagues.18 The authors note that healthcare professionals aim to prescribe the most effective and safe drug for a given indication. However, clinicians currently cannot predict who will develop ACEi-associated cough before starting treatment; clinical guidelines recommend that in patients who develop this side effect, ACEI treatment should be discontinued, or switched to angiotensin receptor blockers. Therefore, better patient–drug matching methods are needed to minimize ACEi-associated cough. Thus, understanding the interindividual differences in the development of ADRs following therapy is essential for personalized treatment. The author states that this large, well-designed GWAS emphasizes the advantages of utilizing prescription data of population-based cohorts to improve our understanding of genetic variants linked to ACEi-associated ADRs leading to drug discontinuation. This study can help identify people at risk and provide new insights into the pathophysiological mechanisms underlying ACEi-associated ADRs.
ECV, extracellular volume; EDV, end-diastolic volume; LV, left ventricle; LVEF, LV ejection fraction; MAPSE, mitral annular plane systolic excursion; TAPSE, tricuspid annular plane systolic excursion.25
Cardiac amyloidosis is a topic of growing interest also because of recent availability of disease-modifying treatments.19–24 In a Clinical Research article entitled ‘Cardiovascular magnetic resonance in light-chain amyloidosis to guide treatment’, Ana Martinez-Naharro from the University College London in the UK, and colleagues sought to establish the role of CMR in the assessment of the response to chemotherapy in patients with light chain cardiac amyloidosis (AL-CA).25 In total, 176 patients with AL-CA were assessed at diagnosis and subsequently at 6, 12, and 24 months after starting chemotherapy. Haematological response was graded as complete response (CR), very good partial response (VGPR), partial response (PR), or no response (NR). CMR response was graded by changes in extracellular volume (ECV) as progression (≥0.05 increase), stable (<0.05 change), or regression (≥0.05 decrease). At 6 months, CMR regression was observed in 3% (all CR/VGPR) and CMR progression in 32% (61% in PR/NR; 39% CR/VGPR). At 2 years, 38% had regression (all CR/VGPR), and 14% had progression (80% in PR/NR; 20% CR/VGPR). Thirty-six (25%) patients died during follow-up (40 ± 15 months); CMR response at 6 months predicted death (hazard ratio 3.82; P < 0.001) and remained prognostic after adjusting for haematological response, N-terminal probrain natriuretic peptide levels, and longitudinal strain (P <0.01) (Figure 1).
The authors conclude that cardiac amyloid deposits frequently regress following chemotherapy, but only in patients who achieve CR or VGPR. Changes in ECV predict outcome after adjusting for known predictors. This manuscript is accompanied by an Editorial by Thibaud Damy from the Henri Mondor University Hospital in Créteil, France, and colleagues.26 The authors note that Martinez Naharro et al. highlight the value of CMR and ECV for determining the treatment response in patients with AL-CA. These results pave the way to better-designed studies of early-stage disease. In the light of recent therapeutic advances (such as the promising combination of daratumumab and bortezomib), further research is needed to establish whether the ECV will become a routinely used tool for guiding the management of patients with AL-CA and thus reducing the suffering caused by this severe disease.
![Scleraxis was required for pressure overload-induced [via transverse aortic constriction (TAC)] recruitment of RNA polymerase II to profibrotic genes, activation of cardiac fibroblasts to myofibroblasts, and cardiac fibrosis. Scleraxis gene deletion attenuated fibroblast activation and fibrosis to ameliorate cardiac functional loss regardless of whether deletion occurred prior to or following TAC.29](https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/eurheartj/43/45/10.1093_eurheartj_ehac688/1/m_ehac688f2.jpeg?Expires=1750184638&Signature=pd8WRNynncx9awDTSVVtPPKjzBC-aeQdvTCf4RMt9n38sXhiOQiJBdzXqT6aMrCR4Bvg0UZKHkvciTub73e87KeX1iK4DcvB9lu43tUILNaPOzhWIixPnVW4unAa70VQBYADDBFELtCj6uuuXHnm6lSnQbR~b1rZbQyCcTtgtL2wA6g6m3t0q~kevCrntwg3RXUu1CjnV6AcWtItbXEVQ-oFFXDxgiKVHKv80TaOwrXPTOOt0OYaYvurQ05kekLLD-NesNbVjl8KxLTJX2TaX5XEF9XPMSW-kBhPbWxNgscZq1czAxg1A3nHtswwRBjP4zZJ02ULnoGUc15VI~ElkQ__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
Scleraxis was required for pressure overload-induced [via transverse aortic constriction (TAC)] recruitment of RNA polymerase II to profibrotic genes, activation of cardiac fibroblasts to myofibroblasts, and cardiac fibrosis. Scleraxis gene deletion attenuated fibroblast activation and fibrosis to ameliorate cardiac functional loss regardless of whether deletion occurred prior to or following TAC.29
The mechanisms of myocardial fibrosis are complex and still poorly understood.27,28In vitro, scleraxis regulates cardiac fibroblast activation in response to profibrotic signals via transcriptional control of key fibrosis genes such as collagen and fibronectin; however, its role in vivo is unknown. In a Translational Research article entitled ‘Scleraxis and fibrosis in the pressure-overloaded heart’, Raghu S. Nagalingam from the University of Manitoba, Winnipeg, Canada assessed the impact of scleraxis loss on fibroblast activation, cardiac fibrosis, and dysfunction in pressure overload-induced HF.29 Scleraxis expression was up-regulated in the hearts of non-ischaemic dilated cardiomyopathy patients, and in mice subjected to pressure overload by transverse aortic constriction (TAC). Tamoxifen-inducible fibroblast-specific scleraxis knockout (Scx-fKO) significantly attenuated cardiac fibrosis, and improved cardiac systolic function and ventricular remodelling, following TAC, compared with Scx+/+ TAC mice, concomitant with attenuation of fibroblast activation. Scleraxis deletion, after the establishment of cardiac fibrosis, attenuated the further functional decline observed in Scx+/+ mice, with a reduction in cardiac myofibroblasts. Notably, scleraxis knockout reduced pressure overload-induced mortality from 33% to zero, without affecting the degree of cardiac hypertrophy. Scleraxis directly regulated transcription of the myofibroblast marker periostin, and cardiac fibroblasts lacking scleraxis failed to up-regulate periostin synthesis and secretion in response to profibrotic transforming growth factor β (Figure 2).
The authors conclude that scleraxis governs fibroblast activation in pressure overload-induced HF, and scleraxis knockout attenuates fibrosis and improves cardiac function and survival. These findings identify scleraxis as a viable target for the development of novel antifibrotic treatments. This manuscript is accompanied by an Editorial by Timothy McKinsey, from the University of Colorado–Anschutz Medical Campus Aurora, USA, and colleagues.30 The authors commend Nagalingam and colleagues for providing convincing data that validate a role for scleraxis in the control of cardiac fibrosis. The findings provide the foundation for future mechanistic studies to dissect the molecular mechanisms of scleraxis-mediated extracellular matrix remodelling, and translational work to determine whether scleraxis inhibitors can be developed as safe and effective antifibrotic therapies for the heart.
Sodium–glucose co-transporter (SGLT) inhibitors are rising stars in the treatment of HF.31–38 In a Viewpoint article entitled ‘Does SGLT1 inhibition add to the benefits of SGLT2 inhibition in the prevention and treatment of heart failure?’ Marco Metra from the University of Brescia in Italy, and colleagues describe potential advantages of non-selective SGLT inhibitors compared with selective inhibitors.39 While this hypothesis requires further confirmation in adequately powered direct comparative trials and much remains to be learned about the expression and function of SGLT1 in patients with HF both with and without diabetes, the evidence from the SCORED and SOLOIST trials as well as from a Mendelian randomization study examining missense variants associated with a decrease in SGLT1 function suggest that SGLT1 inhibition might add to the benefits of SGLT2 inhibition in the prevention and treatment of HF, at least in diabetic patients.
The issue is complemented by two Discussion Forum contributions. In ‘Immunosuppressive therapy of myocarditis and inflammatory cardiomyopathy in the light of new data’ Krzysztof Ozieranski from the University of Warsaw in Poland, and colleagues comment on the recent contribution ‘Immunosuppressive therapy in virus-negative inflammatory cardiomyopathy: 20-year follow-up of the TIMIC trial’ by Cristina Chimenti from the Sapienza University of Rome in Italy, and colleagues.40,41 Chimenti et al. respond in a separate contribution.42
The editors hope that this issue of the European Heart Journal will be of interest to its readers.
Dr. Crea reports speaker fees from Amgen, Astra Zeneca, Servier, BMS, other from GlyCardial Diagnostics, outside the submitted work.
With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.
