Editors’ presentation: Focus on cardiomyopathy and heart failure

Systemic amyloidosis encompasses a debilitating group of disorders characterised by the extracellular deposition of misfolded proteins in one or more organs including the heart. In the majority of cases cardiac amyloidosis is caused by two types of amyloid protein: immunoglobulin light chain, which causes light chain amyloidosis (AL), and transthyretin (TTR), which causes hereditary or wild-type (previously called senile systemic amyloidosis) TTR amyloidosis. Previously thought to be very rare, these forms of cardiac amyloidosis are increasingly recognised although they are still under-diagnosed. A timely diagnosis of cardiac amyloidosis is crucial given the recent availability of an array of new and effective treatments. It is based on the early recognition of clinical, laboratory and imaging signs of cardiac involvement, and some of these may be apparent well before the disease becomes clinically manifest.1 In this issue of the European Journal of Preventive Cardiology, Vergaro et al. highlight the many ‘red flags' of cardiac amyloidosis from the clinical history, examination, electrocardiogram, blood biomarkers and cardiac imaging. These include bilateral carpal tunnel syndrome and rupture of the head of the biceps tendon, polyneuropathy and dysautonomia, the combination of low QRS voltage on the electrocardiogram (ECG) and increased left ventricle (LV) wall thickness on echocardiography, mild elevations of troponin on multiple occasions as well as the characteristic patterns of global longitudinal strain on echocardiography and late gadolinium enhancement (LGE) on cardiac magnetic resonance.2 HCM is the most common genetic cardiomyopathy, the object of intense screening in athletes' evaluation.3,4 Despite an equal expected prevalence by sex, women are less represented than men in the HCM cohort and have worse all-cause mortality. Furthermore, women are older at first evaluation and diagnosis, present more frequently with symptoms and, despite a similar degree of hypertrophy, they are more likely to demonstrate obstructive physiology, more pulmonary hypertension (PH), higher natriuretic peptides and worse measures of cardiopulmonary exercise tolerance compared with men.5 To date it remains to be elucidated whether sex-related differences in terms of outcomes are determined by exercise performance. To address this important point in this issue of the Journal, Ghiselli et al. studied 292 adult patients with HCM undergoing exercise echocardiography.6 Women with HCM had significantly more age-related impairment in functional capacity compared with males and were at greater risk of HCM-related complications and death: however, impaired exercise capacity predicted adverse outcomes only in men. Although the study by Ghiselli et al. only provided metabolic equivalents as a measure of peak exercise capacity, it highlights the need for sex-specific management strategies in HCM. The signs and symptoms, as well as the clinical course, of HCM are highly variable.7 A complex and incompletely understood interaction of genotype and environmental factors determines the phenotype and the outcome of the disease. Potential modifiers of HCM expression include endocrine factors, ethnicity and comorbidities such as hypertension, obesity and renal disease. Fumagalli et al. reported that obesity, as assessed by body mass index (BMI), was highly prevalent in HCM patients and it was independently associated with greater left ventricular hypertrophy (LVH) and greater symptom burden confirming that obesity might influence phenotypic variability and long-term prognosis of HCM.8 The study by Park et al., in this issue of the Journal, extends the findings of the aforementioned study, describing the association of obesity and metabolic health status with the incidence of clinical HCM diagnosis.9 This study was based on data from the Korean National Health Insurance system and included 28,679,891 individuals aged 20 years and older. After a median follow-up of 5.2 years the authors demonstrated that the patients with higher values of BMI and waist circumference, as well as patients with metabolic abnormalities, were at higher risk of being diagnosed with HCM. Surprisingly the effect of BMI was more pronounced in several subgroups, including participants with no hypertension and in those aged less than 65 years, suggesting that the development of LVH and clinical HCM in obese individuals is at least partially mediated through pathways that are directly related to increased body fat, and it is not solely explained by concomitant cardiovascular comorbidities. SSc is an autoimmune disease affecting various organs and tissues characterised by vascular dysfunction and microvascular alterations that lead to ischaemia and fibrosis of several organs.10,11 The heart is one of the major organs involved in SSc, with an estimated clinical prevalence between 15–35% of cases. SSc-related cardiomyopathy could lead to heart failure (HF), conduction defects and arrhythmias. The cardiac damage in patients with SSc is often subclinical, especially in the early stages, while the presence of overt clinical signs of cardiac disease results in a poor prognosis; thus a prompt diagnosis is needed. In this context, speckle-tracking-derived global longitudinal strain (GLS) has shown promising results in identifying subclinical heart involvement much earlier than the commonly used echocardiographic parameters. In this issue of the Journal, Stronati et al. investigate the progression of subclinical biventricular cardiac involvement in patients with SSc using speckle-tracking-derived GLS.12 At follow-up, conventional echocardiographic parameters did not differ from baseline, but both LV GLS and right ventricle (RV) GLS deteriorated significantly in the absence of overt fibrosis in cardiac magnetic resonance. Moreover, among patients who have experienced major clinical events during follow-up, the data showed a faster progression of RV GLS impairment. The results of this study confirmed that the use of GLS may contribute not only to diagnosing SSc-related cardiomyopathy but also to better stratify the patients with subclinical disease at risk for developing major complications. AF is the most common arrhythmia in clinical practice, accounting for approximately one-third of admissions resulting from cardiac rhythm disturbances and it is associated with an increased risk of HF. Both disorders often occur together and their combination strongly correlates with a significantly impaired exercise capacity and adverse prognosis also in patients with HF with mid-range ejection fraction.13 Although the causative relationship between the two conditions has not been fully elucidated, their coexistence can be partially explained by the presence of common risk factors such older age, elevated blood pressure, coronary artery disease, valvular heart disease and diabetes mellitus (DM). Previous studies have also shown that an increased inflammatory state is associated with AF and HF. Poor oral hygiene may cause systemic inflammation and is an established risk factor for cardiovascular disease. However, little information has been available on the relationships of poor oral hygiene with the incidence of AF and HF. Here, to clarify this relation Chang et al. studied the associations of various markers of oral hygiene care with AF and HF using data from the National Health Insurance System - National Health Screening Cohort in Korea.14 After a median follow-up of 10.5 years they demonstrated that frequent tooth brushing (>3 times/day) was associated with lower risks of incident AF and HF. Furthermore, subjects who had a high number of missing teeth were at higher risk of HF. Exercise intolerance is a hallmark of chronic HF and is associated with reduced quality of life (QoL) and increased mortality.15 The pathophysiological mechanisms behind exercise intolerance are multifactorial and only partially investigated and understood. Although an impairment in cardiac output (CO) at rest and with physical exertion is considered to be central in HF over recent years, several other abnormalities including impairments in peripheral endothelial-dependent vasodilation, reduction in systemic oxygen delivery, reduction in pulmonary reserve and respiratory muscle perfusion have been proposed to explain the reduced exercise capacity in this syndrome.16 In the current issue of this Journal, Angius and Crisafuli review the literature for the role of an exaggerated feedback from group III/IV muscle afferents in the genesis of fatigue by bringing forward the muscle hypothesis.17 The muscle hypothesis suggests that changes in skeletal muscle metabolism, structure and function in HF produce exaggerated feedback from group III/IV muscle afferents (termed the metaboreflex) sensitive to the metabolic changes occurring during exercise. This exaggerated afferent feedback coming from these fibres potentially causes haemodynamic and ventilatory dysregulation, with excessive sympathoexcitation arteriolar constriction and ventilatory response slope for CO2 during exercise. In support of the ‘muscle hypothesis’ there are experimental findings in heart transplant recipients during metaboreflex activation. In these patients exercise capacity, although improved, remains abnormally impaired after transplant compared to normal individuals, indicating that restoring cardiac function does not fully enhance aerobic metabolism. A large number of studies suggest that one of the earliest, most common and most serious cardiovascular diseases in patients with DM is HF, and patients with DM have over twice the risk of developing HF than patients without DM. HF and DM are linked pathophysiologically and are both characterised by insulin resistance and are accompanied by the activation of neurohormonal systems.18 To date, the only two classes of drugs that that appear to reduce the risk of HF and its adverse consequences in DM are metformin and sodium-glucose cotransporter 2 inhibitors. In particular, recent cardiovascular outcomes trials have revealed an unexpectedly strong cardioprotective signal of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients at high cardiovascular risk with DM. The results of these trials reinforce the importance of initiating therapy with SGLT2i as soon as possible in patients with diabetes. In this context the paper by Ritsinger et al. in this edition of the Journal is particularly welcome.19 In brief, the authors evaluated nearly 74,000 participants in the SWEDEHEART registry with AMI to compare the incidence of HF and death after AMI in patients with and without DM. In this broad patient population patients with DM had a hazard ratio (HR) of 1.52 relative to patients without DM for developing HF after a first AMI event. This risk of HF was more pronounced in patients with a history of myocardial infarction, history of HF and presence of reduced left ventricular ejection fraction (LVEF).