No Heart Is an Island: Hypertrophic Cardiomyopathy, Diabetes, and the Test of Time

Iacopo Olivotto; Niccolò Marchionni


Eur Heart J. 2019;40(21):1678-1680. 

Evolution in the management of cardiovascular disease frequently occurs: what starts as a raging battle gradually evolves into a chess game, when the urge to intervene rapidly and decisively subsides into the need to predict long-term outcome and implement clever and less dramatic countermoves. At that point, action gives way to reflection. Examples include the course of coronary artery disease following ST-segment elevation myocardial infarction (STEMI), the aftermath of acute myocarditis, and the fate of cardio-oncological patients.[1] Genetic cardiomyopathies are not immune from this trend. In the case of hypertrophic cardiomyopathy (HCM), abrupt clinical onset triggered by an acute event is possible, but not the most common presentation. More often, the disease is characterized by chronic symptoms and slow progression, although the need for acute intervention may occur at any time during its course (Figure 1). Whatever the scenario, a diagnosis of HCM results in drama for patients and their families. In the first phase after diagnosis, there is a strong impulse to act quickly in order to gain information and take all possible measures, even when there is no immediate need for concern. Specifically, the emphasis given over the years to HCM as an arrhythmogenic condition prompts physicians to discuss sudden cardiac death (SCD) prevention very early in the assessment process, triggering further understandable concern.[2] The focus of management of HCM patients has long been centred on the priority for arrhythmic risk stratification and prevention, culminating in the widespread use of implantable defibrillators worldwide—sometimes because of action prevailing over reflection. Not surprisingly, this attitude—and the potential link between intense sports activity and SCD—has led to a non-permissive attitude towards exercise in HCM individuals, coupled with frequent neglect of lifestyle issues and cardiovascular prevention in general.[3] After all, HCM is not coronary artery disease.

Figure 1.

The two faces of HCM management. Both are equally important and should be part of a comprehensive, multidisciplinary approach. Control of modifiable risk factors and prevention of co-morbidities are becoming a central focus of management, due to the protracted life span afforded to many HCM patients. CV, cardiovascular; HCM, hypertrophic cardiomyopathy; HF, heart failure; QoL, quality of life.

More recently, however, data from large HCM cohorts have progressively lowered the estimated rates of SCD, consistently highlighting that heart failure is the major cause of long-term morbidity and mortality. Results from the international ShaRe registry have shown that the burden of HCM tends to build up over time, peaking in the 6th–7th decade of life. At or following middle age, the disease takes its toll in a conspicuous proportion of patients, particularly those diagnosed early in life, in the form of atrial fibrillation and heart failure-related complications.[4] This makes clinical sense, given that several aspects of HCM pathophysiology may be seen as an exaggeration of cardiac ageing.[5] The fact that the same decades of life generally mark the development of modifiable cardiovascular risk factors should hardly be seen as a coincidence. Rather, it is plausible to suppose that adverse metabolic and environmental profiles, while seeming to have a limited effect on the phenotypic expression of HCM, may represent critical modifiers of long-term outcome.[3]

The body of literature addressing this important issue, however, remains limited. We know that the association of HCM and coronary artery disease is synergistic rather than additive, with a major impact on mortality.[6] Furthermore, HCM patients frequently tend to be overweight or obese, and weight excess promotes an increase in cardiac mass and outflow obstruction, and is a prognostic factor in itself.[7] Likewise, the development of arterial hypertension is a negative prognostic factor in patients with HCM, irrespective of ethnicity, age, and gender.[8] Obstructive sleep apnoea, reported in as many as 70% of patients with HCM, may adversely affect haemodynamic balance and is associated with atrial fibrillation.[9] On the other hand, we have learned that moderate intensity aerobic training is safe and increases peak oxygen consumption in HCM patients, with potential, although yet unproven, survival benefits.[10] Since the contribution of HCM as a major cause of SCD in young athletes is now being challenged, the concept is emerging that most HCM individuals should be encouraged to exercise regularly.[10] Thus, the picture of a complex and potentially modifiable interplay between a genetically modified myocardium and the environment is beginning to take form, representing an obvious target for intervention.[3]

The study by Wasserstrum et al.,[11] presented in this issue of the European Heart Journal, supports and expands this scenario by looking at the impact of diabetes mellitus (DM) on the clinical profile and outcome of >900 adult HCM patients from Spain and Israel. Of note, DM was present in ~9% of the cohort—a proportion in line with recent European and US statistics, but nevertheless worrying, considering that half of the patients were <60 years of age at enrolment. Not surprisingly, diabetic HCM patients were older at diagnosis and had a higher risk profile in terms of body mass index (BMI), hypertension, hyperlipidaemia, coronary artery disease, and chronic kidney disease compared with non-diabetic individuals. Diabetics also had greater prevalence of atrial fibrillation, diastolic dysfunction, congestive symptoms, and conduction blocks requiring pacemaker implantation. In a cohort matched for the main differing variables, these findings appeared independent of age, gender, hypertension, and coronary artery disease. Over a median follow-up of ~10 years, diabetic patients had higher all-cause mortality than non-diabetics (both matched and non-matched). However, the survival curves separated only after ~10 years, and overall differences were limited. The authors highlight a number of potential mechanisms by which DM might contribute to cardiac dysfunction and ultimately aggravate the course of HCM. These include molecular changes in titin and collagen cross-linking by advanced glycosylation products, leading to increased myocardial stiffness, as well as the exacerbation of features already present in HCM hearts, such as interstitial fibrosis, impaired calcium homeostasis, mitochondrial dysfunction, and oxidative stress.[11,12] An additional hypothesis might include direct toxicity of abnormal glycaemic homeostasis on sarcomere function and protein quality control.[13,14]

The study has several limitations including its retrospective nature and limited information regarding duration of DM and glycaemic control over the years. The type of DM is not specified, and while obviously most patients had type 2 DM, 15% were on insulin treatment. Causes of excess mortality were not dissected, although it is noteworthy that the rates of SCD did not differ in the two groups, suggesting a limited impact of DM on arrhythmic propensity. Because of these limitations, whether DM-mediated morbidity (e.g. coronary artery disease) may have played an independent role is unclear and requires further investigation. Most importantly, the association of DM with outcome was not tested in a multivariable model: despite patient matching, the issue of whether DM retains a predictive value—independent of many adverse features over-represented in the DM cohort—requires further confirmation. Likewise, it remains to be clarified whether more stringent glycaemic control may improve the outcome in HCM, particularly in the light of evolving therapies for DM that have shown multiple beneficial effects on the cardiovascular system.[15]

HCM remains an orphan, unpredictable disease requiring prolonged attention to clinical and pathophysiological detail. Aggressive control of modifiable risk factors—including 'iatrogenic' sedentary lifestyle—is an important component of management: as a working hypothesis, it may be reasonable to implement the standards of secondary rather than primary atherosclerotic disease prevention, including strict targets for lipid profile, blood pressure, and weight control, as well as appropriate exercise and diet.[3] As novel molecular approaches are being pursued with the aim to prevent and even reverse the course of HCM in the near future, we should make sure our patients have no other disease to confront today.