Microvascular disease and arrhythmias: a renewed focus on the myocardial microvasculature?

While much effort has been directed at pharmacological and interventional techniques to improve outcomes for those living with these conditions, less has been directed towards identifying factors associated with increased incident risk of AF and non-AF arrhythmias, and strategies to ameliorate them. Arrhythmia prediction models have long relied on conventional risk factors such as age, diabetes, hypertension, and history of myocardial infarction and heart failure. Additional ways to strengthen such models, and contribute to risk prediction for arrhythmias more broadly, are a welcome addition to current knowledge. Mechanistically, a link between microvascular disease and arrhythmias is certainly plausible. Diabetes and cardiometabolic disease are known to result in microvascular dysfunction and such remodelling in the myocardium can result in structural changes and increased arrhythmogenicity. In adults with type 2 diabetes, the presence and burden of microvascular disease (diabetic kidney disease, retinopathy or neuropathy) have been shown to be associated with increased incident AF, although broader arrhythmia risk associated with microvascular disease is less clear.

In this context, the work by Li and colleagues in their Heart study, provides additional insights about the impact of microvascular disease on arrhythmia risk (AF, bradycardia and ventricular arrhythmia) in a population with type 2 diabetes, including delineation of the impact of varying degrees of risk factor optimisation on arrhythmia outcomes.

Using data from the UK Biobank, the authors included 25 632 participants with type 2 diabetes between the ages of 40 and 69 years, with and without a history of microvascular disease, defined as retinopathy, peripheral neuropathy and chronic kidney disease. Over a follow-up of 12.3 years, the study explored incident arrhythmia development, including AF, bradycardia and ventricular arrhythmia. The presence of at least one of these three types of microvascular disease was associated with an overall 48% increase in risk of arrhythmia development with HRs for individual corresponding arrhythmia found to be statistically significant (1.45 for AF, 1.44 for bradycardia and 1.89 for ventricular arrhythmia). By focusing on four traditional modifiable risk factors (body mass index, smoking, systolic blood pressure and glycosylated haemoglobin), a linear increase in arrhythmia risk was demonstrated with increasing numbers of suboptimally controlled risk factors. For individuals who demonstrated optimal control of all four modifiable risk factors at baseline, the risk of arrhythmia during follow-up was comparable with those without microvascular disease. Additionally, subgroup analysis revealed a higher risk of arrhythmias in women and those under 60 years of age when the presence of microvascular disease and number of risk factors within optimal level were considered together.

This study builds on previous research showing an association between microvascular disease and arrhythmias. While previous studies have focused mainly on AF, this study has broadened this link to other arrhythmia subtypes. By incorporating microvascular disease into a predictive model for arrhythmias, this study also suggests a practical application of these findings to existing secondary prevention measures. The study draws from a large database and extends duration of follow-up to more than 12 years, to ensure robustness of observed associations. It has also incorporated important data related to baseline risk factor control and arrhythmia outcomes, to provide a practical approach to translation of these findings into clinical practice. However, several limitations to this study exist, including those inherent to any large observational datasets. Participants of the UK Biobank are predominantly Caucasians, generally healthier and of higher socioeconomic status, raising questions about the applicability of these findings to broader populations. There is also the potential for inaccuracies due to the limitations of self-reported data and reliance on coding. The study also limited microvascular disease to three common manifestations of this condition. Inclusion of myocardial microvascular disease may provide further enhancement to arrhythmia predictive models in future studies. Further, time-updated covariates from prospective cohort with comprehensive risk factor characterisations would strengthen such data and provide greater understanding as to the impact of varying risk factor trajectories over time on incident arrhythmias.

The overall small although significant improvement to the C-index was demonstrated in this work by Li and colleagues with the addition of microvascular disease to the arrhythmia prediction model. This may imply limited clinical or practical significance beyond current recommendations for cardiovascular risk factor modification and control to prevent incident arrhythmias. However, the ability to detect microvascular dysfunction, which may be potentially reversible and precede development of overt microvascular disease, presents a window of opportunity to alter disease trajectory and resulting sequelae.

It is now critical for us to evaluate non-invasive methods of detecting myocardial microvascular dysfunction, mechanisms involved in adverse myocardial remodelling leading to increased arrhythmogenicity and potential therapeutics that may be beneficial in reversing the milieu conducive for arrhythmia development. Several non-invasive screening tools are currently being explored including pulsed wave Doppler of the proximal left anterior descending artery via echocardiography, CT, positron emission tomography and cardiac MRI.

In keeping with our extensive knowledge of the role of cardiovascular risk factor modification in the prevention and progression of AF, cardiovascular risk factors are known to also play a significant role in the development and progression of microvascular disease.

It is of no surprise that those in the study with microvascular disease and optimally controlled risk factors demonstrated no increase in arrhythmia risk as compared with those without microvascular disease.

Therefore, it is imperative that resources are directed at strategies to enhance risk factor control in the high-risk population of individuals living with diabetes, especially those with manifest microvascular complications. Recognition of microvascular disease as a contributor to increased incident arrhythmia provides the field a new focus to investigate the microvasculature, and the role of its surrounding perivascular adipose tissue and sympathetic innervation in arrhythmogenicity. When we expand our lens beyond the myocytes to the more abundant endothelial cells and their surrounds within the myocardium, we may find improved mechanistic understanding of the intricate links between triggers and substrate for arrhythmias, which may guide development of novel therapeutics in the future.