https://orcid.org/0000-0003-1107-2117
Increased risk of adverse cardiovascular events—conventional and novel approaches to risk stratification and treatment.
BMI, body mass index; CACS, coronary artery calcium score; CFR, coronary flow reserve; CMR, cardiovascular magnetic resonance; CT, computed tomography; EAT, epicardial adipose tissue; FAI, fat attenuation index; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; IMAT, intramuscular adipose tissue; MACE, major adverse cardiovascular events.
This editorial refers to ‘Skeletal muscle adiposity, coronary microvascular dysfunction, and adverse cardiovascular outcomes’, by A.C. do A.H. Souza et al., https://doi.org/10.1093/eurheartj/ehae827.
Obesity is a public health priority. Epidemiological studies clearly show that obesity is associated with increased cardiovascular risk, though this relationship is complex (Graphical Abstract). Adipose tissue is heterogeneous, phenotypically plastic, and highly biologically active. Recent studies indicate that the drivers of elevated risk may not solely be a consequence of the burden of adiposity but are also related to the distribution of adipose tissue. Visceral rather than subcutaneous adiposity is associated with cardio-metabolic disturbances including type 2 diabetes mellitus, insulin resistance, systemic inflammation, atherogenesis, heart failure, and coronary microvascular dysfunction (CMD).1 While attention has primarily been on the prognostic significance of different forms of visceral adiposity, increasing focus is being turned towards skeletal muscle adiposity as a potential marker of increased cardiovascular risk.
In this issue of the European Heart Journal, Souza and colleagues2 hypothesize that skeletal muscle quantity and quality associate with CMD and modify its effect on development of future adverse cardiovascular events independent of body mass index (BMI). They conducted a single-centre observational cohort study in 669 patients referred for positron emission tomography (PET) perfusion imaging to investigate chest pain or dyspnoea, recruited between 2007 and 2014. Thoracic computed tomography (CT) imaging was routinely acquired for attenuation correction of PET images. Patients were selected for inclusion based on a summed stress score <2 and left ventricular ejection fraction ≥ 40%. If coronary flow reserve (CFR) was <2.0, patients were classified as having CMD. Quantitative PET perfusion imaging for measurement of CFR was performed using two radiotracers, rubidium-82 and nitrogen-13 ammonia. Several pharmacological stressors were used, with regadenoson being administered in 57% of scans. CT scans were analysed at the T12 level by a single expert operator using semi-quantitative software to measure areas of skeletal muscle and subcutaneous (SAT) and intermuscular adipose tissue (IMAT). A deep learning algorithm was used for quantification of epicardial adipose tissue (EAT). Patients were followed-up for a median of 5.8 years, with clinical outcomes adjudicated by an independent clinical events committee. All-cause mortality was 8.1%, with rates of hospitalization for myocardial infarction and heart failure of 4.9% and 5.1%, respectively. In this patient population who were predominantly female and had a high rate of obesity, the main findings were that increasing levels of IMAT were associated with a greater occurrence of CMD, and that the presence of both elevated IMAT and CMD was associated with the highest rate of future adverse cardiovascular events, with this effect being independent of BMI. These data reinforce the importance of low CFR as a marker of increased clinical risk and now suggest IMAT as an additional risk stratifier in this elevated-risk group. The clinical utility of these results will require verification in an independent cohort.
Whilst many studies have previously investigated the relationship between anthropometric measures and cardiovascular outcomes, few have evaluated these metrics in combination with imaging-based assessments of adiposity and myocardial perfusion. The authors should be congratulated on harnessing the richness of contemporary multimodality imaging to enhance clinical risk assessment. Their approach may be further refined by adopting the previously reported paradigm3 of implementing artificial intelligence to develop pathway-specific proinflammatory radiomic signatures within IMAT which reflect its biological properties. Support for using analyses of adipose tissue for stratification of future cardiovascular risk has recently been reported.4 Coronary inflammation can be assessed by analysis of the perivascular fat around the coronary arteries. The ORFAN study showed that in patients undergoing CT coronary angiography for investigation of chest pain but who had no evidence of obstructive coronary artery disease, the use of a perivascular Fat Attenuation Index (FAI) score resulted in significant re-stratification of the risk of cardiac mortality and major adverse cardiovascular events.4
The interesting results provided by Souza et al. are hypothesis-generating and should be interpreted in the context of several limitations. This is a retrospective observational study. Whilst a number of potential mechanisms are suggested to explain the relationship between elevated IMAT and impaired CFR, these were not directly evaluated. In particular, no details of circulating inflammatory biomarkers, insulin resistance, endothelial function, diet, skeletal muscle physiology, or exercise performance were given. Evaluation of skeletal muscle biopsies obtained from areas with IMAT for analysis of histopathological features, metabolic activity, the inflammasome, and secretome would ideally have been provided to demonstrate potential mechanistic and causal links between IMAT, CMD, and increased cardiovascular risk. The inclusion of coronary artery scoring, which is now routinely available in contemporary PET-CT imaging, may further improve risk stratification.
The authors suggest that these findings are applicable to patients with ischaemia and non-obstructive coronary arteries (INOCA). It should be noted that INOCA encompasses patients having myocardial ischaemia due to multiple mechanisms. These may include CMD and its associated endotypes, but also myocardial bridging, vasospastic disorders of both the epicardial coronary arteries and microcirculation, or their combination.5 The potential implications of the results of the current study to the wider INOCA population are yet to be established. Furthermore, no coronary anatomical information, either invasive or non-invasive, which would be conventionally needed to diagnose INOCA, or invasive coronary physiology data were provided for: (i) documentation of coronary calcium score, plaque burden, and high-risk plaque features;6 or (ii) assessment of CMD and associated structural or functional endotypes, which are both known to be associated with cardiovascular risk.5,7 This work may provide a rationale for evaluating skeletal muscle adiposity as an additional component of risk assessment for the wider INOCA population.
It is well established that CMD can occur across a wide spectrum of cardiovascular diseases.8,9 It is increasingly apparent that CMD may be a cardiac manifestation of a wider systemic disorder.10 As there are many systemic factors in common linking both CMD and IMAT, including diabetes mellitus, insulin resistance, and inflammation, it is conceivable that the increase in IMAT may potentially be a manifestation of the direct effect of either the above factors on skeletal muscle or microvascular dysfunction extending beyond the heart. This raises the hypothesis that delivering interventions targeted at modifying these shared mechanisms may potentially lead to improved cardiovascular outcomes. Indirect evidence supporting this is provided by the results of recent clinical trials demonstrating improvement of cardiovascular outcomes with glucagon-like peptide-1 (GLP-1), with or without glucose-dependent insulinotropic polypeptide (GIP) agonism.11,12 Preliminary data suggest the potential of GLP-1 agonists to favourably modify imaging biomarkers of abdominal visceral adiposity including IMAT.13 However, the rationale for conducting a stratified medicine trial of a cardiometabolic modulatory strategy in patients with CMD and elevated IMAT would require additional confirmation of (i) the causal relationship between elevated IMAT, CMD, and clinical outcomes, and (ii) that these pharmacological strategies achieve positive adaptive responses within skeletal muscle.14
Recent studies also show that non-pharmacological weight reduction can alter coronary microvascular function. BMI reduction through bariatric surgery has been associated with improvements in CFR, markers of insulin resistance, and hepatic fat fraction.15 Whether similar observations can be achieved by pharmacological, exercise, and lifestyle interventions and be augmented in patients defined as being at higher risk remains to be explored.
The data presented by Souza et al. are intriguing and, importantly, further highlight patients with CMD as a population of patients at increased clinical risk. Their work should stimulate further investigation into establishing the added value of markers of adiposity to conventional and emerging cardiac risk stratification in order to identify those patients who may benefit prognostically from targeted cardiometabolic interventions.
Declarations
Disclosure of Interest
All authors declare no disclosure of interest for this contribution.
References
Author notes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
