Coronary Volume–to–Myocardial Mass Ratio Giving Additional Insights in Coronary Artery Disease Pathophysiology

See also article by Holmes et al in this issue.

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Myocardial ischemia in patients with coronary artery disease (CAD) is caused by a mismatch between coronary blood supply and myocardial oxygen demand. While invasive coronary angiography and fractional flow reserve assess the epicardial coronary tree, noninvasive evaluation through coronary CT angiography (CCTA), CT perfusion, and CT fractional flow reserve (CT-FFR) can characterize both the coronary arteries and the myocardium, providing additional anatomic and functional information. Coronary artery lumen volume–to–myocardial mass ratio (V/M) has been suggested as a marker of supply-demand mismatch, able to provide useful insight into cardiac physiology. The V/M concept, rooted in allometric scaling laws, underscores the linear correlation between coronary volume and myocardial mass. A low V/M signifies insufficient coronary supply for a given myocardial demand, elevating the risk of ischemia when conditions increasing oxygen demand occur (1). An increase in myocardial mass, as observed in myocardial hypertrophy (2), or a decrease in coronary volume, as observed in atherosclerosis (3), can both alter the ratio and lead to a supply-demand imbalance, causing ischemia. Conversely, higher coronary volume–to–unaltered myocardial mass, and consequent higher V/M, imply better coronary reserve, resulting in lower risk of ischemia. Recent studies have shown that V/M can be used as a prognostic marker, which can impact the clinical management and understanding of the patient's cardiovascular risk (4). Particularly, the role of V/M has been evaluated in different clinical scenarios and in relation to different risk factors, such as hypertension (5) and sex. Of these studies, the work of Fairbairn et al (6) on the ADVANCE registry represents the largest, evaluating V/M in 3110 patients with chronic CAD. Specifically, the authors focused on sex-based differences in CT-FFR and V/M; they concluded that women tend to have higher CT-FFR for the same degree of stenosis than men and higher V/M, with an overall lower rate of obstructive CAD and consequent revascularization in this population. The study also emphasized that higher V/M in women was predictive of decreased likelihood of revascularization, independently of CT-FFR and degree of stenosis. Thus, the addition of V/M in the decision-making process of revascularization could overcome sex-based differences.

V/M can be computed directly from CCTA data. The process requires segmentation of the coronary tree and the left ventricle. With the recent advances in artificial intelligence and greater availability of deep learning algorithms, it should not come as a surprise that quantification of V/M has become easier and more accessible by automating the process using a deep learning approach. Thanks to its promising role in clinical management, V/M and its assessment have been the focus of an increasing number of publications in recent years, and further research is needed to fully understand its potential and shape its clinical use.

In this issue of Radiology: Cardiothoracic Imaging, Holmes et al (7) examined the relationship between smoking and V/M, shedding light on the correlation of this marker with a cardiovascular risk factor, an area in which literature is lacking. Smoking is a well-established cardiovascular risk factor for CAD; however, only current smoking status seems to correlate with higher risk of major adverse cardiac events, despite age, sex, and other risk factors, suggesting that the pathophysiological explanation goes beyond the sole atherosclerotic burden (8). Thus, Holmes et al fill the gap in existing literature by evaluating the impact of smoking on V/M, providing insights into smoking-related cardiovascular pathologic changes.

The study evaluated 2874 patients with known smoking status and coronary stenosis equal to or greater than 30% from the ADVANCE registry (6). Patients underwent CT-FFR and V/M analysis and were divided based on smoking status (current, former, or never-smokers). In accordance with the literature, current smoking status was associated with higher rates of stenosis equal to or greater than 50%, stenosis equal to or greater than 70%, and stenosis equal to or greater than 50% involving multiple vessels when compared with never-smokers, confirming the role of smoking as a CAD risk factor. With regard to V/M, the authors observed that both current and former smoking status were independently associated with low V/M. Interestingly, the reduction in V/M was mostly driven by an increase in myocardial mass while coronary lumen volume remained relatively stable, suggesting that ventricular remodeling could be the main factor altering the myocardial supply-demand mismatch in smokers contributing to the increased risk, in addition to decreased luminal volume due to atherosclerosis. On the other hand, a lack of change in coronary volume, in response to increased myocardial mass, could also express a failure of coronary compensation in smokers. This finding could be related to a vasomotor impairment caused by smoke inhalation. Furthermore, the study showed a progressive reduction of V/M going from never to former to current smokers among patients with 50% or greater stenosis. Increasingly lower V/M among smokers with more severe stenosis further highlights the harmful effect of smoking on myocardial supply-demand mismatch as atherosclerotic lesions progress and luminal volume decreases. With this work, Holmes et al emphasize the need to better understand the pathophysiology of CAD and the involvement of the myocardium in addition to coronary evaluation, and their results encourage further investigation to fully comprehend the mechanisms responsible for the low V/M in smokers.

The multiple regression analysis showed that stenosis equal to or greater than 50%, diabetes, typical angina, and dyspnea were independent predictors of low V/M, proposing the potential use of V/M to assess microvascular dysfunction in these subgroups of patients. Conversely, age of 65 years or older and female sex were predictors of higher V/M, the latter in accordance with prior studies (6). Female patients classically present with less typical symptoms, lower cardiovascular risk scores, and lower incidence of obstructive CAD, yet worse prognosis when compared with their male counterparts (9). The use of V/M in this cohort might aid management and treatment decision-making. Moreover, women tend to have higher overall V/M; this might explain why women are less likely to have an abnormal CT-FFR (<0.80) and have lower rates of revascularization (6). Interestingly, in the study Holmes et al, only 27.6% of the current smokers and 22.8% of former smokers were female. Thus, further focused investigation is needed to evaluate the impact of smoking, causing subsequent lower V/M driven by increased myocardial mass, in a female population, in which V/M is higher due to decreased myocardial mass. Whether the reduction of myocardial mass in female individuals is counteracted by the negative effects of smoking is yet to be established. V/M might represent the key to assessing microvascular function among female smokers.

The potential of V/M may be hindered by the technique used to compute the ratio. V/M is, similarly to CT-FFR, highly dependent on lumen segmentation, which can be influenced by the quality of the CCTA acquisition. Additionally, while sublingual nitroglycerin administration prior to CCTA is a well-established recommendation for proper CCTA acquisition, the use of this agent may impact both CT-FFR and V/M computation. Studies have shown that using 0.8 versus 0.4 mg of sublingual nitroglycerin is associated with increased coronary volume, without significant change in V/M (10). However, recent advances in technology have allowed acquisition of high-quality CCTA images even without administration of nitroglycerin. Further studies are needed to assess the impact of a nitroglycerin versus a nonnitroglycerin acquisition strategy on V/M and CT-FFR.

As the authors rightfully stated, further research is needed to assess the clinical applicability of V/M. Although this study did not examine the relationship between V/M and clinical outcomes across smoking groups, Holmes et al are to be congratulated for focusing on a previously unexplored area of the literature. Their work is an important step forward in understanding the influence of smoking on CAD and directs future investigation on V/M as a tool to reclassify cardiovascular risk and aid decision-making and treatment.