Skeletal muscle microvascular blood flow responsiveness: relationship with myocardial microvascular blood flow in coronary artery disease

Grace Young

doi:10.25907/00743

Despite advances in the primary and secondary prevention of coronary artery disease (CAD), CAD remains the most prevalent form of atherosclerotic cardiovascular disease (CVD) and the leading cause of morbidity and mortality. Therefore, the early identification of CAD is an important global public health goal. The first symptom of CAD typically presents as stable angina (chest pain), corresponding with myocardial ischaemia. However, up to 50% of people with symptomatic myocardial ischaemia demonstrate angiographically normal coronary arteries (0% stenosis) or non-obstructive CAD (<50% stenosis). In addition to the public health burden associated with diagnostic investigations, symptomatic people with no angiographic evidence of obstructive (>50% stenosis) CAD experience acute cardiovascular events, including death. These symptoms and events are often attributed to microvascular angina, caused by coronary microvascular dysfunction. However, the underlying mechanisms of coronary microvascular dysfunction are not completely understood. Furthermore, coronary microvascular dysfunction is underdiagnosed and undertreated in clinical practice. Therefore, early identification presents a potential opportunity to treat coronary microvascular dysfunction and/or prevent adverse cardiovascular events in people with symptomatic myocardial ischaemia and unobstructed coronary arteries. Due to the challenging nature of assessing coronary microvascular function and the systemic nature of microvascular dysfunction, it is plausible that surrogate markers of peripheral microvascular function may increase the early identification of coronary microvascular dysfunction. Skeletal muscle is a large and easily accessible metabolic tissue-bed where microvascular blood flow responsiveness is known to be impaired in people with cardiovascular risk factors in response to transient arterial limb cuff occlusion. Contrast-enhanced ultrasound (CEUS) is commonly used to assess microvascular blood flow in organs, including the heart, brain, and kidneys. Compared with other methods of assessment, CEUS is portable, more economical, and uses a non-radiological contrast agent. However, the reliability of CEUS measures has been questioned. Therefore, there is a need to optimise and standardise protocols to establish the reliability of this method. As the magnitude of the stimulus used may affect the reliability of measures, this thesis first investigated the effect of cuff occlusion duration on skeletal muscle microvascular blood flow responsiveness in older adults (Study 1). This study demonstrated that CEUS-derived measures of skeletal muscle microvascular blood flow were significantly greater following a 5-min cuff occlusion (3.47 ± 1.48 aU.s-1) compared with a 1-min cuff occlusion (2.42 ± 1.27 aU.s-1, P = 0.002) (Chapter 3). Reliability was good following 5-min [intraclass correlation coefficient (ICC), 0.49] compared with poor following 1-min (ICC, 0.34) and 3-min (ICC, 0.35). To further explore the relationships between non-invasive measures of skeletal muscle microvascular blood flow responsiveness, the associations between CEUS and near-infrared spectroscopy (NIRS)-derived measures were investigated in older adults (Study 2). Strong correlations between the peak response (measured as 95% of the time to peak response) derived from CEUS and NIRS measures (r = 0.834, P < 0.001) and the corresponding rate of rise, measured as the slope of the response (r = 0.735, P = 0.004) were demonstrated (Chapter 4). The extent to which skeletal muscle microvascular blood flow responsiveness is affected in people with non-obstructive CAD is largely unknown. Using CEUS, this thesis aimed to determine the relationships between myocardial and skeletal muscle microvascular blood flow responsiveness in people with symptomatic myocardial ischaemia and non-obstructive CAD, and those with angiographically normal coronary arteries (Study 3, Chapter 5). No significant associations were demonstrated between dipyridamole-induced myocardial blood flow reserve (MBFR), calculated as the ratio of peak to resting myocardial blood flow, and skeletal muscle microvascular blood flow responsiveness. While MBFR was shown to be significantly higher in people with non-obstructive CAD (2.45 ± 0.44) compared with those with angiographically normal coronary arteries (2.09 ± 0.42, P = 0.026), no corresponding between-group difference in post-occlusion skeletal muscle microvascular blood flow was demonstrated. This thesis has established that the 1-min cuff occlusion protocols commonly used in CEUS studies may produce an insufficient stimulus for representative values of post-occlusion reactive hyperaemia to be assessed. Importantly, this research also demonstrates that the use of a longer 5-min cuff occlusion duration is associated with increased test-retest reliability, which provides a basis for the use of skeletal muscle microvascular assessments in future research and clinical practice. Considering the potential for skeletal muscle microvascular blood flow responsiveness to be assessed early in people at risk of microvascular dysfunction, including those with CVD, accurate and reliable measures are crucial prior to clinical use. Secondly, due to the non-invasive nature, low-cost and portability of NIRS devices, compared with the need for an intravenous ultrasound enhancing agent and the technical data analysis associated with CEUS, this research highlights the use of NIRS-derived measures as potentially useful surrogate markers of peripheral microvascular function for use in clinical assessments. Finally, this thesis established that measures of myocardial and skeletal muscle microvascular hyperaemia were not associated in people with symptomatic myocardial ischaemia and unobstructed coronary arteries. This raises important questions about the need for definitive cut-off values for impaired MBFR derived from MCE in people with unobstructed coronary arteries, and a need for further research to establish valid and reliable markers of myocardial microvascular dysfunction.

Skeletal muscle microvascular blood flow responsiveness: relationship with myocardial microvascular blood flow in coronary artery disease

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