Abstract
AimsCoronary microvascular smooth muscle cells (SMCs) respond to luminal pressure by developing myogenic tone (MT), a process integral to the regulation of microvascular perfusion. The cellular mechanisms underlying poor myogenic reactivity in patients with heart valve disease are unknown and form the focus of this study.Methods and resultsIntramyocardial coronary micro-arteries (IMCAs) isolated from human and pig right atrial (RA) appendage and left ventricular (LV) biopsies were studied using pressure myography combined with confocal microscopy. All RA- and LV-IMCAs from organ donors and pigs developed circa 25% MT. In contrast, 44% of human RA-IMCAs from 88 patients with heart valve disease had poor (<10%) MT yet retained cell viability and an ability to raise cytoplasmic Ca2+ in response to vasoconstrictor agents. Comparing across human heart chambers and species, we found that based on patient medical history and six tests, the strongest predictor of poor MT in IMCAs was increased expression of the synthetic marker caldesmon relative to the contractile marker SM-myosin heavy chain. In addition, high resolution imaging revealed a distinct layer of longitudinally aligned SMCs between ECs and radial SMCs, and we show poor MT was associated with disruptions in these cellular alignments.ConclusionThese data demonstrate the first use of atrial and ventricular biopsies from patients and pigs to reveal that impaired coronary MT reflects a switch of viable SMCs towards a synthetic phenotype, rather than a loss of SMC viability. These arteries represent a model for further studies of coronary microvascular contractile dysfunction.
Highlights
This study reports the outcomes of assessing pressure-induced MT for each intramyocardial coronary micro-arteries (IMCAs) studied from every biopsy transported to the laboratory, without exclusion
We commenced our succession of protocols using surgically provided biopsies (h-right atrial (RA)-IMCAs) (Figure 1A–C) and later extended these to include (i) RA and left and results ventricular (LV) IMCAs from organ donor procedures; and (ii) porcine IMCAs (p-RA-IMCAs and p-LV-IMCAs)
The key finding of this study is the demonstration that poor MT observed in human IMCAs (h-IMCAs) isolated from non-ischaemic human myocardium is associated with a synthetic phenotype in still viable radial SMC (r-SMC)
Summary
Coronary vascular smooth muscle cells (SMCs) exert physiological functions through both contractile and synthetic SMC phenotypes, together maintaining effective function of the coronary circulation.[1,2] Within the coronary microcirculation, contractile SMCs exert myogenic reactivity and tone,[3,4] which is an important regulator of myocardial perfusion.[3,4,5,6,7,8,9] contractile SMCs react to vasoactive factors acting directly on SMCs or via the endothelium, often released and acting in response to metabolic demand.[3,4,5,6,7,8,9] In parallel, synthetic SMCs secrete extracellular matrix components and may increase proliferation and migration during vessel remodelling, e.g. exercise, pregnancy, or vascular repair.[1,2,10] The role of contractile and synthetic SMCs in intramyocardial coronary micro-arteries (IMCAs) in patients with no significant coronary ischaemic disease has not been investigated. Coronary microvascular dysfunction in the absence of obstructive coronary disease is associated with anginalike chest pain, heart failure, inflammation, and poor prognosis.[11,12,13,14,15,16,17] the causes of the microvascular dysfunction, in particular poor myogenic reactivity, in isolated human IMCAs (h-IMCAs) from viable myocardia are not known, and this knowledge is of prime importance for myocardial function
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