Echocardiographic assessment of primary microvascular angina and primary coronary microvascular dysfunction

There is an increasing interest in the role of echocardiography in the evaluation of primary microvascular angina, which is attributed to primary coronary microvascular dysfunction. Valid echocardiographic techniques are expected to facilitate the diagnosis and follow-up of these patients and would be valuable for research purposes and therapy evaluation. However, adequate echocardiographic data are lacking, and the interpretation of the limited available literature is hindered by the previous addition of microvascular angina under more inclusive entities, such as cardiac syndrome X. In experienced hands, the assessment of primary coronary microvascular dysfunction in patients with suspected primary microvascular angina, using multiple echocardiographic techniques is feasible, relatively inexpensive, and safe. Exclusion of obstructive epicardial coronary artery disease is, however, a prerequisite for diagnosis. Two-dimensional transthoracic echocardiography, routine stress echocardiography, and speckle-tracking echocardiography indirectly assess primary coronary microvascular dysfunction by evaluating potential impairment in myocardial function and lack diagnostic sensitivity and specificity. Conversely, certain echocardiographic techniques, including Doppler-derived coronary flow velocity reserve and myocardial contrast echocardiography, assess some coronary microvascular dysfunction parameters and have exhibited diagnostic and prognostic potentials. Doppler-derived coronary flow velocity reserve is the best studied and only guideline-approved echocardiographic technique for documenting coronary microvascular dysfunction in patients with suspected microvascular angina. Myocardial contrast echocardiography, by comparison, can detect heterogeneous and patchy myocardial involvement by coronary microvascular dysfunction, which is an advantage over the common practice of coronary flow velocity reserve assessment in a single vessel (commonly the left anterior descending artery) which only reflects regional microvascular function. However, there is no consensus regarding the diagnostic criteria, and expertise performing this technique is limited. Echocardiography remains underexplored and inadequately utilized in the setting of microvascular angina and coronary microvascular dysfunction. Appraisal of the current echocardiographic literature regarding coronary microvascular dysfunction and microvascular angina is important to stay current with the progress in its clinical recognition and create a basis for future research and technological advancements.     

Ischemia-reperfusion-induced pancreatic microvascular injury

With the concept that ischemia-reperfusion injury may contribute to the pathogenesis of acute pancreatitis, we have quantitatively analyzed the pancreatic microcirculation of rats during postischemic reperfusion using intravital fluorescence microscopy. Ischemia to the pancreas of Sprague-Dawley rats (N=7) was induced by clamping the arteriae gastroduodenalis, lienalis, gastrica sinistra, and gastricae breves for 60 min followed by 120 min of reperfusion. Ischemic conditions were verified by measurement of microvascular hemoglobin oxygenation using reflection spectrophotometry (N=9). Postischemic reperfusion was characterized by a significant (P<0.05) reduction of functional capillary density to 69% of baseline (no reflow). Reperfusion-induced inflammatory response was reflected by a marked increase (100-fold;P<0.01) of the number of permanently adherent leukocytes in postcapillary venules (reflow paradox). Postischemic reperfusion was further associated with increased serum lipase activities, and histomorphological analysis revealed alterations, similar as known in acute interstitial pancreatitis, ie, neutrophil infiltration, interstitial edema, and hemorrhagic lesions. We, therefore, conclude that ischemia-reperfusion-associated events, ie, no reflow and reflow paradox, may be considered as trigger mechanisms in the manifestation of distinct types of acute pancreatitis, in particular posttransplant pancreatitis.     

Angiotensin II-mediated microvascular thrombosis

Hypertension is associated with an increased risk of thrombosis that appears to involve an interaction between the renin-angiotensin system and hemostasis. In this study we determined whether angiotensin II-mediated thrombosis occurs in arterioles and/or venules and assessed the involvement of type 1 (AT?), type 2 (AT?), and type 4 (AT?) angiotensin II receptors, as well as receptors for endothelin 1 and bradykinin 1 and 2 in angiotensin II-enhanced microvascular thrombosis. Thrombus development in mouse cremaster microvessels was quantified after light/dye injury using the time of onset of the thrombus and time to blood flow cessation. Wild-type and AT? receptor-deficient mice were implanted with an angiotensin II-loaded ALZET pump for 2 weeks. Angiotensin II administration in both wild-type and ATAT? receptor-deficient mice significantly accelerated thrombosis in arterioles. Genetic deficiency and pharmacological antagonism of AT? receptors did not alter the thrombosis response to angiotensin II. Isolated murine platelets aggregated in response to low (picomolar) but not high (nanomolar) concentrations of angiotensin II. The platelet aggregation response to angiotensin II depended on AT? receptors. Antagonism of AT? receptors in vivo significantly prolonged the onset of angiotensin II-enhanced thrombosis, whereas an AT? receptor antagonist prolonged the time to flow cessation. Selective antagonism of either endothelin 1 or bradykinin 1 receptors largely prevented both the onset and flow cessation responses to chronic angiotensin II infusion. Our findings indicate that angiotensin II induced hypertension is accompanied by enhanced thrombosis in arterioles, and this response is mediated by a mechanism that involves AT?, AT?, bradykinin 1, and endothelin 1 receptor-mediated signaling.     

Gender and microvascular angina

There are gender differences in the presentation, diagnosis, and treatment of chest pain. When compared to men, women may have more atypical presentations of chest pain. In addition, current diagnostic tools are often not definitive regarding cardiac etiology for chest pain in women. The current diagnostic model of chest pain focuses on significant obstructions within the large coronary arteries as the cause for angina. Microvascular angina (MVA) represents an under-recognized pathophysiologic mechanism that may explain the apparent disparities and elucidate an etiology for the common finding in women of chest pain, ischemia on stress testing, and no obstructive coronary artery disease (CAD) on angiography in the presence of abnormal coronary reactivity testing. Endothelial dysfunction, estrogen deficiency, and abnormal nociception play a role in the pathophysiology of MVA. Treatments are targeted toward these underlying mechanisms. Recognizing the role gender and other pathophysiologic models of chest pain can play in the work-up and treatment of angina may identify a treatable cardiac condition, that would otherwise be discounted as non-cardiac in origin.     

Hypertension and microvascular remodelling

In the present review, microvascular remodelling refers to alterations in the structure of resistance vessels contributing to elevated systemic vascular resistance in hypertension. We start with some historical aspects, underscoring the importance of Folkow's contribution made half a century ago. We then move to some basic concepts on the biomechanics of blood vessels, and explicit the definitions proposed by Mulvany for specific forms of remodelling, especially inward eutrophic and inward hypertrophic. The available evidence for the existence of remodelled resistance vessels in hypertension comes next, with relatively more weight given to human, in comparison with animal data. Mechanisms are discussed. The impact of antihypertensive drug treatment on remodelling is described, again with emphasis on human data. Some details are given on the three studies to date which point to remodelling of subcutaneous resistance arteries as an independent predictor of cardiovascular risk in hypertensive patients. We terminate by considering the potential role of remodelling in the pathogenesis of end-organ damage and in the perpetuation of hypertension.     

Mechanics of microvascular remodeling

This paper reviews work on microvascular remodeling that has been done over the past years in our lab. It is not our purpose to fully cover the field; rather we explain our progress in a more or less chronological order. We address physiological and pathological remodeling in resistance vessels, the biomechanics of the vascular wall and the factors that determine vascular caliber. Subsequently, the intimate link between maintained vascular tone and inward remodeling is discussed, and we highlight our view that tone and remodeling form hallmarks in a continuous process of vascular adaptation. Finally, the role of transglutaminases in remodeling is described.     

Aging-induced adaptations of microvascular reactivity

Control of blood flow to skeletal muscle depends on the vasomotor tone present in the resistance vasculature. Although muscle blood flow has been shown to decline with advancing age, our knowledge of how alterations of reactivity of the resistance vasculature contribute to reduced delivery or altered distribution of blood in the aged is limited. Recent work has demonstrated that age alters the reactivity of resistance arteries and arterioles from skeletal muscle, and that impairment of both vasodilator and vasoconstrictor responses occurs with advancing age. The alterations in cellular mechanisms that contribute to age-related impairment of vasoreactive responses encompass both the vascular endothelium and smooth muscle, and differ in muscles of varying function and fiber type. Current research suggests that some degree of age-induced endothelial dysfunction occurs in resistance arteries and arterioles from most skeletal muscle; however, the severity of endothelial impairment appears greater in resistance arteries and arterioles from highly oxidative locomotory muscles. Age-related impairment of vasoconstrictor responses to metabolites and endogenous constrictor agents has also been documented. These age-related reductions in vasoreactivity that occur in the skeletal muscle resistance vasculature may contribute to inadequate delivery or distribution of blood flow during exercise and ultimately be a factor in loss of exercise capacity that occurs with advancing age.     

Retroviral transformation of cerebral microvascular endothelial cells: macrophage-like and microvascular endothelial cell properties

We report that L-cell-conditioned medium (LCM) transforms porcine cerebral microvascular (PCMV) endothelial cells into cells with macrophage-like properties. LCM is known to contain both cytokine(s) and the L-cell virus, a murine retrovirus found in the L929 cell and LCM. Our evidence suggests that both LCM cytokine(s) and the L-cell virus are involved in this PCMV endothelial cell transformation. Criteria for transformation include focus formation, decreased serum requirements for growth, changes in morphology including nonadherence, propagation in suspension culture, and a decreased growth response to stimulation with a known endothelial cell mitogen. Macrophage-like characteristics of this transformed cell, designated as RVTE, include pinocytosis of low-density lipoprotein, Fc receptor-mediated phagocytosis, phagocytosis of bacteria and zymosan, the expression of macrophage enzyme markers, and constitutive production of colony-stimulating factor 1. However, the transformed cell retains several properties of the nontransformed cell including the expression of FVIII:RAg and in vitro self-organization into capillary-like structures. Cloning of RVTE cells clearly shows that both macrophage-like and cerebral microvascular endothelial cell properties are present in the same cell. During self-organization, nontransformed cells express morphologic and functional characteristics classically associated with the macrophage. These findings suggest that some brain capillary pathophysiologies could involve macrophage-like cerebral microvascular endothelial cells. Furthermore, the "reticuloendothelial" phenotypic repertoire expressed by this transformed cerebral microvascular endothelial cell may show that the cerebral capillary endothelial cell in vivo is derived from a hematopoietic and/or phagocytic precursor.     

Information transfer in microvascular networks

The adequate and efficient functioning of the circulatory system requires coordination of vessel diameters and of vascular responses to local and remote stimuli. Such coordination implies transfer of information about functional status and demands to all parts of the vascular system. In the peripheral circulation, blood flow must be controlled locally to accommodate spatial variations in demand. This requires information transfer from peripheral vessels to the more proximal vessels that feed and drain them. Principal mechanisms available for this information transfer are hemodynamic coupling, diffusive and convective transport of metabolites, and responses conducted along vessel walls. Current knowledge of these mechanisms is reviewed here. Theoretical models provide a framework for examining how information transfer mechanisms and vascular responses are integrated, so as to provide short-term regulation of blood flow and long-term structural adaptation of microvascular networks.     

Heterogeneous microvascular coronary alpha-adrenergic vasoconstriction

We tested the hypothesis that humoral or neurogenic alpha-adrenergic activation in the coronary circulation would produce heterogeneous vascular reactions. To accomplish this, the epicardial coronary microcirculation was viewed through an intravital microscope using stroboscopic epi-illumination. Microvascular diameters were measured under control conditions during beta-adrenergic blockade (propranolol 1 mg/kg) and beta-adrenergic blockade with pacing; during coronary alpha-adrenergic activation in the presence of beta-adrenergic blockade with three doses of norepinephrine infusion (0.1, 0.5, and 1.0-2.0 micrograms/kg/min) or three frequencies of bilateral stellate nerve stimulation (2, 10, and 20 Hz); and during combined alpha- and beta-adrenergic blockade (phentolamine 2 mg/kg and propranolol 1 mg/kg). Diameters of both arterial and venous vessels were reduced during beta-adrenergic blockade but returned back to baseline with pacing. At the lowest level of norepinephrine infusion or frequency of bilateral stellate stimulation, microvessel constriction was not observed. At the higher doses of norepinephrine a -5.1 +/- 0.9% (1.0-2.0 micrograms/kg/min) and a -4.0 +/- 1.1% (0.5 micrograms/kg/min) decrease in diameter of arterial vessels greater than 100 microns in diameter were observed (p less than 0.05). At 10 Hz and 20 Hz of stellate stimulation, diameter decreased by -4.8 +/- 1.9% and -4.4 +/- 2.1%, respectively, in these relatively large vessels. Small coronary arterioles (less than 100 microns diameter) dilated significantly during the highest levels of nerve stimulation (9.2 +/- 2.5% increase in diameter) or infusion rate of norepinephrine (13.6 +/- 2.7% increase in diameter) (p less than 0.05). These constrictor and dilator responses were abolished following combined alpha- and beta-adrenergic blockade. Norepinephrine infusion resulted in a decrease in diameter of coronary veins and venules (7.2 +/- 1.3%) (p less than 0.05), whereas stellate stimulation did not significantly reduce venous and venular diameters. In summary, the coronary venous and venular vasculature responds to alpha-adrenergic activation from circulating norepinephrine but is not affected by stellate stimulation. In contrast, stellate stimulation and norepinephrine infusion elicit similar responses in the coronary arterial and arteriolar microvasculature. Constriction occurs in vessels greater than 100 microns in diameter, whereas dilation predominates in vessels less than 100 microns in diameter. Such heterogeneous arterial responses would undoubtedly result in a redistribution of coronary vascular resistance toward larger coronary arteries and arterioles.     

Recent developments in microvascular angina

Microvascular angina (Syndrome X) is an extremely heterogeneous clinical entity that is the product of genetic, coronary microvascular, metabolic, and clinical factors, which combine together to produce distinct cardiac manifestations and complications. The interactions of these abnormalities remain poorly understood. The diagnosis is considered in patients with anginal symptoms and no epicardial coronary narrowing. Therapy is also problematic, with β-blockers as first-line pharmacotherapy followed by angiotensin-converting enzyme inhibitors and calcium channel blockers.     

Three-year follow-up of the Japanese patients with microvascular angina attributable to coronary microvascular spasm.

BACKGROUND: We recently reported that coronary microvascular spasm could cause angina in patients with chest pain and normal coronary arteriograms. However, the long-term prognosis of these patients or the effect of calcium channel blockers is not known. METHODS: Of consecutive 283 patients who underwent acetylcholine testing for the evaluation of chest pain, we identified 68 patients with microvascular angina attributable to coronary microvascular spasm. All patients were discharged on calcium channel blockers and followed up for an average period of 3.3 years. RESULTS: As compared with those having epicardial spasm (n=169), there was a female predominance in the microvascular spasm group (P<0.01), and 81% of the female patients were postmenopausal. During the follow-up, no patient died and one patient (1%) developed non-Q wave myocardial infarction. The frequency of chest pain was unchanged or increased in 24 patients (36%) and decreased or disappeared in 42 patients (64%). The angina status was improved only in 16 of 33 patients treated with calcium channel blockers alone. By contrast, it was improved in 18 of 21 patients on the combination of calcium channel blockers and angiotensin converting enzyme inhibitors (P<0.05). CONCLUSIONS: Patients with microvascular angina in the present study were more women and had a different risk factor profile as compared with those having epicardial spasm. Long-term prognosis was excellent with regard to mortality, but angina persisted in many patients even on calcium channel blockers. The result warrants prospective studies to evaluate the efficacy of angiotensin converting enzyme inhibitors as adjunct to calcium channel blockers in this population.