Elevated Microvascular Resistance Research Articles

Diseases of the Coronary Microcirculation: Diagnosis and Treatment.

Coronary microvascular dysfunction (CMD) comprises a variety of pathogenic mechanisms that impair the microcirculation of the heart. Clinical studies have shown that 30-50% of patients suffering from myocardial ischemia without significant coronary artery stenosis have CMD. The disease is associated with elevated mortality and poor quality of life. Whenever a patient presents with symptoms of angina pectoris and no underlying disease is detected by the usual methods, CMD should be considered a possible cause. This review is based on publications retrieved by a selective search in PubMed and on current international guidelines and recommendations of specialty societies. The diagnosis of CMD is based on objective evidence of a microvascular origin of symptoms. The guidelines contain a class IIa recommendation for invasive coronary flow reserve and microvascular resistance measurements. Noninvasive tests such as positron emission tomography and cardiac magnetic resonance imaging are less accurate and are given a class IIb recommendation. No high-quality therapeutic trials are available to date, and the treatment of CMD is thus based on that of chronic coronary syndrome. Lifestyle modification is performed to reduce risk factors. Patients with an abnormal coronary flow reserve or elevated microvascular resistance can be treated with an ACE inhibitor or angiotensin receptor blocker. Beta-blockers and calcium channel antagonists can relieve angina pectoris. Statins lower the LDL level and have positive pleiotropic effects. First-line treatment can be supplemented with further medications. Approximately 25% of patients with CMD have symptoms that do not respond to intensive treatment with the currently available modalities. New treatments, including interventional therapies, are being studied. Their long-term benefit remains to be assessed and compared to that of the existing methods.

Elevated Microvascular Resistance in Conjunction With Reduced Coronary Flow Reserve Predicts Adverse Long-Term Outcomes After Percutaneous Coronary Intervention

The index of microcirculatory resistance (IMR) and coronary flow reserve (CFR) are commonly used to assess the coronary microcirculation. However, their values are often contradictory and the prognostic impact of IMR and CFR discordance after percutaneous coronary intervention (PCI) is unknown.

Persistently Elevated Microvascular Resistance Postrecanalization.

Background and Purpose- Impaired microvascular reperfusion despite complete recanalization (no-reflow) represents a potential therapeutic target to improve outcomes after recanalization therapies. Although well documented in animal models, this phenomenon has not been demonstrated clinically. We investigated whether transcranial Doppler can detect acute microvascular changes postrecanalization as a biomarker of the no-reflow phenomenon in stroke patients. Methods- Consecutive patients with recanalized (Thrombolysis in Cerebral Infarction grade IIb/III) acute middle cerebral artery occlusion by thrombectomy at a Comprehensive Stroke Centre with a high-volume neurovascular laboratory were retrospectively identified. Sonographic measures of middle cerebral artery territory microvascular resistance (pulsatility index and resistive index) on days 1 to 3 follow-up transcranial Doppler were compared between patients and age/gender-matched controls. Results- In 53 patients, middle cerebral artery pulsatility index was significantly more likely to be asymmetrically increased on interside comparison (27.9% versus 4.9%; P=0.007) and abnormally elevated beyond normal reference ranges (46.7% versus 22.0%; P=0.016) in the symptomatic hemisphere. Middle cerebral artery pulsatility index elevation was associated with less hemorrhagic infarction (9.5% versus 45.8%; P=0.009) but worse functional outcome irrespective of infarct volume as assessed on 90-day modified Rankin Scale (score of ≤1, 18.2% versus 58.1%; P=0.035). Conclusions- Elevated microvascular resistance within the ischemic territory is commonly present after successful recanalization as measured by pulsatility index on transcranial Doppler and may be a readily available and clinically relevant biomarker of the no-reflow phenomenon.

Abstract 21224: Coronary Microvascular Dysfunction in Patients With Normal and Abnormal Diastolic Function in Patients With Heart Failure and Preserved Ejection Fraction

Introduction: A potential mechanism for impaired diastolic relaxation and stiffness in patients with heart failure with preserved ejection fraction (HFpEF) is the presence of coronary microvascular dysfunction (CMD). Invasive studies have demonstrated that HFpEF can be present in patients regardless of the presence or absence of echocardiographic diastolic dysfunction. Hypothesis: We hypothesize that CMD is common in HFpEF with normal and abnormal echocardiographic diastolic function. Methods: In a prospective study of HFpEF patients (n=30), clinical, echocardiographic, hemodynamic, and coronary physiology (CP) data were evaluated. CP parameters measured included coronary flow reserve (CFR) and index of microvascular resistance (IMR). Echocardiographic diastolic dysfunction (DD) was graded according to current ASE guidelines. Baseline clinical, echocardiographic, hemodynamic, and CP data were compared between grade 0 DD (n=10) and grade 1-3 DD (n=11), excluding patients with indeterminate DD grade (n=10). Results: Age, gender, and comorbidities were similar in the grade 0 compared to grade 1-3 DD groups. Median BNP was higher in the grade 1-3 compared to the grade 0 DD group (462 vs. 98, p=0.012). All DD and strain measurements were significantly abnormal in the grade 1-3 compared to grade 0 DD groups, as were mean pulmonary artery, and left-sided filling pressures. Mean IMR was elevated and similar in patients with and without DD (30.5 vs. 27.9, p=0.58), however mean CFR was abnormal and lower in the grade 1-3 compared to grade 0 DD groups (2.05 vs. 3.30, p=0.053). Conclusions: Although BNP, LV and left atrial strain, and LV filling pressures were higher in HFpEF patients with abnormal diastolic function compared to "normal" diastolic function, we found that elevated microvascular resistance is present in patients with HFpEF and "normal" diastolic function, but these patients have relatively preserved CFR.

The effect of microvascular pattern alterations on network resistance in spontaneously hypertensive rats

Structural microvascular rarefaction, defined by a loss of vessels, is a common characteristic of hypertension and has been associated with elevated microvascular resistance. However, determining the causal relationship between microvascular network structure and resistance requires a consideration of all pattern changes throughout a network. The objectives of this study were to determine whether microvascular rarefaction is associated with other network pattern alterations and to evaluate whether pattern alterations in hypertension necessarily contribute to increased microvascular resistance. Mesenteric tissues from age-matched (15-16weeks) male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were harvested and immunolabeled for PECAM. SHR networks displayed a decreased microvascular area, arteriolar-venular (AV) length, number of AV branches, and number of capillary segments. In addition, SHR networks displayed increased AV connections per network compared to WKY networks. Based on network geometries, resistance per network was calculated using a computational model. For simulations with equal vessel diameter and with relative diameters based on reported intravital measurements, SHR microvascular network resistance was not elevated compared to the WKY level. Our results suggest that microvascular pattern alterations associated with hypertension are more complex than vessel loss, and that these combined alterations do not necessarily lead to elevated resistance.

Effects of atherosclerosis on the coronary microcirculation

We tested the hypothesis that atherosclerosis potentiates coronary vasoconstriction to serotonin and ergonovine. Coronary microvascular pressures and diameters were measured in the beating left ventricle in normal and atherosclerotic cynomolgus monkeys. Pressures were measured in arteries (190-350 microns diam) that were distal to atherosclerotic lesions. Microvascular pressure and simultaneous measurements of aortic pressure and myocardial blood flow were used to calculate segmental vascular resistance (large artery resistance and microvascular resistance) during serotonin, phenylephrine, and ergonovine dosages. Aortic pressure was maintained constant during all interventions. Administration of phenylephrine (50 micrograms.kg-1.min-1 iv) produced a similar increase in microvascular resistance from base line (P less than 0.05) in atherosclerotic and normal animals, 26 +/- 5 and 14 +/- 9 mmHg.min.g.ml-1, respectively. Serotonin (50 micrograms/min) did not influence coronary resistance in normal animals but produced a significant increase in both large artery (8 +/- 3 mmHg.min.g.ml-1) and microvascular resistance (21 +/- 6 mmHg.min.g.ml-1) in atherosclerotic animals (P less than 0.05). A higher dose of serotonin (200 micrograms/min) produced a modest increase in large artery resistance from base line in normal animals (3 +/- 1 mmHg.min.g.ml-1) and a greater increase in atherosclerotic animals (9 +/- 4 mmHg.min.g.ml-1) (P less than 0.05 vs. normals). Ergonovine (10 micrograms.kg-1.min-1 iv) elevated microvascular resistance in both normal and atherosclerotic animals (P less than 0.05) but increased large artery resistance only in atherosclerotic animals (10 +/- 4 mmHg.min.g.ml-1) (P less than 0.05). In summary, coronary vasoconstrictor responses to serotonin and ergonovine were potentiated by atherosclerosis. Because augmented constrictor responses to serotonin were observed in both the diseased arteries and the microcirculation of atherosclerotic animals, we speculate that the pathophysiological consequences of atherosclerosis extend into the microcirculation.

Effects of α-Adrenoceptor Antagonists on Striated Muscle Microcirculation of Conscious Rats

Recent studies have shown an important role for the microcirculation in the pathogenesis and maintenance of hypertension (Bohlen 1989; Schmid-Schonbein & Chien 1986).The greatest increase in vascular resistance occurs in the smallest arteries and arterioles, of which the most important are those in skeletal muscle (Evenwel et al. J983). Mechanisms that cause elevated microvascular resistance are not yet completely understood but arteriolar diameters have been shown to be decreased (Bohlen 1983; Le Noble et al. 1990), perhaps because of a decrease in vascular wall: lumen ratio or an increase in microvascular tone. Furthermore, the absolute number of arterioles may be decreased , either temporarily (functional rarefaction) or permanently (anatomical or structural rarefaction). Adrenergic mechanisms play an important role in the regulation of vascular diameter and tone in general. There are several reports indicating that various vessel types are subserved by different a-adrenoceptor populations (Alabaster & Davey 1984; De Mey & Vanhoutte 1981; Heusch et al. 1984; Langer & Hicks 1984), and differences in aadrenoceptor subtype distribution might be involved in differential regulation of vascular tone at distinct vascular levels and in various beds (Faber 1988; Faber et al. 1988). Regulation of peripheral resistance via microvascular effects is essential for the explanation of the antihypertensive effects of o-adrenoceptor antagonists. Therefore , we investigated the effects of specific aland az-adrenoceptor antagonists on microvessels of the cutaneous maximus muscle of conscious spontaneously hypertensive rats (SHR).

Hemodynamics and microcirculatory alterations in reduced renal mass hypertension.

The objectives of this study were to determine the hemodynamic and microcirculatory changes that occur during reduced renal mass hypertension in rats. In conscious animals with 75% reduction of total renal mass, mean arterial pressure was initially (4-8 hours) elevated by 15-20 mm Hg during intravenous infusion with isonatremic (145.4 mM) NaCl. Cardiac index was elevated by 15-20%, and total peripheral resistance index was normal or reduced. Cardiac index subsequently returned toward normal, but mean arterial pressure remained elevated (20-40 mm Hg), presumably because of an elevated total peripheral resistance. Cremasteric arterioles were actively constricted (35-50%) in rats with short-term (36 hours), but not chronic (5-6 weeks) reduced renal mass hypertension. Total microvessel density was approximately 15% lower in maximally dilated cremaster muscles of chronically hypertensive rats versus sham-operated controls, which suggests that arterioles are lost during sustained reduced renal mass hypertension. Arteriolar constriction in response to increased superfusate PO2 (0% to 5% O2) was 2-4 times greater in rats with both short-term and chronic reduced renal mass hypertension than in normotensive controls, which suggests that oxygen-dependent autoregulatory mechanisms are altered. The hemodynamic and microcirculatory alterations observed in these experiments suggest that classic short-term autoregulatory mechanisms and an enhanced response of arterioles to increased oxygen availability contribute to the elevated total peripheral resistance in short-term reduced renal mass hypertension, whereas structural changes and altered vascular oxygen responses contribute to an elevated microvascular resistance in chronic reduced renal mass hypertension.

Microvascular pressure, flow, and resistance in spontaneously hypertensive rats.

Microvascular resistance (MVR), determined as the ratio of the second-order arteriolar blood pressure (servo-null method) to blood flow (dual-slit), was assessed in the cremaster muscle preparation of 7- to 8-week-old normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). The MVR was used as an index of resistance during 1) control conditions; 2) superfusion of graded concentrations of the catecholamine norepinephrine (NE; WKY n = 8, SHR n = 8); 3) superfusion with NE and in the presence of a fixed concentration of the vasodilator sodium nitroprusside (NP; 10(-5) M); and 4) superfusion with the noncatecholamine phenylephrine (PE; WKY n = 8, SHR n = 9). The vasoconstrictor challenges were carried out to determine if there was any differential vascular sensitivity between the hypertensive and nonhypertensive rats to the exposure of an endogenous-like constrictor possessing a catechol nucleus as opposed to a strictly synthetic analog. The presence of NP was employed to assess the degree of vasoconstriction normally present under control conditions. The combination of NE and NP was used to test for a differential vasoconstrictor sensitivity, beginning from maximally dilated conditions. The MVR, assessed at the second-order arteriolar level, represents approximately 35% of the total resistance of the skeletal muscle and is intimately involved in maintaining proper end-organ perfusion pressure. The microvascular resistance of the SHR group was almost four times greater than that of the WKY group under control conditions. Maximum vasodilation with topical NP reduced the MVR in both groups, but the SHR microvascular resistance remained two times greater than that found in the WKY. The SHR had greater MVR responses following challenge with both NE and PE and also in the presence of NP during NE challenge. The conclusions are: 1) the microvascular resistance of the SHR is elevated under control conditions due to structural modifications of the vasculature and exacerbated following constrictor challenge as a result of heightened vasoconstrictor sensitivity; and 2) the elevated MVR in the SHR is not due to a simple arterial vasoconstriction that can be totally eliminated with vasodilation.

Microcirculatory Blood Flow, Capillary Morphology, and Local Oxygen Pressure of the Hamster Amelanotic Melanoma A-Mel-3<xref ref-type="fn" rid="fn2">2</xref><xref ref-type="fn" rid="fn3">3</xref>

Transparent chambers and permanent indwelling catheters were implanted in the dorsal skin flaps of 24 inbred golden Syrian hamsters. After 48 hours, 4 x 10(4) amelanotic melanoma cells (A-Mel-3) were transplanted sc (12 hamsters) in areas exposed for intravital microscopy. A platinum multiwire electrode and techniques for a quantitative analysis of television images were used for measurements of local oxygen pressure (PO2), capillary blood cell velocity, capillary density, and capillary diameter and length, whereas capillary morphology was evaluated by electron microscopy. Compared to the mean local PO2 of the skin flaps of controls (12 hamsters), the mean local PO2 on the tumor surface of melanoma-bearing hamsters decreased with tumor size. Although capillary density of the melanoma was elevated 4 days after tumor transplantation, it decreased significantly until day 12. Of hemodynamic significance were huge platelet conglomerates in short, dilated capillaries. Electron microscopy revealed endothelial hyperplasia, open endothelial junctions, and disintegration of the capillary endothelium. These findings strongly suggest that elevated microvascular resistance, intratumor tissue pressure, and widening of intercapillary distances in the melanoma might significantly diminish the impact of chemotherapeutic treatment.