Myocardial Perfusion in Hypoplastic Left Heart Syndrome: Risk Factors for the Right Ventricular Microcirculation

Background: The status of the systemic right ventricular coronary microcirculation in hypoplastic left heart syndrome (HLHS) is largely unknown. It is presumed that the systemic right ventricle’s coronary microcirculation exhibits unique pathophysiological characteristics of HLHS in Fontan circulation. The present study sought to quantify myocardial blood flow by cardiac magnetic resonance imaging and evaluate the determinants of microvascular coronary dysfunction and myocardial ischemia in HLHS. Methods: One hundred nineteen HLHS patients (median age, 4.80 years) and 34 healthy volunteers (median age, 5.50 years) underwent follow-up cardiac magnetic resonance imaging ≈1.8 years after total cavopulmonary connection. Right ventricle volumes and function, myocardial perfusion, diffuse fibrosis, and late gadolinium enhancement were assessed in 4 anatomic HLHS subtypes. Myocardial blood flow (MBF) was quantified at rest and during adenosine-induced hyperemia. Coronary conductance was estimated from MBF at rest and catheter-based measurements of mean aortic pressure (n=99). Results: Hyperemic MBF in the systemic ventricle was lower in HLHS compared with controls (1.89±0.57 versus 2.70±0.84 mL/g per min; P <0.001), while MBF at rest normalized by the rate-pressure product, was similar (1.25±0.36 versus 1.19±0.33; P =0.446). Independent risk factors for a reduced hyperemic MBF were an HLHS subtype with mitral stenosis and aortic atresia ( P =0.017), late gadolinium enhancement ( P =0.042), right ventricular diastolic dysfunction ( P =0.005), and increasing age at total cavopulmonary connection ( P =0.022). The coronary conductance correlated negatively with systemic blood oxygen saturation (r, −0.29; P =0.02). The frequency of late gadolinium enhancement increased with age at total cavopulmonary connection ( P =0.014). Conclusions: The coronary microcirculation of the systemic ventricle in young HLHS patients shows significant differences compared with controls. These hypothesis-generating findings on HLHS-specific risk factors for microvascular dysfunction suggest a potential benefit from early relief of frank cyanosis by total cavopulmonary connection.

Abstract 067: Long-Term Ivabradine Treatment Does Not Preserve Myocardial Perfusion and Coronary Reserve in Middle-Aged Rats with Large Myocardial Infarction

Background: We have previously shown that 1-month treatment with ivabradine (IVA), the selective cardiac pacemaker I f current inhibitor, preserved myocardial perfusion and coronary perfusion reserve in post-MI middle-aged rats. However, the persistence of this cardioprotective effect after a prolonged period of IVA treatment remains to be determined. Methods: Acute MI was induced in 12-month-old male Sprague-Dawley rats by left coronary artery ligation. Twenty four hours later, the rats with a confirmed large transmural MI (>50% of the left ventricular (LV) free wall) were randomly assigned in two experimental groups. In a first group, rats were treated with IVA i.p. via osmotic pumps in a dose of 10.5 mg/kg/day for 3 months (MI+IVA). In a second group, rats received placebo treatment (5% dextrose) during the same time period (MI). Sham-operated rats served as an age-matched control. At the end of experimental period, myocardial perfusion (baseline and maximal coronary conductance per 100g of tissue) and coronary perfusion reserve (fold increase between baseline and maximal coronary conductance) were determined in non-infarcted LV free wall and interventricular septum by using the neutron-activated stable isotope-labeled microsphere technique. Results: During 3 months of IVA treatment, heart rate in MI+IVA rats was consistently reduced compared to untreated MI rats by mean of 30.6%. Nevertheless, we found that the infarct size and the extent of LV remodeling were relatively comparable between MI and MI+IVA rats three months after surgery. Moreover, the levels of baseline and maximal coronary conductance were similar in LV free wall and septum between two experimental groups. Consequently, IVA-treated rats revealed no difference in coronary perfusion reserve as compared to untreated post-MI animals (2.22±0.46 vs. 2.59±0.41 in LV free wall and 2.30±0.59 vs. 2.68±0.44 in septum, respectively). However, the rats of both post-MI groups had markedly reduced levels of maximal coronary blood flow as compared to non-infarcted controls (p≤0.01). Conclusion: Our data demonstrate that long-term IVA treatment does not provide sustainable improvement in LV myocardial perfusion and coronary perfusion reserve in middle-aged rats following large MI.

Acute attenuation of glycocalyx barrier properties increases coronary blood volume independently of coronary flow reserve

Vascular endothelium is covered with an extensive mesh of glycocalyx constituents, which acts like an effective barrier up to several micrometers thick that shields the luminal surface of the vasculature from direct exposure to flowing blood. Many studies report that various enzymatic and pharmaceutical challenges are able to increase glycocalyx porosity, resulting in farther permeation of plasma macromolecules and greater access of red blood cells into glycocalyx domain. Attenuation of glycocalyx barrier properties therefore potentially increases the amount of blood that effectively occupies available microvascular volume. We tested in the present study whether attenuation of coronary glycocalyx barrier properties actually increases coronary blood volume and whether such changes would be noticeable during measurements of coronary flow reserve using adenosine. In anesthetized goats ( n = 6) with cannulated left main coronary artery that were perfused under controlled pressure, coronary blood volume was measured via the indicator-dilution technique using high-molecular-weight (2,000 kDa) dextrans as plasma tracer and labeled red blood cells as red blood cell tracer. Coronary blood volume was determined at baseline and during intracoronary infusion of adenosine causing maximal vasodilation (0.2–0.6 mg·kg−1·h−1) before and after intracoronary hyaluronidase treatment (170,000 units) of the glycocalyx. With an intact glycocalyx, coronary blood volume was 18.9 ± 1.1 ml/100 g heart tissue at baseline, which increased to 26.3 ± 2.7 ml/100 g after hyaluronidase treatment of the coronary glycocalyx. Maximal vasodilation by administration of adenosine further increased coronary blood volume to 33.9 ± 6.8 ml/100 g, a value not different from the maximal coronary blood volume of 33.2 ± 5.3 ml/100 g obtained by administration of adenosine in the absence of hyaluronidase treatment. Adenosine-induced increases in coronary conductance were not affected by hyaluronidase treatment. We conclude that acute attenuation of glycocalyx barrier properties increases coronary blood volume by ∼40%, which is of similar magnitude as additional changes in coronary blood volume during subsequent maximal vasodilation with adenosine. Furthermore, maximal coronary blood volume following administration of adenosine was similar with and without prior hyaluronidase degradation of the glycocalyx, suggesting that adenosine and hyaluronidase potentially increase glycocalyx porosity to a similar extent. Hyaluronidase-mediated changes in coronary blood volume did not affect baseline and adenosine-induced increases in coronary conductance, demonstrating that measurements of coronary flow reserve are insufficient to detect impairment of coronary blood volume recruitment in conditions of damaged glycocalyx.

Hyaluronidase treatment of coronary glycocalyx increases reactive hyperemia but not adenosine hyperemia in dog hearts

Because adenosine is commonly used for inducing maximal coronary hyperemia in the clinic, it is imperative that adenosine-induced hyperemia (AH) resembles coronary hyperemia that can be attained by endogenous stimuli. In the present study we hypothesized that coronary reactive hyperemia (RH) is limited compared with AH due to the presence of the glycocalyx and that the AH response is therefore unable to detect glycocalyx modifications. In anesthetized open-chest dogs, blood flow and pressure were measured in the left circumflex artery. RH after 15-s occlusion was compared with an intracoronary infusion of adenosine (650 μg; AH) during control conditions and after intracoronary treatment of the glycocalyx with hyaluronidase (20.000 U, 2 × 20 min; n = 6) or heat-inactivated hyaluronidase ( n = 5). During control, coronary conductance during RH was 1.49 ± 0.15 ml·mmHg−1·min−1 and 76 ± 7% of coronary conductance during AH ( P < 0.05). After hyaluronidase, RH conductance increased ( P < 0.01) by 43 ± 13% and became 93 ± 4% of AH conductance ( P = NS). Heat-inactivated hyaluronidase had no effect on RH and AH conductance. Our results demonstrate that adenosine-induced coronary hyperemia profoundly exceeds RH and that the difference is virtually abolished on selective removal of the glycocalyx. It is concluded that, compared with RH, adenosine-induced coronary hyperemia is not affected by modification of the glycocalyx. This glycocalyx insensitivity should be taken into account when using adenosine-induced coronary hyperemia as a marker for vasodilating capacity to an ischemic stimulus.

Mechanisms of Oxygen Demand/Supply Balance in the Right Ventricle

Few studies have investigated factors responsible for the O2 demand/supply balance in the right ventricle. Resting right coronary blood flow is lower than left coronary blood flow, which Is consistent with the lesser work of the right ventricle. Because right and left coronary artery perfusion pressures are Identical, right coronary conductance is less than left coronary conductance, but the signal relating this conductance to the lower right ventricular O2 demand has not been defined. At rest, the left ventricle extracts ~75% of the O2 delivered by coronary blood flow, whereas right ventricular O2 extraction Is only ~50%. As a result, resting right coronary venous PO2 is ~30 mm Hg, whereas left coronary venous PO2 is ~20 mm Hg. Right coronary conductance does not sufficiently restrict flow to force the right ventricle to extract the same percentage of O2 as the left ventricle. Endogenous nitric oxide impacts the right ventricular O2 demand/supply balance by increasing the right coronary blood flow at rest and during acute pulmonary hypertension, systemic hypoxia, norepinephrine infusion, and coronary hypoperfusion. The substantial right ventricular O2 extraction reserve is used preferentially during exercise-induced increases in right ventricular myocardial O2 consumption. An augmented, sympathetic-mediated vasoconstrictor tone blunts metabolically mediated dilator mechanisms during exercise and forces the right ventricle to mobilize its O2 extraction reserve, but this tone does not limit resting right coronary flow. During exercise, right coronary vasodilation does not occur until right coronary venous PO2 decreases to ~20 mm Hg. The mechanism responsible for right coronary vasodilation at low PO2 has not been delineated. In the poorly autoregulating right coronary circulation, reduced coronary pressure unloads the coronary hydraulic skeleton and reduces right ventricular systolic stiffness. Thus, normal right ventricular external work and O2 demand/supply balance can be maintained during moderate coronary hypoperfusion.

Estrogen therapy induces collateral and microvascular remodeling

Estrogen increases proliferation and migration of cultured endothelial cells and perfusion of ischemic hindlimbs of rabbits. We tested the hypothesis that estrogen is angiogenic and arteriogenic in the heart during progressive coronary occlusion. Ovariectomized (OVX) and 17β-estradiol (1 mg · kg–1 · wk–1 im)-treated OVX (OVX-ES) female New Zealand White rabbits were instrumented with an ameroid occluder on a proximal coronary artery. Four weeks after implantation of an ameroid occluder, we measured myocardial perfusion with microspheres at rest and during adenosine-induced maximal vasodilation. The heart was fixed by perfusion at physiological pressure, and capillary angiogenesis and remodeling were assessed by image analysis of tissue sections in collateral-dependent myocardium. Coronary conductance was higher at rest and during maximal vasodilation in collateral-dependent myocardium of OVX-ES than OVX rabbits. Estrogen treatment increased the wall-to-lumen ratio of collateral vessels while it decreased the wall-to-lumen ratio of noncollateral arteries in normal regions. In normal and collateral-dependent myocardium, mean capillary diameter and capillary volume density were greater in OVX-ES rabbits. However, estrogen had no effect on capillary length density in either region of the myocardium. These data suggest that estrogen induces remodeling of the collateral vasculature and may stimulate growth of the resistance vessels, thereby providing protection during development of a gradual coronary occlusion.