Effects of graded reductions in coronary perfusion pressure on the diastolic pressure-segment length relation and the rate of isovolumic relaxation in the resting conscious dog.

Farhi, E R; Canty, John M.; Klocke, Francis J.

doi:10.1161/01.cir.80.5.1458

Cited by 16 publications

(5 citation statements)

References 45 publications

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“…A central role for co-morbidity-induced microvascular dysfunction underlying the development of cardiac diastolic dysfunction has recently been proposed. Indeed, although independent of risk factors, a link between impaired coronary O 2 delivery and impaired cardiac ventricular function has been reported in chronically instrumented dogs [16] and swine [24]. In the present study, FH swine exhibited a significant impairment of cardiac efficiency and stroke volume as well as increased left atrial pressures.…”

Section: Discussionsupporting

confidence: 45%

Severe familial hypercholesterolemia impairs the regulation of coronary blood flow and oxygen supply during exercise

et al. 2016

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Accelerated development of coronary atherosclerosis is a defining characteristic of familial hypercholesterolemia (FH). However, the recent data highlight a significant cardiovascular risk prior to the development of critical coronary stenosis. We, therefore, examined the hypothesis that FH produces coronary microvascular dysfunction and impairs coronary vascular control at rest and during exercise in a swine model of FH. Coronary vascular responses to drug infusions and exercise were examined in chronically instrumented control and FH swine. FH swine exhibited ~tenfold elevation of plasma cholesterol and diffuse coronary atherosclerosis (20-60 % plaque burden). Similar to our recent findings in the systemic vasculature in FH swine, coronary smooth muscle nitric oxide sensitivity was increased in vivo and in vitro with maintained endothelium-dependent vasodilation in vivo in FH. At rest and during exercise, FH swine exhibited increased myocardial O2 extraction resulting in reduced coronary venous SO2 and PO2 versus control. During exercise in FH swine, the transmural distribution of coronary blood flow was unchanged; however, a shift toward anaerobic cardiac metabolism was revealed by increased coronary arteriovenous H(+) concentration gradient. This shift was associated with a worsening of cardiac efficiency (relationship between cardiac work and O2 consumption) in FH during exercise owing, in part, to a generalized reduction in stroke volume which was associated with increased left atrial pressure in FH. Our data highlight a critical role for coronary microvascular dysfunction as a contributor to impaired myocardial O2 balance, cardiac ischemia, and impaired cardiac function prior to the development of critical coronary stenosis in FH.

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Section: Discussionsupporting

confidence: 45%

Severe familial hypercholesterolemia impairs the regulation of coronary blood flow and oxygen supply during exercise

et al. 2016

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“…For instance, in healthy dogs, reduced coronary perfusion increases cardiac isovolumic relaxation time (i.e., impaired cardiac relaxation) 28 . In agreement with previous work 20,21 , ZO rats demonstrated impaired coronary arteriolar vasodilation at 14–16 weeks of age that was normalized by LSp beginning at 29 wk of age and this may explain the improvement in CFR in type 2 diabetic patients following MR blockade 13 .…”

Section: Discussionmentioning

confidence: 99%

Mineralocorticoid Receptor Antagonism Treats Obesity-Associated Cardiac Diastolic Dysfunction

et al. 2015

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Patients with obesity and diabetes exhibit a high prevalence of cardiac diastolic dysfunction (DD), an independent predictor of cardiovascular events for which no evidence-based treatment exists. In light of renin-angiotensin-aldosterone system activation in obesity and the cardioprotective action of mineralocorticoid receptor (MR) antagonists in systolic heart failure, we examined the hypothesis that MR blockade with a blood pressure-independent low dose spironolactone (LSp) would treat obesity-associated DD in the Zucker obese (ZO) rat. Treatment of ZO rats exhibiting established DD with LSp normalized cardiac diastolic function, assessed by echocardiography. This was associated with reduced cardiac fibrosis, but not reduced hypertrophy, and restoration of endothelium-dependent vasodilation of isolated coronary arterioles via a nitric oxide-independent mechanism. Further mechanistic studies revealed that LSp reduced cardiac oxidative stress and improved endothelial insulin signaling with no change in arteriolar stiffness. Infusion of Sprague-Dawley rats with the MR agonist aldosterone reproduced the DD noted in ZO rats. Additionally, improved cardiac function in ZO-LSp rats was associated with attenuated systemic and adipose inflammation and an anti-inflammatory shift in cardiac immune cell mRNAs. Specifically, LSp increased cardiac markers of alternatively activated macrophages and regulatory T cells. ZO-LSp rats had unchanged blood pressure, serum potassium, systemic insulin sensitivity, or obesity-associated kidney injury, assessed by proteinuria. Taken together, these data demonstrate that MR antagonism effectively treats established obesity-related DD via blood pressure-independent mechanisms. These findings help identify a particular population with DD that might benefit from MR antagonist therapy, specifically patients with obesity and insulin resistance.

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“…This phenomenon was attributed to an "erectile effect" of the coronary vasculature. Although some investigators could not reproduce this effect (1,398), it is generally agreed that an increase in coronary perfusion shifts the diastolic ventricular pressure-volume relationship upward and leftward, leading to increased ventricular stiffness (89,121,130,131,287,289,304,313,334,431,449). However, there is discussion whether flow is related to shear force or to pressure in the vasculature, or both (212).…”

Section: A Coronary Flow and Cardiac Muscle In Diastolementioning

confidence: 99%

Cross-Talk Between Cardiac Muscle and Coronary Vasculature

Westerhof¹,

Boer²,

Lamberts³

et al. 2006

Physiological Reviews

231

209

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The cardiac muscle and the coronary vasculature are in close proximity to each other, and a two-way interaction, called cross-talk, exists. Here we focus on the mechanical aspects of cross-talk including the role of the extracellular matrix. Cardiac muscle affects the coronary vasculature. In diastole, the effect of the cardiac muscle on the coronary vasculature depends on the (changes in) muscle length but appears to be small. In systole, coronary artery inflow is impeded, or even reversed, and venous outflow is augmented. These systolic effects are explained by two mechanisms. The waterfall model and the intramyocardial pump model are based on an intramyocardial pressure, assumed to be proportional to ventricular pressure. They explain the global effects of contraction on coronary flow and the effects of contraction in the layers of the heart wall. The varying elastance model, the muscle shortening and thickening model, and the vascular deformation model are based on direct contact between muscles and vessels. They predict global effects as well as differences on flow in layers and flow heterogeneity due to contraction. The relative contributions of these two mechanisms depend on the wall layer (epi- or endocardial) and type of contraction (isovolumic or shortening). Intramyocardial pressure results from (local) muscle contraction and to what extent the interstitial cavity contracts isovolumically. This explains why small arterioles and venules do not collapse in systole. Coronary vasculature affects the cardiac muscle. In diastole, at physiological ventricular volumes, an increase in coronary perfusion pressure increases ventricular stiffness, but the effect is small. In systole, there are two mechanisms by which coronary perfusion affects cardiac contractility. Increased perfusion pressure increases microvascular volume, thereby opening stretch-activated ion channels, resulting in an increased intracellular Ca2+ transient, which is followed by an increase in Ca2+ sensitivity and higher muscle contractility (Gregg effect). Thickening of the shortening cardiac muscle takes place at the expense of the vascular volume, which causes build-up of intracellular pressure. The intracellular pressure counteracts the tension generated by the contractile apparatus, leading to lower net force. Therefore, cardiac muscle contraction is augmented when vascular emptying is facilitated. During autoregulation, the microvasculature is protected against volume changes, and the Gregg effect is negligible. However, the effect is present in the right ventricle, as well as in pathological conditions with ineffective autoregulation. The beneficial effect of vascular emptying may be reduced in the presence of a stenosis. Thus cardiac contraction affects vascular diameters thereby reducing coronary inflow and enhancing venous outflow. Emptying of the vasculature, however, enhances muscle contraction. The extracellular matrix exerts its effect mainly on cardiac properties rather than on the cross-talk between cardiac muscle and coronary c...

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Effects of graded reductions in coronary perfusion pressure on the diastolic pressure-segment length relation and the rate of isovolumic relaxation in the resting conscious dog.

Cited by 16 publications

References 45 publications

Severe familial hypercholesterolemia impairs the regulation of coronary blood flow and oxygen supply during exercise

Severe familial hypercholesterolemia impairs the regulation of coronary blood flow and oxygen supply during exercise

Mineralocorticoid Receptor Antagonism Treats Obesity-Associated Cardiac Diastolic Dysfunction

Cross-Talk Between Cardiac Muscle and Coronary Vasculature

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