Cardiovascular consequences of metabolic syndrome Tune, Johnathan D; Goodwill, Adam G; Sassoon, Daniel J ...
Translational research : the journal of laboratory and clinical medicine,
05/2017, Letnik:
183
Journal Article
Recenzirano
Odprti dostop
The metabolic syndrome (MetS) is defined as the concurrence of obesity-associated cardiovascular risk factors including abdominal obesity, impaired glucose tolerance, hypertriglyceridemia, decreased ...HDL cholesterol, and/or hypertension. Earlier conceptualizations of the MetS focused on insulin resistance as a core feature, and it is clearly coincident with the above list of features. Each component of the MetS is an independent risk factor for cardiovascular disease and the combination of these risk factors elevates rates and severity of cardiovascular disease, related to a spectrum of cardiovascular conditions including microvascular dysfunction, coronary atherosclerosis and calcification, cardiac dysfunction, myocardial infarction, and heart failure. While advances in understanding the etiology and consequences of this complex disorder have been made, the underlying pathophysiological mechanisms remain incompletely understood, and it is unclear how these concurrent risk factors conspire to produce the variety of obesity-associated adverse cardiovascular diseases. In this review, we highlight current knowledge regarding the pathophysiological consequences of obesity and the MetS on cardiovascular function and disease, including considerations of potential physiological and molecular mechanisms that may contribute to these adverse outcomes.
The goal of the present study was to evaluate the effects of SGLT2i on cardiac contractile function, substrate utilization, and efficiency before and during regional myocardial ischemia/reperfusion ...injury in normal, metabolically healthy swine. Lean swine received placebo or canagliflozin (300 mg PO) 24 h prior to and the morning of an invasive physiologic study protocol. Hemodynamic and cardiac function measurements were obtained at baseline, during a 30-min complete occlusion of the circumflex coronary artery, and during a 2-h reperfusion period. Blood pressure, heart rate, coronary flow, and myocardial oxygen consumption were unaffected by canagliflozin treatment. Ventricular volumes remained unchanged in controls throughout the protocol. At the onset of ischemia, canagliflozin produced acute large increases in left ventricular end-diastolic and systolic volumes which returned to baseline with reperfusion. Canagliflozin-mediated increases in end-diastolic volume were directly associated with increases in stroke volume and stroke work relative to controls during ischemia. Canagliflozin also increased cardiac work efficiency during ischemia relative to control swine. No differences in myocardial uptake of glucose, lactate, free fatty acids or ketones, were noted between treatment groups at any time. In separate experiments using a longer 60 min coronary occlusion followed by 2 h of reperfusion, canagliflozin increased end-diastolic volume and stroke volume and significantly diminished myocardial infarct size relative to control swine. These data demonstrate that SGLT2i with canagliflozin preserves cardiac contractile function and efficiency during regional myocardial ischemia and provides ischemia protection independent of alterations in myocardial substrate utilization.
OBJECTIVE—The effects of coronary perivascular adipose tissue (PVAT) on vasomotor tone are influenced by an obese phenotype and are distinct from other adipose tissue depots. The purpose of this ...investigation was to examine the effects of lean and obese coronary PVAT on end-effector mechanisms of coronary vasodilation and to identify potential factors involved.
APPROACH AND RESULTS—Hematoxylin and eosin staining revealed similarities in coronary perivascular adipocyte size between lean and obese Ossabaw swine. Isometric tension studies of isolated coronary arteries from Ossabaw swine revealed that factors derived from lean and obese coronary PVAT attenuated vasodilation to adenosine. Lean coronary PVAT inhibited KCa and KV7, but not KATP channel-mediated dilation in lean arteries. In the absence of PVAT, vasodilation to KCa and KV7 channel activation was impaired in obese arteries relative to lean arteries. Obese PVAT had no effect on KCa or KV7 channel-mediated dilation in obese arteries. In contrast, obese PVAT inhibited KATP channel-mediated dilation in both lean and obese arteries. The differential effects of obese versus lean PVAT were not associated with changes in either coronary KV7 or KATP channel expression. Incubation with calpastatin attenuated coronary vasodilation to adenosine in lean but not in obese arteries.
CONCLUSIONS—These findings indicate that lean and obese coronary PVAT attenuates vasodilation via inhibitory effects on vascular smooth muscle K channels and that alterations in specific factors such as calpastatin are capable of contributing to the initiation or progression of smooth muscle dysfunction in obesity.
Our understanding of the pathophysiological basis of chronic thromboembolic pulmonary hypertension (CTEPH) will be accelerated by an animal model that replicates the phenotype of human CTEPH. ...Sprague-Dawley rats were administered a combination of a single dose each of plastic microspheres and vascular endothelial growth factor receptor antagonist in polystyrene microspheres (PE) + tyrosine kinase inhibitor SU5416 (SU) group. Shams received volume-matched saline; PE and SU groups received only microspheres or SU5416, respectively. PE + SU rats exhibited sustained pulmonary hypertension (62 ± 13 and 53 ± 14 mmHg at 3 and 6 weeks, respectively) with reduction of the ventriculoarterial coupling in vivo coincident with a large decrement in peak rate of oxygen consumption during aerobic exercise, respectively. PE + SU produced right ventricular hypokinesis, dilation, and hypertrophy observed on echocardiography, and 40% reduction in right ventricular contractile function in isolated perfused hearts. High-resolution computed tomographic pulmonary angiography and Ki-67 immunohistochemistry revealed abundant lung neovascularization and cellular proliferation in PE that was distinctly absent in the PE + SU group. We present a novel rodent model to reproduce much of the known phenotype of CTEPH, including the pivotal pathophysiological role of impaired vascular endothelial growth factor–dependent vascular remodeling. This model may reveal a better pathophysiological understanding of how PE transitions to CTEPH in human treatments.
The local metabolic hypothesis proposes that myocardial oxygen tension determines the degree of autoregulation by increasing the production of vasodilator metabolites as perfusion pressure is ...reduced. Thus, normal physiologic levels of coronary venous PO
2
, an index of myocardial oxygenation, are proposed to be required for effective autoregulation. The present study challenged this hypothesis through determination of coronary responses to changes in coronary perfusion pressure (CPP 140–40 mmHg) in open-chest swine in the absence (
n
= 7) and presence of euvolemic hemodilution (~ 50% reduction in hematocrit), with (
n
= 5) and without (
n
= 6) infusion of dobutamine to augment MVO
2
. Coronary venous PO
2
decreased over similar ranges (~ 28–15 mmHg) as CPP was lowered from 140 to 40 mmHg in each of the groups. However, coronary venous PO
2
was not associated with changes in coronary blood flow (
r
= − 0.11;
P
= 0.29) or autoregulatory gain (
r
= − 0.29;
P
= 0.12). Coronary zero-flow pressure (Pzf) was measured in 20 mmHg increments and determined to be directly related to vascular resistance (
r
= 0.71;
P
< 0.001). Further analysis demonstrated that changes in coronary blood flow remained minimal at Pzf > 20 mmHg, but progressively increased as Pzf decreased below this threshold value (
r
= 0.68;
P
< 0.001). Coronary Pzf was also positively correlated with autoregulatory gain (
r
= 0.43;
P
= 0.001). These findings support that coronary autoregulatory behavior is predominantly dependent on an adequate degree of underlying vasomotor tone, independent of normal myocardial oxygen tension.
Recognition that coronary blood flow is tightly coupled with myocardial metabolism has been appreciated for well over half a century. However, exactly how coronary microvascular resistance is tightly ...coupled with myocardial oxygen consumption (MV̇o
) remains one of the most highly contested mysteries of the coronary circulation to this day. Understanding the mechanisms responsible for local metabolic control of coronary blood flow has been confounded by continued debate regarding both anticipated experimental outcomes and data interpretation. For a number of years, coronary venous Po
has been generally accepted as a measure of myocardial tissue oxygenation and thus the classically proposed error signal for the generation of vasodilator metabolites in the heart. However, interpretation of changes in coronary venous Po
relative to MV̇o
are quite nuanced, inherently circular in nature, and subject to confounding influences that remain largely unaccounted for. The purpose of this review is to highlight difficulties in interpreting the complex interrelationship between key coronary outcome variables and the arguments that emerge from prior studies performed during exercise, hemodilution, hypoxemia, and alterations in perfusion pressure. Furthermore, potential paths forward are proposed to help to facilitate further dialogue and study to ultimately unravel what has become the Gordian knot of the coronary circulation.
AIMSSodium glucose co-transporter 2 inhibitors (SGLT2i) demonstrate cardioprotective benefits independent of a glucose lowering effect including preservation of cardiac function during a myocardial ...ischemia. Sodium‑hydrogen exchanger-1 (NHE-1), has been hypothesized to contribute to the cardiac effects of SGLT2i. We characterized the beneficial effects of acute pre-ischemia exposure to SGLT2i and explored the possibility that these effects are explained by NHE-1 inhibition. METHODS AND RESULTSSwine were anesthetized and instrumented for invasive hemodynamic measurements. After baseline data collection, swine received a 15-30 min intravenous infusion of vehicle (DMSO), the SGLT2i canagliflozin (~1 mg/kg), or the NHE-1 inhibitor cariporide (~0.03 mg/kg) ending immediately prior to occlusion of the left circumflex artery. Measurements were obtained at baseline, during a 60-min complete occlusion of the circumflex coronary artery, and during a 2-h reperfusion period. Blood pressure, heart rate, left anterior descending artery flow, and associated myocardial oxygen consumption were unaffected by acute pre-treatment with canagliflozin or cariporide during ischemia and reperfusion. Acute pre-ischemic treatment with canagliflozin significantly increased diastolic filling and stroke work, producing a rightward shift in the Frank-Starling relationship, and also improved cardiac work efficiency relative to untreated control hearts during ischemia. Effects of NHE-1 inhibition with cariporide were modest and dissimilar. Examination of AP-1 cells transfected with wild-type NHE-1 and iPSC-derived cardiomyocytes confirmed dose-dependent-inhibition of NHE-1 activity by cariporide, while canagliflozin had no significant effect on NHE-1 activity. CONCLUSIONAcute pre-treatment with SGLT2i produces cardioprotective effects during ischemia, including improved work efficiency. These effects are not explained by NHE-1 inhibition. TRANSLATIONAL PERSPECTIVESGLT2 inhibitors have been shown to improve cardiac outcomes in patient including reducing myocardial infarction incidence and mortality. The mechanism(s) explaining this effect are not clear. This manuscript demonstrates a protective effect from acute SGLT2i exposure, as short as 15 min, prior to experimental infarction in swine. These effects were independent of NHE1 inhibition. These observations suggest that SGLT2 inhibitors can confer cardioprotective effects on a very short time scale. It is possible that such effects provide an ongoing contribution to ischemic protection even in the setting of chronic treatment.
The lack of pre‐clinical large animal models of heart failure with preserved ejection fraction (HFpEF) remains a growing, yet unmet obstacle to improving understanding of this complex condition. This ...study tested the hypothesis that chronic, high‐rate pacing induces a HFpEF‐like phenotype in obese Ossabaw swine. Swine were fed standard chow or an excess calorie, high‐fat, high‐fructose diet for ~18 weeks. Obese swine were implanted with a pacemaker to increase heart rate to 180 beats/min for 4 weeks (obese HF). Compared to lean swine, chronic pacing did not affect baseline (un‐paced) blood pressure or heart rate, but increased heart weight (P= 0.03), fibrosis (P< 0.001), and tended to reduce capillary density (P= 0.06). Cardiac output was increased in obese HF (P= 0.02) and associated with ~45% increase in ventricular stroke volume (P= 0.01), elevated end‐diastolic pressure (25 ± 2 mmHg; P< 0.001), and a normal ejection fraction of 56 ± 7% (P= 0.57). Baseline coronary blood flow was increased in obese HF (P= 0.03); however, MVO2 (P= 0.48) and coronary venous PO2 (P= 0.14) remained unchanged. Hemorrhage studies revealed impairment of the chronotropic response (59 ± 10 to 158 ± 19 bpm in lean control vs. 70 ± 5 vs. 84 ± 5 bpm in obese HF; P< 0.001) and augmented reductions in coronary blood flow (0.39 ± 0.03 to 0.19 ± 0.04 ml/min/g in lean control vs. 0.60 ± 0.05 to 0.21 ± 0.04 ml/min/g in obese HF) as blood pressure decreased from 109 ± 3 to 42 ± 1 mmHg in lean control vs. 102 ± 4 to 42 ± 1 mmHg in obese HF swine. These findings support that chronic high‐rate pacing of obese Ossabaw swine induces key phenotypic features of the human HFpEF condition and provides a distinct preclinical tool for future mechanistic and therapeutic study.
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