Diseases of the Coronary Microcirculation: Diagnosis and Treatment.

BACKGROUND: 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 ele - vated 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. METHODS: This review is based on publications retrieved by a selective search in PubMed and on current international guidelines and recommendations of specialty societies. RESULTS: 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 highquality 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. CONCLUSION: 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.

Lactobacillus plantarum probiotic induces Nrf2-mediated antioxidant signaling and eNOS expression resulting in improvement of myocardial diastolic function.

Yorkshire swine were fed standard diet (n = 7) or standard diet containing applesauce rich in caffeic acid with Lactobacillus plantarum (n = 7) for 3 wk. An ameroid constrictor was next placed around the left coronary circumflex artery, and the dietary regimens were continued. At 14 wk, cardiac function, myocardial perfusion, vascular density, and molecular signaling in ischemic myocardium were evaluated. The L. plantarum-applesauce augmented NF-E2-related factor 2 (Nrf2) in the ischemic myocardium and induced Nrf2-regulated antioxidant enzymes heme oxygenase-1 (HO-1), NADPH dehydrogenase quinone 1 (NQO-1), and thioredoxin reductase (TRXR-1). Improved left ventricular diastolic function and decreased myocardial collagen expression were seen in animals receiving the L. plantarum-applesauce supplements. The expression of endothelial nitric oxide synthase (eNOS) was increased in ischemic myocardial tissue of the treatment group, whereas levels of asymmetric dimethyl arginine (ADMA), hypoxia inducible factor 1α (HIF-1α), and phosphorylated MAPK (pMAPK) were decreased. Collateral-dependent myocardial perfusion was unaffected, whereas arteriolar and capillary densities were reduced as determined by α-smooth muscle cell actin and CD31 immunofluorescence in ischemic myocardial tissue. Dietary supplementation with L. plantarum-applesauce is a safe and effective method of enhancing Nrf2-mediated antioxidant signaling cascade in ischemic myocardium. Although this experimental diet was associated with a reduction in hypoxic stimuli, decreased vascular density, and without any change in collateral-dependent perfusion, the net effect of an increase in antioxidant activity and eNOS expression resulted in improvement in diastolic function.NEW & NOTEWORTHY Colonization of the gut microbiome with certain strains of L. Plantarum has been shown to convert caffeic acid readily available in applesauce to 4-vinyl-catechol, a potent activator of the Nrf2 antioxidant defense pathway. In this exciting study, we show that simple dietary supplementation with L. Plantarum-applesauce-mediated Nrf2 activation supports vascular function, ameliorates myocardial ischemic diastolic dysfunction, and upregulates expression of eNOS.

Berries and Their Polyphenols as a Potential Therapy for Coronary Microvascular Dysfunction: A Mini-Review.

Ischemia with no obstructive coronary artery disease (INOCA) is a common diagnosis with a higher prevalence in women compared to men. Despite the absence of obstructive coronary artery disease and no structural heart disease, INOCA is associated with major adverse cardiovascular outcomes as well a significant contributor to angina and related disability. A major feature of INOCA is coronary microvascular dysfunction (CMD), which can be detected by non-invasive imaging and invasive coronary physiology assessments in humans. CMD is associated with epicardial endothelial-dependent and -independent dysfunction, diffuse atherosclerosis, and left-ventricular hypertrophy, all of which lead to insufficient blood flow to the myocardium. Inflammatory and oxidative stress signaling, upregulation of the renin-angiotensin-aldosterone system and adrenergic receptor signaling are major drivers of CMD. Treatment of CMD centers around addressing cardiovascular risk factors; however, there are limited treatment options for those who do not respond to traditional anti-anginal therapies. In this review, we highlight the ability of berry-derived polyphenols to modulate those pathways. The evidence supports the need for future clinical trials to investigate the effectiveness of berries and their polyphenols in the treatment of CMD in INOCA patients.

Tongmai Yangxin pill reduces myocardial No-reflow via endothelium-dependent NO-cGMP signaling by activation of the cAMP/PKA pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The Tongmai Yangxin pill (TMYX) is derived from the Zhigancao decoction recorded in Shang han lun by Zhang Zhongjing during the Han dynasty. TMYX is used for the clinical treatment of chest pain, heartache, and qi-yin-deficiency coronary heart disease. Previous studies have confirmed that TMYX can improve vascular endothelial function in patients with coronary heart disease by upregulating nitric oxide activity and then regulating vascular tension. Whether TMYX can further improve myocardial NR by upregulating NO activity and then dilating blood vessels remains unclear. AIM OF THE STUDY: This study aimed to reveal whether TMYX can further improve myocardial NR by upregulating NO activity and then dilating blood vessels. The underlying cAMP/PKA and NO-cGMP signaling pathway-dependent mechanism is also explored. MATERIALS AND METHODS: The left anterior descending coronary arteries of healthy adult male SD rats were ligated to establish the NR model. TMYX (4.0 g/kg) was orally administered throughout the experiment. Cardiac function was measured through echocardiography. Thioflavin S, Evans Blue, and TTC staining were used to evaluate the NR and ischemic areas. Pathological changes in the myocardium were assessed by hematoxylin-eosin staining. An automated biochemical analyzer and kit were used to detect the activities of myocardial enzymes and myocardial oxidants, including CK, CK-MB, LDH, reactive oxygen species, superoxide dismutase, malonaldehyde, and NO. The expression levels of genes and proteins related to the cAMP/PKA and NO/cGMP signaling pathways were detected via real-time fluorescence quantitative PCR and Western blot analysis, respectively. A microvascular tension sensor was used to detect coronary artery diastolic function in vitro. RESULTS: TMYX elevated the EF, FS, LVOT peak, LVPWd and LVPWs values, decreased the LVIDd, LVIDs, LV-mass, IVSd, and LV Vols values, demonstrating cardio-protective effects, and reduced the NR and ischemic areas. Pathological staining showed that TMYX could significantly reduce inflammatory cell number and interstitial edema. The activities of CK, LDH, and MDA were reduced, NO activity was increased, and oxidative stress was suppressed after treatment with TMYX. TMYX not only enhanced the expression of Gs-α, AC, PKA, and eNOS but also increased the expression of sGC and PKG. Furthermore, TMYX treatment significantly decreased ROCK expression. We further showed that TMYX (25-200 mg/mL) relaxed isolated coronary microvessels. CONCLUSIONS: TMYX attenuates myocardial NR after ischemia and reperfusion by activating the cAMP/PKA and NO/cGMP signaling pathways, further upregulating NO activity and relaxing coronary microvessels.

Effects of crude oil vapors on the cardiovascular flow of embryonic Gulf killifish.

Direct contact with toxicants in crude oil during embryogenesis causes cardiovascular defects, but the effects of exposure to airborne volatile organic compounds released from spilled oil are not well understood. The effects of crude oil-derived airborne toxicants on peripheral blood flow were examined in Gulf killifish (Fundulus grandis) since this model completes embryogenesis in the air. Particle image velocimetry was used to measure in vivo blood flow in intersegmental arteries of control and oil-exposed embryos. Significant effects in oil-exposed embryos included increased pulse rate, reduced mean blood flow speed and volumetric flow rate, and decreased pulsatility, demonstrating that normal-appearing oil-exposed embryos retain underlying cardiovascular defects. Further, hematocrit moderately increased in oil-exposed embryos. This study highlights the potential for fine-scale physiological measurement techniques to better understand the sub-lethal effects of oil exposure and demonstrates the efficacy of Gulf killifish as a unique teleost model for aerial toxicant exposure studies.

Diagnostic analysis of new quantitative parameters of low-dose dynamic myocardial perfusion imaging with CZT SPECT in the detection of suspected or known coronary artery disease.

The goal of this study is to explore and evaluate the diagnostic values of myocardial blood flow (MBF), myocardial flow reserve (MFR) and relative flow reserve (RFR) obtained with low-dose dynamic CZT SPECT for patients with suspected or known coronary artery disease (CAD). Fifty-seven consecutive patients who underwent low-dose dynamic CZT SPECT and CAG were enrolled. MBF, MFR and RFR were calculated on the vessel level with dedicated quantitative software, and the difference and correlation of each parameter was compared according to the reference standard of stenosis ≥ 50% or ≥ 75% on CAG, respectively. ROC curves were made by stress MBF (sMBF), rest MBF (rMBF), MFR and RFR. The optimal cut-off values and corresponding diagnostic efficacy were obtained and compared with each other. Results indicated that when stenosis ≥ 50% or ≥ 75% on CAG was used as the reference standard at the vessel level, there was no statistically significant difference in rMBF between the negative group and the positive group (P > 0.05), and the sMBF and MFR in positive groups were significantly lower than that in the negative group (all P < 0.05). There was a moderate to significant correlation between sMBF and MFR, sMBF and RFR, MFR and RFR (all P < 0.0001). These results indicate that low-dose dynamic CZT SPECT imaging can easily obtain the sMBF, MFR and RFR, and there is a good correlation among the three parameters, which has a certain diagnostic value for patients with suspected or known CAD, and is a useful supplement to the conventional qualitative or semi-quantitative diagnostic methods.

Effect of Shexiang Tongxin dropping pill on stable coronary artery disease patients with normal fractional flow reserve and coronary microvascular disease: A study protocol.

INTRODUCTION: Coronary microvascular disease (CMVD) can affect the structure, function, and metabolism of the heart, and has an important impact on the occurrence, development and prognosis of coronary artery disease (CAD). Shexiang Tongxin dropping pill (STDP) can dilate blood vessels, alleviate inflammation, reduce endothelial damage, and improve coronary microvascular function in mice with myocardial infarction. This study aims to assess the impact of STDP on stable coronary artery disease (SCAD) patients with normal FFR and CMVD. METHODS AND ANALYSIS: This is a single-center, prospective randomized trial that will enroll 64 SCAD patients, CAD with normal FFR and CMVD. Patients will be randomly divided into study group and control group in a 1:1 fashion. On the basis of conventional drug treatment, the former will receive STDP while the latter will not. The follow-up period of the subjects is 12 months, and clinical follow-up will be conducted before discharge, 30 days, 3 months, 6 months, and 12 months after procedure to complete the detection of relevant indicators. The primary endpoint is the change of index of microcirculatory resistance (ΔIMR) at 12-month follow-up. DISCUSSION: The present study will be the first randomized control study to evaluate the efficacy and safety of STDP on SCAD patients, CAD with normal FFR and CMVD, which will provide a broader idea and more experimental basis for improving the treatment of CMVD. TRIAL REGISTRATION: This is a protocol for the randomized clinical trial which has been registered in the Chinese clinical Trial Registry with an identifier: ChiCTR2000032429.

Enhanced dimethylarginine degradation improves coronary flow reserve and exercise tolerance in Duchenne muscular dystrophy carrier mice.

Duchenne muscular dystrophy (DMD) is an X-linked disease caused by null mutations in dystrophin and characterized by muscle degeneration. Cardiomyopathy is common and often prevalent at similar frequency in female DMD carriers irrespective of whether they manifest skeletal muscle disease. Impaired muscle nitric oxide (NO) production in DMD disrupts muscle blood flow regulation and exaggerates postexercise fatigue. We show that circulating levels of endogenous methylated arginines including asymmetric dimethylarginine (ADMA), which act as NO synthase inhibitors, are elevated by acute necrotic muscle damage and in chronically necrotic dystrophin-deficient mice. We therefore hypothesized that excessive ADMA impairs muscle NO production and diminishes exercise tolerance in DMD. We used transgenic expression of dimethylarginine dimethylaminohydrolase 1 (DDAH), which degrades methylated arginines, to investigate their contribution to exercise-induced fatigue in DMD. Although infusion of exogenous ADMA was sufficient to impair exercise performance in wild-type mice, transgenic DDAH expression did not rescue exercise-induced fatigue in dystrophin-deficient male mdx mice. Surprisingly, DDAH transgene expression did attenuate exercise-induced fatigue in dystrophin-heterozygous female mdx carrier mice. Improved exercise tolerance was associated with reduced heart weight and improved cardiac ß-adrenergic responsiveness in DDAH-transgenic mdx carriers. We conclude that DDAH overexpression increases exercise tolerance in female DMD carriers, possibly by limiting cardiac pathology and preserving the heart's responses to changes in physiological demand. Methylated arginine metabolism may be a new target to improve exercise tolerance and cardiac function in DMD carriers or act as an adjuvant to promote NO signaling alongside therapies that partially restore dystrophin expression in patients with DMD.NEW & NOTEWORTHY Duchenne muscular dystrophy (DMD) carriers are at risk for cardiomyopathy. The nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) is released from damaged muscle in DMD and impairs exercise performance. Transgenic expression of dimethylarginine dimethylaminohydrolase to degrade ADMA prevents cardiac hypertrophy, improves cardiac function, and improves exercise tolerance in DMD carrier mice. These findings highlight the relevance of ADMA to muscular dystrophy and have important implications for therapies targeting nitric oxide in patients with DMD and DMD carriers.

Effects on Suxiao Jiuxin Pills in the Treatment of Patients with Acute Coronary Syndrome Undergoing Early Percutaneous Coronary Intervention: A Multicenter Randomized Double-Blind Placebo-Controlled Trial.

Objectives: Acute coronary syndrome (ACS) is an acute disease with high mortality. Although early percutaneous coronary intervention (PCI) is proved to be the practical approach in treating ACS, the incidence of cardiovascular events is still far from satisfactory. The combination of Suxiao Jiuxin Pill (SJP) and Western medicine is one conventional approach in the treatment of ACS. Many elementary and clinical trials have proved the efficacy and safety in the improvement of cardiocerebral vascular conditions. The aim of this project is to evaluate the safety and efficacy of SJP on ACS with early PCI patients. Trial Design: This is a multicenter randomized, double-blind placebo-controlled trial. Trial registration: ChiCTR-TRC-13003053. Settings: Hospitals. Subjects: A total of 200 ACS with early PCI patients were randomly divided into SJP group (n = 100) and placebo group (n = 100). Interventions: The SJP group was treated with routine treatment and SJP (taking eight SJP pills orally each time, three times per day). The placebo group was treated with routine treatment along with equal amounts of SJP placebo. The course of treatment was 6 months and a follow-up visit at 12 months. Outcome Measures: Assessments of major adverse cardiovascular events (MACE), safety assessments, adverse events, left ventricular systolic function (LVEF), Seattle angina questionnaire (SAQ), troponin C (cTNI), C-reactive protein (CRP), fibrinogen (Fib), and cystatin C (cysC). Results: The SJP group had a relatively low incidence of MACE than the placebo (p < 0.05, odds ratio: 1.916, 95% confidence interval [0.999-3.674]). LVEF was significantly higher in the SJP group than the placebo group on the 360-day follow-up (p < 0.01). SJP had a significant increase score in the SAQ subscale of physical limitation, angina frequency, and treatment satisfaction (p < 0.05). There is no significant difference in the cTNI and CRP level between the two groups. The serum concentration of Fib and cysC in the SJP was significantly decreased compared with the placebo (p < 0.05). The numbers of adverse events between the two groups were not statistically different (p > 0.05). Conclusions: SJP is associated with a reduction in MACE, and an improvement of heart function and quality of life in ACS patients with early PCI, and is probably safe to use.

Tongmai Yangxin pill reduces myocardial no-reflow by regulating apoptosis and activating PI3K/Akt/eNOS pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Tongmai Yangxin pill (TMYX) is derived from the Zhigancao decoction recorded in Shang han lun by Zhang Zhongjing during the Han dynasty and was further improved by Professor Ruan Shiyi, a cardiovascular expert at Tianjin University of Traditional Chinese Medicine. TMYX is used for the clinical treatment of chest pain, heartache, and qi-yin-deficiency coronary heart disease and can improve vascular endothelial function in patients with angina pectoris or coronary heart disease by up-regulating nitric oxide activity and then regulating vascular tension. Whether TMYX can further improve myocardial no-reflow by up-regulating NO activity and then dilating blood vessels remains unclear. AIM OF THE STUDY: This study aimed to reveal whether TMYX can further improve myocardial NR by up-regulating NO activity and then dilating blood vessels. The mechanism underlying PI3K/Akt/eNOS pathway activation and apoptosis regulation is also explored. MATERIALS AND METHODS: The left anterior descending coronary arteries of healthy adult male SD rats were ligated to establish a NR model. The rats were assigned to 14 groups: control, sham, NR, TMYX (4.0 g/kg), sodium nitroprusside (SNP), Tongxinluo capsule (TXL), PI3K blocker (LY), TMYX + LY, SNP + LY, TXL + LY, eNOS blocker (L-NAME), TMYX + L-NAME, SNP + L-NAME, and TXL + L-NAME groups. Cardiac function was measured through echocardiography. Thioflavin S, Evans Blue, and TTC staining were adopted to evaluate NR and ischemic areas. Cell inflammation degree and edema were assessed by hematoxylin-eosin staining. Automated biochemical analyzer and kit were used to detect the activities of myocardial oxidants, including reactive oxygen species, super oxide dismutase, malonaldehyde, and NO. The expression levels of genes and proteins in the PI3K/Akt/eNOS signaling pathway and apoptosis were detected via real-time fluorescence quantitative PCR and Western blot analysis, respectively. A microvascular tension sensor was adopted to detect coronary artery diastolic function in vitro. RESULTS: TMYX reduced NR and ischemic areas; suppressed LV-mass; enhanced EF, FS, LVOT peak, and LVSV; and improved cardiac structure and function. Moreover, it decreased creatine kinase (CK), CK-MB, and lactic dehydrogenase activities. TMYX increased NO and super oxide dismutase activities; inhibited malonaldehyde activity; reduced muscle fiber swelling and inflammatory cell infiltration; and improved vasodilation in vitro. In the NR myocardium, TMYX stimulated myocardial PI3K activities and PI3K (Tyr458) phosphorylation and enhanced Akt activities and Akt phosphorylation at Tyr315. TMYX increased the activities of eNOS and the phosphorylation of eNOS at Ser1177 in the NR myocardium and attenuated cardiomyocyte apoptosis by increasing the expression of Bcl-2 and decreasing that of caspase-3 and Bax. All these effects of TMYX were abolished by the specific inhibitors of PI3K (LY) and eNOS (L-NAME). CONCLUSIONS: TMYX attenuates myocardial NR after ischemia and reperfusion by activating the PI3K/Akt/eNOS pathway and regulating apoptosis, further up-regulating NO activity and relaxing coronary microvessels.

Combined Intravenous Sildenafil and L-Arginine Administration in a Porcine Animal Model: Hemodynamic Safety Profile and Effects on Coronary Blood Flow.

BACKGROUND: Endothelial dysfunction in the nitric oxide-cyclic guanosine monophosphate pathway is a potential contributor to perioperative myocardial ischemia. The nitric oxide precursor, L-arginine, and the cyclic guanosine monophosphate degradation blocker, sildenafil, have vasodilatory effects under high dosage. OBJECTIVE: This study examined the hemodynamic safety and effect profiles of the combined administration of L-arginine and sildenafil using an in-vivo pig model. METHODS: Hemodynamic safety including mean arterial pressure, central venous pressure, heart rate, coronary vascular resistance, and systemic vascular resistance, as well as effect profiles including cardiac output and left anterior descending blood flow were measured in ten female swine after administrations of L-arginine, sildenafil, as well as combined L-arginine and sildenafil. Measurements were compared using repeated-measures analysis of variance and linear mixed models. RESULTS: The combination of L-arginine and sildenafil produced a significant dose-dependent increase in left anterior descending flow and cardiac output. In contrast, mean arterial pressure, heart rate, central venous pressure, coronary vascular resistance, and systemic vascular resistance did not show any significant changes. No significant change in serum osmolality was observed after administrations of L-arginine. CONCLUSIONS: The combined intravenous administration of sildenafil and L-arginine in a porcine animal model was safe, well tolerated, and had at least additive effects on left anterior descending artery blood flow. Simultaneous application of both drugs might have dose-sparing effects leading to desired coronary effects at lower and safer sildenafil and L-arginine plasma concentrations. Hyperosmolality was only a minor factor in L-arginine hemodynamic effects.

Refractory Angina: From Pathophysiology to New Therapeutic Nonpharmacological Technologies.

Despite optimal combination of guideline-directed anti-ischemic therapies and myocardial revascularization, a substantial proportion of patients with stable coronary artery disease continues to experience disabling symptoms and is often referred as "no-option." The appraisal of the pathways linking ischemia to symptom perception indicates a complex model of heart-brain interactions in the generation of the subjective anginal experience and inspired novel approaches that may be clinically effective in alleviating the angina burden of this population. Conversely, the prevailing ischemia-centered view of angina, with the focus on traditional myocardial revascularization as the sole option to address ischemia on top of medical therapy, hinders the experimental characterization and broad-scale clinical implementation of strongly needed therapeutic options. The interventionist, often the first physician to establish the diagnosis of refractory angina pectoris (RAP) following coronary angiography, should be aware of the numerous emerging technologies with the potential to improve quality of life in the growing population of RAP patients. This review describes the current landscape and the future perspectives on nonpharmacological treatment technologies for patients with RAP, with a view on the underlying physiopathological rationale and current clinical evidence.

Initiate Danhong Injection before or after percutaneous coronary intervention for microvascular obstruction in ST-elevation myocardial infarction (DIRECTION): study protocol for a randomized controlled trial.

BACKGROUND: No treatment has convincingly been proven to be beneficial for microvascular obstruction (MVO) in patients with ST-elevation myocardial infarction (STEMI). Several studies have described the effects of Danhong Injection. However, evidence of a rigorously designed verification study is still lacking, and the intervention timing of Danhong Injection is uncertain. METHODS: The DIRECTION study is a multicenter, prospective, randomized, evaluator-blind study. A total of 336 patients with STEMI receiving percutaneous coronary intervention (PCI) will be randomly assigned to conventional treatment, the preoperative Danhong Injection, or the postoperative Danhong Injection. The primary outcome is rate of ST-segment resolution (STR) ≥ 70% at 90 min after PCI. The secondary outcomes are the degree of STR, Thrombolysis in Myocardial Infarction (TIMI) flow grade, TIMI myocardial perfusion grade, left ventricular ejection fraction, N-terminal prohormone brain natriuretic peptide, high-sensitivity C-reactive protein, and infarct size expressed as area under the curve for cardiac troponin I (cTnI) and for creatine kinase MB. The major adverse cardiovascular events and hospital readmission events will be recorded. Health quality will be assessed with the 12-item Short Form Health Survey. The safety outcomes include bleeding events, adverse events, and abnormal changes in routine blood tests. Psychological status and dietary patterns will be evaluated using Hamilton Depression Rating Scale and Food Frequency Questionnaire as the relevant indicators. DISCUSSION: This trial will evaluate the efficacy and safety of Danhong Injection, as well as its optimal timing of intervention to prevent MVO in patients with STEMI. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1900021440. Registered on February 21, 2019.

The Potential Role of Undercarboxylated Osteocalcin Upregulation in Microvascular Insufficiency in a Rat Model of Diabetic Cardiomyopathy.

BACKGROUND: Diabetic cardiomyopathy (DCM) is accompanied by microvascular complications that lead to myocardial dysfunction and heart failure. Most conventional therapies cannot ameliorate the microvascular insufficiency in DCM. In this study, we tested the hypothesis that undercarboxylated osteocalcin (ucOC) may be a new adjuvant therapy against the progression of DCM and its underlying microvascular pathology. MATERIALS AND METHODS: Diabetes was induced in Wistar rats with a high-fat diet combined with streptozotocin injections, and ucOC was upregulated after warfarin administration in the treated group. After 8 weeks, cardiac functions were assessed using a Langendorff apparatus. Cardiac tissue samples were also extracted to assess the ucOC receptor and vascular endothelial growth factor (VEGF) for histopathological studies. RESULTS: Both the systolic and the diastolic dysfunction observed in the DCM group were significantly improved after the increase in ucOC blood levels. Significant improvement in VEGF and CD31 expression after warfarin injection was associated with increased capillary density, neovascularization, and decreased myocardial fibrosis together with the reestablishment of myocardial structural and ultrastructural patterns. CONCLUSION: Undercarboxylated osteocalcin may have a promising effect in improving microvascular insufficiency and myocardial dysfunction in DCM.

Effectiveness and safety of intracoronary papaverine, alprostadil, and high dosages of nicorandil and adenosine triphosphate for measurement of the index of coronary microcirculatory resistance in a pig model.

BACKGROUND: Papaverine is used to induce maximal hyperemia for index of coronary microcirculatory resistance (IMR) measurement in animal experiments, although it can lead to polymorphic ventricular tachycardia and ventricular fibrillation. OBJECTIVES: This study investigated the effect of an intracoronary (IC) bolus of high adenosine triphosphate (ATP) and nicorandil doses for IMR measurement and explored the possibility of inducing maximal hyperemia with an IC alprostadil bolus. MATERIAL AND METHODS: Index of coronary microcirculatory resistance was measured in a hyperemic state induced by 7 experimental conditions in 21 pigs (IC bolus of papaverine (18 mg), ATP (40 µg, 80 µg, 160 µg, and 240 µg), and nicorandil (2 mg and 4 mg)). The 7 conditions were induced sequentially, and the average IMR was calculated. Because of the long-term hyperemic condition in the pilot experiments, the IMR was measured 1, 3, 5, 8, and 10 min after an IC bolus of alprostadil (10 µg) in another 7 pigs. RESULTS: The IMR induced by 240 µg of ATP or 4 mg of nicorandil was not significantly different from that induced by 18 mg of papaverine (both p > 0.05). A strong linear correlation was observed between IMRs with papaverine (18 mg) and nicorandil (4 mg) (R2 = 0.936, p < 0.001) and with papaverine (18 mg) and ATP (240 µg) (R2 = 0.838, p < 0.05). The IC bolus of nicorandil (4 mg) produced the smallest changes, whereas papaverine caused the most significant changes in mean blood pressure and heart rate (p < 0.05). Tachypnea and transient ST depression were more common with increasing ATP dosages (especially 240 µg). Alprostadil (5 min) yielded a significant hyperemic response but reduced baseline blood pressure by almost 40% for a long time. CONCLUSIONS: Intracoronary bolus administration of 4 mg of nicorandil was better than 18 mg of papaverine or 240 µg of ATP for induction of maximal hyperemia and IMR measurement in a pig model, whereas alprostadil was not suitable for IMR measurement.

Effect of Vitamin D and parathyroid hormone levels on the coronary slow-flow phenomenon.

BACKGROUND: The presence of vitamin D, and parathyroid hormone receptors has been demonstrated in the vascular endothelium. Variations in vitamin D, and parathyroid hormone levels may affect coronary flow and cause the coronary slow-flow phenomenon (CSF). METHODS: We enrolled 93 patients who had undergone coronary angiography and had near-normal coronary arteries. Blood samples were taken to determine the calcium, phosphorus, 25-hydroxy vitamin D, and parathyroid hormone levels. Vitamin D deficiency was defined as a serum 25-hydroxy vitamin D level of less than 20 ng/mL. We divided the study population into two groups according to thrombolysis in myocardial infarction frame count (TFC) levels. RESULTS: Patients with TFC ≤27 were in the control group (n = 39), and those with TFC >27 were in the CSF group (n = 54). 25-Hydroxy vitamin D levels were similar in both groups: 17.5 [3.3-36.1] ng/ml in the CSF group and 15.2 [5.3-34] ng/ml in the control group (P = 0.129). When we analyzed TFC for each of the coronary arteries, we found a weak negative correlation between vitamin D level and TFC of the right coronary artery in the CSF group (r = -0.314, P = 0.021). Parathyroid hormone levels were similar in both groups: 48 [16-140] pg/ml in the CSF group and 52 [25-125] pg/ml in the control group (P = 0.297). CONCLUSION: The study failed to demonstrate a relationship between serum parathyroid hormone level and CSF. However, a weak negative correlation was found between vitamin D level and TFC of the right coronary artery.

Preconditioning with hyperbaric oxygen and calcium and potassium channel modulators in the rat heart.

The aim of this study was to establish the effect of combined therapy with hyperbaric oxygen (HBO2) therapy and verapamil, amlodipine or nicorandil on functional recovery and oxidative stress markers after ischemia in the isolated rat heart. The study included 48 rats (Wistar albino, male gender, eight weeks old, body weight 200±50g). All animals were exposed to HBO2 treatment over 14 days. Isolated heart rats were perfused by the Langendorff retrograde method at a constant coronary pressure of 70 cm H2O. After stabilization period the hearts were divided into the following groups: HBO2 group (animals exposed to only HBO2 preconditioning); HBO2 + verapamil; HBO2 + amlodipine; andHBO2 + nicorandil (animals pretreated with HBO2 and appropriate pharmacological agent). Afterward, the hearts in all groups were subjected to 20-minute global ischemia and 30-minute reperfusion. Parameters of heart function were registered, including maximum and minimum rate of pressure development, systolic and diastolic left ventricular pressure, heart rate and coronary flow. Levels of pro-oxidants such as index of lipid peroxidation, measured as thiobarbituric acid-reactive substances, nitrites, levels of superoxide anion radicals and hydrogen peroxide were determined in coronary venous effluent. Changes in cardiac tissue were evaluated by hematoxylin and eosin staining. Obtained results clearly indicate that blockage of calcium channel or the activation of adenosine triphosphate-sensitive potassium (KATP) in combination with HBO2 prevented ischemia/reperfusion-induced cardiac deleterious effects, thus contributing to improvement of functional recovery of the heart. However, future studies are certainly necessary for better understanding the mechanisms through which combination of these two maneuvers of preconditioning triggers cardioprotection.

Effects and mechanisms of QiShenYiQi pills and major ingredients on myocardial microcirculatory disturbance, cardiac injury and fibrosis induced by ischemia-reperfusion.

Coronary heart disease remains a major threaten for public health worldwide, and pharmacological or mechanical coronary reperfusion are currently used for treatment of acute coronary syndrome. However, restoration of blood flow to ischemic myocardium leads to ischemia/reperfusion (I/R) injury. Microcirculatory disturbance and cardiac injury after I/R occur via a complex pathologic process including metabolism impairment in the ischemia phase and oxidative stress in the reperfusion phase. Obviously, any treatment targeting a single link is insufficient to cope with I/R injury. Investigation in the past decade in our laboratory as well as in other's demonstrated the cardioprotection potential of QiShenYiQi Pills (QSYQ) and ingredients in experimental animal models of I/R injury. These results have offered insight into the mechanism thereby QSYQ prevents against cardiac I/R injury in clinic. This review will outline the results with respect to the effect of QSYQ and major bioactive ingredients on I/R-induced microcirculatory disturbance, cardiac injury and fibrosis, with emphasis on the underlying mechanisms.

Index of microvascular resistance to assess the effect of rosuvastatin on microvascular function in women with chest pain and no obstructive coronary artery disease: A double-blind randomized study.

INTRODUCTION: Many women undergoing coronary angiography for chest pain have no or only minimal coronary artery disease (CAD). However, despite the lack of obstructive CAD, they still have an increased risk of major adverse cardiovascular events. Pleiotropic effects of statins may influence microvascular function, but if statins improve microvascular function in unselected chest pain patients is not well studied. This study assessed microvascular function by using the thermodilution-derived test "the index of microvascular resistance" (IMR) with the aim of determining the (i) IMR level in women with chest pain and non-obstructive CAD and if (ii) IMR is modified by high-dose statin treatment in these patients. Additional objectives were to identify the influence of statins on the health status as assessed with generic health questionnaires and on biomarkers of endothelial activation. MATERIALS AND METHODS: The study was a randomized, double-blind, single-center trial comparing 6 months of rosuvastatin treatment with placebo. In total, 66 women without obstructive CAD were included. Mean age was 52.7 years and 55.5 years in the placebo and rosuvastatin group, respectively. Microvascular function was assessed using the IMR, health status was assessed using the SF-36 and EQ-5D questionnaires, and biochemical values were assessed at baseline and 6 months later. RESULTS AND CONCLUSIONS: In the placebo group IMR was 14.6 (SD 5.7) at baseline and 14.4 (SD 6.5) at follow-up. In the rosuvastatin group IMR was 16.5 (SD 7.5) at baseline and 14.2 (SD 5.8) at follow-up. IMR did not differ significantly between the two study groups at follow-up controlled for preintervention values. C-reactive protein (CRP) was comparable between the groups at baseline, while at follow-up CRP was significantly lower in the rosuvastatin group compared to placebo [0.6 (±0.5) mg/L vs. 2.6 (±3.0) mg/L; p = 0.002]. Whereas rosuvastatin treatment for 6 months attenuated CRP levels, it did not improve microvascular function as assessed by IMR (Clinical Trials.gov NCT01582165, EUDRACT 2011-002630-39.3tcAZ).

A review of the mechanism of action of Dantonic® for the treatment of chronic stable angina.

Chronic stable angina (CSA) presents as a complication of coronary heart disease, leading to a high incidence and mortality rate worldwide. Dantonic® or Compound Danshen Dripping Pills (CDDP) is a well-known traditional Chinese medicine used for the treatment of myocardial ischemic diseases, such as angina pectoris (AP), myocardial infarction, and sudden death. Dantonic® has been extensively utilized in clinical practice in China for more than 14 years and has proved to be an effective therapy for the treatment of many myocardial ischemic diseases since its approval by CFDA in 1994. Clinical studies in China have shown that Dantonic® is an effective and safe drug for the treatment of angina pectoris manifested with ameliorating anginal symptoms and showing few adverse effects. Nevertheless, the mechanism of Dantonic® for the treatment of angina has been underestimated. Therefore, in this review, we mainly focus on discussing the pharmacological mechanism of action (MoA) of Dantonic® for the treatment of CSA, including the promotion of coronary microcirculation, the optimization of myocardial energy metabolism, and the inhibition of platelet aggregation.