Cardioprotective effects of alantolactone on isoproterenol-induced cardiac injury and cobalt chloride-induced cardiomyocyte injury.

OBJECTIVES: Alantolactone (AL) is a compound extracted from the roots of Inula Racemosa that has shown beneficial effects in cardiovascular disease. However, the cardioprotective mechanism of AL against hypoxic/ischemic (H/I) injury is still unclear. This research aimed to determine AL's ability to protect the heart against isoproterenol (ISO)-induced MI injury in vivo and cobalt chloride (CoCl2) induced H/I injury in vitro. METHODS: Electrocardiography (ECG), lactate dehydrogenase (LDH), creatine kinase (CK), and cardiac troponin I (cTnI) assays in addition to histological analysis of the myocardium were used to investigate the effects of AL in vivo. Influences of AL on L-type Ca2+ current (ICa-L) in isolated rat myocytes were observed by the patch-clamp technique. Furthermore, cell viability, apoptosis, oxidative stress injury, mitochondrial membrane potential, and intracellular Ca2+ concentration were examined in vitro. RESULTS: The results indicated that AL treatment ameliorated the morphological and ECG changes associated with MI, and decreased levels of LDH, CK, and cTnI. Furthermore, pretreatment with AL elevated antioxidant enzyme activity and suppressed ROS production. AL prevented H/I-induced apoptosis, mitochondria damage, and calcium overload while reducing ICa-L in a concentration and time dependent fashion. The 50% inhibiting concentration (IC50) and maximal inhibitory effect (Emax) of AL were 17.29 µmol/L and 57.73 ± 1.05%, respectively. CONCLUSION: AL attenuated MI-related injury by reducing oxidative stress, apoptosis, calcium overload, and mitochondria damage. These cardioprotective effects may be related to the direct inhibition of ICa-L.

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.

Increasing the Power of Polyphenols through Nanoencapsulation for Adjuvant Therapy against Cardiovascular Diseases.

Polyphenols play a therapeutic role in vascular diseases, acting in inherent illness-associate conditions such as inflammation, diabetes, dyslipidemia, hypertension, and oxidative stress, as demonstrated by clinical trials and epidemiological surveys. The main polyphenol cardioprotective mechanisms rely on increased nitric oxide, decreased asymmetric dimethylarginine levels, upregulation of genes encoding antioxidant enzymes via the Nrf2-ARE pathway and anti-inflammatory action through the redox-sensitive transcription factor NF-κB and PPAR-γ receptor. However, poor polyphenol bioavailability and extensive metabolization restrict their applicability. Polyphenols carried by nanoparticles circumvent these limitations providing controlled release and better solubility, chemical protection, and target achievement. Nano-encapsulate polyphenols loaded in food grade polymers and lipids appear to be safe, gaining resistance in the enteric route for intestinal absorption, in which the mucoadhesiveness ensures their increased uptake, achieving high systemic levels in non-metabolized forms. Nano-capsules confer a gradual release to these compounds, as well as longer half-lives and cell and whole organism permanence, reinforcing their effectiveness, as demonstrated in pre-clinical trials, enabling their application as an adjuvant therapy against cardiovascular diseases. Polyphenol entrapment in nanoparticles should be encouraged in nutraceutical manufacturing for the fortification of foods and beverages. This study discusses pre-clinical trials evaluating how nano-encapsulate polyphenols following oral administration can aid in cardiovascular performance.

Electroacupuncture improves cardiac function and reduces infarct size by modulating cardiac autonomic remodeling in a mouse model of myocardial ischemia.

BACKGROUND: Sympathetic and parasympathetic nerve remodeling play an important role in cardiac function after myocardial ischemia (MI) injury. Increasing evidence indicates that electroacupuncture (EA) can regulate cardiac function by modulating the autonomic nervous system (ANS), but little is known about its effectiveness on neural remodeling post-MI. OBJECTIVES: To investigate the role of EA in ANS remodeling post-MI. METHODS: Adult male C57/BL6 mice were equally divided into the Control (Ctrl), MI and EA groups after generating the MI model by ligating the left anterior descending (LAD) coronary artery. Echocardiography and 2,3,5-triphenyltetrazolium (TTC) staining were employed to evaluate cardiac function and infarct size after EA treatment for five consecutive days. Serum norepinephrine (NE) levels were measured by ELISA to quantify sympathetic activation. Then, ANS remodeling was detected by immunohistochemistry (IHC), RT-qPCR, and Western blotting. RESULTS: Our preliminary findings showed that EA increased ejection fraction and fractional shortening and reduced infarct area after MI injury. Serum NE levels in the EA group were significantly decreased compared with those in the MI group. IHC staining results demonstrated that the density of growth associated protein (GAP)43 and tyrosine hydroxylase (TH) positive nerve fibers in the EA group were decreased with increased choline acetyltransferase (CHAT) and vesicular acetylcholine transporter (VACHT). Meanwhile, the results verified that mRNA and protein expression of GAP43 and TH were significantly inhibited by EA treatment in the MI mice, accompanied by elevated CHAT and VACHT. CONCLUSIONS: EA treatment could improve cardiac function and reduce infarct size by modulating sympathetic and parasympathetic nerve remodeling post-MI, thus helping the cardiac ANS reach a new balance to try to protect the heart from further possible injury.

Integrating network pharmacology and experimental evidence to decipher the cardioprotective mechanism of Yiqihuoxue decoction in rats after myocardial infarction.

ETHNOPHARMACOLOGICAL RELEVANCE: "Qi deficiency and blood stasis" syndrome is one of the most common syndromes treated with Traditional Chinese Medicine among ischemic heart disease (IHD) patients in clinic. As a Chinese herbal formula with the function of tonifying Qi and activating blood, Yiqihuoxue Decoction (YQHX) has been frequently proven to be effective in the clinical treatment of IHD. AIM OF THE STUDY: The cardioprotective mechanisms of YQHX in treating ischemic heart disease were investigated, with emphasis on the key targets and pathways. MATERIALS AND METHODS: In the present study, the potential targets of compounds identified in YQHX were predicted using PharmMapper, Symmap, and STITCH databases, and a "herb-compound-target" network was constructed using Cytoscape. Subsequently, the GO and KEGG functional enrichment analyses were analyzed using the DAVID database. Furthermore, a protein-protein interaction network was constructed using STRING to obtain the key target information. Besides, we used a myocardial ischemia rat model to investigate the cardioprotective effects of YQHX. Transmission electron microscopy and Western blotting were used to observe apoptotic bodies and confirm protein expressions of key candidate targets, respectively. RESULTS: Network pharmacology showed that a total of 141 potential targets were obtained from these databases. The functional analysis results revealed that the targets of YQHX were largely associated with apoptosis, and the PI3K-AKT and MAPK pathways might represent key functional pathways. The hub genes of network include ALB, TP53, AKT1, TNF, VEGFA, EGFR, MAPK1, CASP3, JUN, FN1, MMP9, and MAPK8. In vivo, YQHX significantly improved cardiac function and suppressed apoptosis in ischemic rat myocardium. Furthermore, YQHX could significantly upregulate Nrf2 and HO-1 expression, and inhibit JNK phosphorylation. CONCLUSIONS: Based on network pharmacology and experimental evidence, this study proves that the cardioprotective effects and mechanisms of YQHX depend on multi-component, multi-target, and multi-pathway. In particular, YQHX exerts anti-apoptotic effects potentially by regulating the Nrf2/HO-1 and JNK-MAPK pathways.

Ginsenoside Rg2 alleviates myocardial fibrosis by regulating TGF-ß1/Smad signalling pathway.

CONTEXT: Panax ginseng C.A. Meyer (Araliaceae) has cardioprotective effects. Ginsenosides are responsible for most of the pharmacological activities of ginseng. OBJECTIVE: This study investigates the effect of ginsenoside Rg2 on myocardial fibrosis in myocardial ischaemia rats. MATERIALS AND METHODS: Male Wistar rats were divided into control, isoproterenol, ginsenoside Rg2 (5, 20 mg/kg) groups (n = 8). The rats were subcutaneously injected with isoproterenol (5 mg/kg) or normal saline (control group) once daily for 7 days. The animals were intragastrically treated with ginsenoside Rg2 or 0.5% CMC-Na (control and isoproterenol groups) daily for 28 days. At day 28, cardiac function, myocardial fibrosis, and TGF-ß1/Smad signalling pathway were evaluated. RESULTS: Compared with myocardial ischaemic rats, ginsenoside Rg2 at doses of 5, 20 mg/kg abated partially the augment of LVEDP (8.9 ± 1.3 vs. 7.5 ± 0.7, 7.2 ± 1.0 mmHg) and the decreases of the LVSP (96.75 ± 13.2 vs. 118.3 ± 19.4, 124.3 ± 21.3 mmHg), the + dp/dt (2142.8 ± 309.3 vs. 2598.6 ± 404.0, 2661.5 ± 445.2 mmHg/s), and the -dp/dt (1996.3 ± 306.3 vs. 2476.6 ± 289.7, 2509.6 ± 353.1 mmHg/s). Ginsenoside Rg2 (9.2 ± 0.9%, 8.5 ± 0.8%) alleviated myocardial fibrosis when compared with the isoproterenol group (10.1 ± 1.0%), which was accompanied by suppressed TGF-ß1/Smad signalling in heart tissues. CONCLUSIONS: Ginsenosides from ginseng possess the property of alleviating myocardial fibrosis, improving cardiac function after myocardial ischaemia. Ginsenosides may be promising agents for improving the outcomes of patients with myocardial ischaemia.

Functional assessment of myocardial ischaemia by intracoronary ECG.

INTRODUCTION: In patients with chronic coronary syndrome, percutaneous coronary intervention targets haemodynamically significant stenoses, that is, those thought to cause ischaemia. Intracoronary ECG (icECG) detects ischaemia directly where it occurs. Thus, the goal of this study was to test the accuracy of icECG during pharmacological inotropic stress to determine functional coronary lesion severity in comparison to the structural parameter of quantitative angiographic per cent diameter stenosis (%S), as well as to the haemodynamic indices of fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR). METHOD: The primary study endpoint of this prospective trial was the maximal change in icECG ST-segment shift during pharmacological inotropic stress induced by dobutamine plus atropine obtained within 1 min after reaching maximal heart rate(=220 - age). IcECG was acquired by attaching an alligator clamp to the angioplasty guidewire positioned downstream of the stenosis. For the pressure-derived stenosis severity ratios, coronary perfusion pressure and simultaneous aortic pressure were continuously recorded. RESULTS: There was a direct linear relation between icECG ST-segment shift and %S: icECG=-0.8+0.03*%S (r2=0.164; p<0.0001). There were inverse linear correlations between FFR and %S: FFR=1.1-6.1*10-3*%S (r2=0.494; p<0.0001), and between iFR and %S: iFR=1.27-8.6*10-3*%S (r2=0.461; p<0.0001). Using a %S-threshold of ≥50% as the reference for structural stenosis relevance, receiver operating characteristics-analysis of absolute icECG ST-segment shift during hyperemia showed an area under the curve (AUC) of 0.678±0.054 (p=0.002; sensitivity=85%, specificity=50% at 0.34 mV). AUC for FFR was 0.854±0.037 (p<0.0001; sensitivity=64%, specificity=96% at 0.78), and for iFR it was 0.816±0.043 (p<0.0001;sensitivity=62%, specificity=96% at 0.83). CONCLUSIONS: Hyperaemic icECG ST-segment shift detects structurally relevant coronary stenotic lesions with high sensitivity, while they are identified highly specific by FFR and iFR.

Electroacupuncture pretreatment promotes angiogenesis via hypoxia-inducible factor 1α and vascular endothelial growth factor in a rat model of chronic myocardial ischemia.

OBJECTIVE: Electroacupuncture (EA) pretreatment appears useful in the treatment of chronic myocardial ischemia (CMI). The goal of this study was to investigate the effect of EA preconditioning on the regulation of hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) proteins in a CMI model of vascular regeneration. METHODS: A CMI model was established by subcutaneous injection of isoprinosine hydrochloride (ISO) for 14 days in 45 Wistar rats, which had been randomly divided into a model group (n = 15), a CMI group pretreated with sham EA for 21 days (CMI + Sham group, n = 15) and a CMI group pretreated with verum EA for 21 days (CMI + EA, n = 15) prior to modeling. An additional 15 Wistar rats received 0.9% sodium chloride via intraperitoneal injection for 14 consecutive days (control group). Serum levels of VEGF and HIF-1α were measured by ELISA, while protein expression of VEGF and HIF-1α in the area of myocardial infarction was measured by Western blotting. The area of myocardial infarction and fibrosis of the myocardial tissue in the study groups were visualized by hematoxylin-eosin (HE) staining and Masson staining, respectively. RESULTS: EA pretreatment improved cardiac function by regulating left ventricular end-diastolic diameter and left ventricular end-systolic diameter, left ventricular ejection fraction and the ST segment voltage of the electrocardiogram. EA pretreatment promoted vascular regeneration by increasing serum levels of VEGF and HIF-1α and by increasing protein expression of HIF-1α and VEGF in the infarcted region of the myocardium, leading to a reduction in the area of myocardial infarction on HE staining and reduction of myocardial fibrosis on Masson staining. CONCLUSION: EA pretreatment promotes protein expression of HIF-1α and VEGF in areas of ischemic myocardium, which may represent useful biomarkers for coronary collateral establishment and offer potential targets for therapeutic angiogenesis in patients with CMI.

Traditional Chinese Medicines alleviated myocardial ischemia by regulating Qi and promoting blood circulation.

OBJECTIVE: To investigate the efficacy of Chinese medicines on Qi stagnation and blood stasis in rats with myocardial ischemia. METHODS: Fifty male Wistar rats were randomly divided into five groups (n = 10) as follows: (a) sham operation (Sham), (b) myocardial ischemia (Model), (c) treatment that regulates Qi (Qi), (d) treatment that promotes blood circulation (Blood), (e) treatment that both regulates Qi and promotes blood circulation (QB). The rat model was established via activities restriction for 6 h followed by tail clamp stimulation for 5 mins every day for 7 d and occlusion left coronary anterior descending artery. Afterwards rats were treated with medicines that regulate Qi and/or promote blood circulation via gavage for 14 d. Behavioral parameters were evaluated using open field and elevated plus-maze tests. The tongue color and sublingual vein were visually examined. Blood flow perfusion of tongue and auricle were detected using PIM Ⅱ. The mesenteric microcirculation was examined via capillaroscopy, and hemodynamics was assessed using a polygraph system. Serum homocysteine (Hcy), creatine kinase isoenzyme (CKMB) levels and endothelin-1 (ET-1) were measured. Hematoxylin and eosin staining and transmission electron microscopy were employed to detect the myocardial morphology and ultrastructure, respectively. RESULTS: Compared with findings in Sham group, rats in model group had coarse hair, dark mucosa of the lips and claw, low activity, and increased anxiety. Compared with findings in Model group, rats in the three treatment groups exhibited a lighter tongue color without an extended and varicose sublingual vein. There were significant increases of auricle blood flow perfusion in the Qi group and tongue bottom blood flow perfusion in the QB group. Compared with findings in Model rats, rats in Blood group exhibited improved mesenteric microcirculation associated with increased mesenteric blood flow and a larger arteriole diameter. Moreover, compared with findings in Model rats, Qi and QB rats exhibited increased left ventricular ± dp/dtmax, decreased serum CKMB, Hcy, ET-1 levels, and reduced myocardial ultrastructural damage. CONCLUSION: Myocardial ischemia damage was suppressed by Traditional Chinese Medicines that regulate Qi and promote blood circulation.

The synergistic mechanism of total saponins and flavonoids in Notoginseng-Safflower pair against myocardial ischemia uncovered by an integrated metabolomics strategy.

The Notoginseng-Safflower pair composed of Panax notoginseng (Burk.) F. H. Chen and Carthamus tinctorius L. has remarkable clinical efficacy for preventing and treating cardiovascular diseases in China. Notoginseng total saponins (NS) and Safflower total flavonoids (SF) are the major effective ingredients in Notoginseng and Safflower, respectively. Though our previous study showed that the combination of NS and SF (NS-SF) exhibits significant cardioprotective effects for myocardial ischemia (MI), there might be difference in their action mechanisms. However, the anti-MI characteristics of individual NS and SF remains unclear. Herein, an integrated metabolomics strategy coupled with multiple biological methods were employed to investigate the cardioprotective effects of NS and SF alone or in combination against isoproterenol (ISO)-induced MI and to further explore the synergistic relationship between NS and SF. Our results demonstrated that pretreatments with NS, SF, and NS-SF all showed cardioprotective effects against MI injury and NS-SF exhibited to be the best. Interestingly, the results demonstrated that NS and SF exhibited differentiated metabolic targets and mediators in the glycerophospholipid metabolism. Furthermore, administration of NS alone exhibited greater effects on reversing the elevated the proinflammatory metabolites and mediators in MI rats compared to SF alone. However, individual SF showed greater amelioration of MI-disturbed antioxidant and prooxidative metabolites and better inhibition of the oxidative stress than NS alone. Collectively, our study demonstrated that the capability of NS-SF to regulate both metabolic targets of NS and SF might be the basis of NS-SF to produce a cooperative effect greater than their individual effects that enhance the anti-MI efficacy and provided valuable information for the clinical application of Notoginseng-Safflower pair.

Identification of Target Genes of Antiarrhythmic Traditional Chinese Medicine Wenxin Keli.

Wenxin Keli (WXKL) is a traditional Chinese medicine drug approved for the treatment of cardiovascular diseases. This study aimed to identify WXKL-targeting genes involved in antiarrhythmic efficacy of WXKL. The Traditional Chinese Medicine Systems Pharmacology (TCMSP) technology platform was used to screen active compounds of WXKL and WXKL-targeting arrhythmia-related genes. A pig model of myocardial ischemia (MI) was established by balloon-expanding the endothelium of the left coronary artery. Pigs were divided into the model group and WXKL group (n = 6). MI, QT interval, heart rate, and arrhythmia were recorded, and the mRNA expression of target genes in myocardial tissues was detected by PCR. Eleven active ingredients of WXKL and eight WXKL-targeting arrhythmia-related genes were screened. Five pathways were enriched, and an "ingredient-gene-path" network was constructed. WXKL markedly decreased the incidence of arrhythmia in the MI pig model (P < 0.05). The QT interval was significantly shortened, and the heart rate was slowed down in the WXKL group compared with the model group (P < 0.05). In addition, the expression of sodium channel protein type 5 subunit alpha (SCN5A) and beta-2 adrenergic receptor (ADRB2) was downregulated, while muscarinic acetylcholine receptor M2 (CHRM2) was upregulated in the WXKL group (P < 0.05). In conclusion, WXKL may shorten the QT interval and slow down the heart rate by downregulating SCN5A and ADRB2 and upregulating CHRM2 during MI. These findings provide novel insight into molecular mechanisms of WXKL in reducing the incidence of ventricular arrhythmia.

Meconopsis horridula Hook. f. & Thomson extract and its alkaloid oleracein E exert cardioprotective effects against acute myocardial ischaemic injury in mice.

Meconopsis horridula Hook. f. & Thomson (MH) is a traditional Tibetan medicine used to promote blood circulation, remove bruises, remove stasis and relieve chest pain which benefit to cardiovascular diseases. Oleracein E (OE), a major tetrahydroisoquinoline alkaloid, can be isolated from MH ethanol extract. The antioxidant and anti-apoptotic effects of OE have been reported by previous pharmacological research. The objective of this article was to investigate the cardioprotective effects of MH extract and OE in an ICR mouse of acute myocardial ischaemic injury. A left anterior descending (LAD) artery ligation mouse model of AMI was established. In vivo, cardiac function after MH and OE treatment was determined through measurement of EF, FS, LVEDd, and LVEDs by echocardiography. The levels of SOD, MDA, CK-MB and LDH in serum were also detected. A TUNEL assay was used to verify apoptosis. Changes in collagen deposition and inflammatory cell infiltration in ischemic myocardial tissue were observed by histopathological examination. In vitro, H9c2 cells were pre-treated with OE for 6 h, and then cultured in serum-free medium with H2O2 for 2 h. CCK8 assay measured cell viability, and flow cytometry determined apoptosis levels and ROS content. The mechanism was explored by western blotting. These results showed that MH and OE significantly affected acute myocardial ischaemia by improving cardiac function and that OE downregulated the expression of related proteins in the MAPK signalling pathway. These findings provide substantial evidence of MH may applicate in clinic, and indicate that such medicines have potential value for the treatment of ischaemia-induced heart disease.

Incidence and risk markers of 5-fluorouracil and capecitabine cardiotoxicity in patients with colorectal cancer.

Background: Fluoropyrimidines are mainstay chemotherapeutics in the treatment of gastrointestinal cancers and are also used to treat breast cancer and head and neck cancers. However, 5-flourouracil (5-FU) and capecitabine may induce cardiotoxicity that mostly presents as acute coronary syndromes. We compared the incidence of cardiotoxicity induced by 5-FU and capecitabine in patients with colorectal cancer and sought to identify risk markers for cardiotoxicity.Methods: We reviewed all consecutive patients with colorectal cancer who received 5-FU or capecitabine at one institution in the neoadjuvant (2007-2016), adjuvant (2000-2016) or metastatic setting (2007-2016).Results: Totally, 995 patients received 5-FU and 1241 received capecitabine. The incidence of cardiotoxicity induced by 5-FU was 5.2% [95% confidence interval (CI): 3.8-6.6%] and 4.1% (95% CI: 3.0-5.2%) induced by capecitabine (p = .21). The most common events were angina without ischemia (5-FU: 1.6%, capecitabine: 1.3%, p = .53), angina with ischemia on ECG (5-FU: 0.9%, capecitabine: 0.8%, p = .53), unspecified chest pain (5-FU: 0.9%, capecitabine: 0.6%, p = .34), ST-elevation myocardial infarction (5-FU: 0.5%; capecitabine: 0.4%, p = .76) and non-ST-elevation myocardial infarction (5-FU: 0.7%, capecitabine: 0.5%, p = .50). Cardiac arrest or sudden death occurred in 0.5 and 0.4%, respectively (p = 1). No risk markers for cardiotoxicity induced by 5-FU were identified. In the capecitabine group, ischemic heart disease was a risk marker (odds ratio: 2.9, 95% CI: 1.2-7.0, p = .016).Conclusions: Five percent of patients treated with 5-FU developed cardiotoxicity and 4% treated with capecitabine. Ischemic heart disease was a risk marker for cardiotoxicity induced by capecitabine.

Effects and Mechanisms of Traditional Chinese Herbal Medicine in the Treatment of Ischemic Cardiomyopathy.

The incidence of ischemic cardiomyopathy (ICM) is increasing yearly, which seriously endangers human health. There is rarely any remarkable progress in the treatment of ICM from the available drugs. Recent research shows that natural herbal medicine may have beneficial effects in the prevention and treatment of cardiovascular diseases. The effective extracts of the herbs may improve myocardial ischemia through various actions, such as hemodynamic, hemorheological, and vascular actions, and on various cell biology aspects, such as intracellular calcium balance, mitochondria function, cell apoptosis, and scavenging free radicals. Here, we review the animal research progress and potential mechanisms in the treatment of ICM using extracts of well-known traditional Chinese herbal medicines.

A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Effectiveness of a Food Supplement Containing Creatine and D-Ribose Combined with a Physical Exercise Program in Increasing Stress Tolerance in Patients with Ischemic Heart Disease.

The aim of this study is to establish whether a supplement of creatine and ribose combined with a physical exercise program can improve the total work capacity during exercise in a population of patients with known ischemic heart disease. A double-blind, six-month study was designed in which 53 patients were enrolled and randomized to take either a nutraceutical composition containing creatine, D-ribose, vitamin B1, and vitamin B6 (active treatment) or the placebo. Both the nutraceutical supplement and the placebo were supplied by Giellepi S.p.A. Health Science in Lissone, Italy. After six months of study, the cardiac double product at the peak of the load, the delta double product, and the chronotropic index were higher in the active treatment group than in the placebo group. We can conclude that a supplementation with creatine, D-ribose, vitamin B1, and vitamin B6, in addition to standard therapy and a physical exercise program, seems to be helpful in improving exercise tolerance compared to the placebo in a population with cardiovascular disease. However, this needs to be further studied, given that there is no clear evidence that the double product can be used as a surrogate measure of exercise tolerance.

Multisize Electrodes for Substrate Identification in Ischemic Cardiomyopathy: Validation by Integration of Whole Heart Histology.

OBJECTIVES: This study sought to evaluate the value of combined electrogram (EGM) information provided by simultaneous mapping using micro- and conventional electrodes in the identification of post-myocardial infarction ventricular tachycardia substrate. BACKGROUND: Ventricular tachycardias after myocardial infarction are related to scars with complex geometry. Scar delineation and ventricular tachycardia substrate identification relies on bipolar voltages (BV) and EGM characteristics. Early reperfusion therapy results in small, nontransmural scars, the details of which may not be delineated using 3.5 mm tip catheters. METHODS: Nine swine with early reperfusion myocardial infarction were mapped using Biosense Webster's QDOT Micro catheter, incorporating 3 microelectrodes at the tip of the standard 3.5 mm electrode. Analysis of EGM during sinus rhythm, right ventricular pacing, and short-coupled right ventricular extrastimuli was performed. The swine were sacrificed and mapping data were projected onto the heart. Transmural biopsies (n = 196) corresponding to mapping points were obtained, allowing a head-to-head comparison of EGM recorded by micro- and conventional electrodes with histology. RESULTS: To identify scar areas using standard electrodes, unique cutoff values of unipolar voltage <5.44 mV, BV <1.27 mV (conventional), and BV <2.84 mV (microelectrode) were identified. Combining the information provided by unipolar voltage and BV mapping, the sensitivity of scar identification was increased to 93%. Micro-EGM were better able to distinguish small near-fields corresponding to a layer of viable subendocardium than conventional EGM were. CONCLUSIONS: The combined information provided by multisize electrode mapping increases the sensitivity with which areas of scar are identified. EGM from microelectrodes, with narrower spacing, allow identification of near-fields arising from thin subendocardial layer and layers activated with short delay obscured in EGM from conventional mapping catheter.

Targeted Ablation of Ventricular Tachycardia Guided by Wavefront Discontinuities During Sinus Rhythm: A New Functional Substrate Mapping Strategy.

BACKGROUND: Accurate and expedited identification of scar regions most prone to reentry is needed to guide ventricular tachycardia (VT) ablation. We aimed to prospectively assess outcomes of VT ablation guided primarily by the targeting of deceleration zones (DZ) identified by propagational analysis of ventricular activation during sinus rhythm. METHODS: Patients with scar-related VT were prospectively enrolled in the University of Chicago VT Ablation Registry between 2016 and 2018. Isochronal late activation maps annotated to the latest local electrogram deflection were created with high-density multielectrode mapping catheters. Targeted ablation of DZ (>3 isochrones within 1cm radius) was performed, prioritizing later activated regions with maximal isochronal crowding. When possible, activation mapping of VT was performed, and successful ablation sites were compared with DZ locations for mechanistic correlation. Patients were prospectively followed for VT recurrence and mortality. RESULTS: One hundred twenty patients (median age 65 years [59-71], 15% female, 50% nonischemic, median ejection fraction 31%) underwent 144 ablation procedures for scar-related VT. 57% of patients had previous ablation and epicardial access was employed in 59% of cases. High-density mapping during baseline rhythm was performed (2518 points [1615-3752] endocardial, 5049±2580 points epicardial) and identified an average of 2±1 DZ, which colocalized to successful termination sites in 95% of cases. The median total radiofrequency application duration was 29 min (21-38 min) to target DZ, representing ablation of 18% of the low-voltage area. At 12±10 months, 70% freedom from VT recurrence (80% in ischemic cardiomyopathy and 63% in nonischemic cardiomyopathy) was achieved. The overall survival rate was 87%. CONCLUSIONS: A novel voltage-independent high-density mapping display can identify the functional substrate for VT during sinus rhythm and guide targeted ablation, obviating the need for extensive radiofrequency delivery. Regions with isochronal crowding during the baseline rhythm were predictive of VT termination sites, providing mechanistic evidence that deceleration zones are highly arrhythmogenic, functioning as niduses for reentry.

Monophasic action potential amplitude for substrate mapping.

Although radiofrequency ablation has revolutionized the management of tachyarrhythmias, the rate of arrhythmia recurrence is a large drawback. Successful substrate identification is paramount to abolishing arrhythmia, and bipolar voltage electrogram's narrow field of view can be further reduced for increased sensitivity. In this report, we perform cardiac mapping with monophasic action potential (MAP) amplitude. We hypothesize that MAP amplitude (MAPA) will provide more accurate infarct sizes than other mapping modalities via increased sensitivity to distinguish healthy myocardium from scar tissue. Using the left coronary artery ligation Sprague-Dawley rat model of ischemic heart failure, we investigate the accuracy of in vivo ventricular epicardial maps derived from MAPA, MAP duration to 90% repolarization (MAPD90), unipolar voltage amplitude (UVA), and bipolar voltage amplitude (BVA) compared with gold standard histopathological measurement of infarct size. Numerical analysis reveals discrimination of healthy myocardium versus scar tissue using MAPD90 (P = 0.0158) and UVA (P < 0.001, n = 21). MAPA and BVA decreased between healthy and border tissue (P = 0.0218 and 0.0015, respectively) and border and scar tissue (P = 0.0037 and 0.0094, respectively). Contrary to our hypothesis, BVA mapping performed most accurately regarding quantifying infarct size. MAPA mapping may have high spatial resolution for myocardial tissue characterization but was quantitatively less accurate than other mapping methods at determining infarct size. BVA mapping's superior utility has been reinforced, supporting its use in translational research and clinical electrophysiology laboratories. MAPA may hold potential value for precisely distinguishing healthy myocardium, border zone, and scar tissue in diseases of disseminated fibrosis such as atrial fibrillation.NEW & NOTEWORTHY Monophasic action potential mapping in a clinically relevant model of heart failure with potential implications for atrial fibrillation management.

Effect of glutamate and aspartate on ischemic heart disease, blood pressure, and diabetes: a Mendelian randomization study.

BACKGROUND: Evolutionary biology suggests reproduction trades off against longevity. Genetic selection in favor of fertility and ischemic heart disease (IHD) exists in humans. Observationally, soy protects against IHD. Soy amino acids, glutamate and aspartate, may lower androgens. No large randomized controlled trials testing their health effects exist. OBJECTIVE: Using Mendelian randomization, we assessed how genetically predicted glutamate and aspartate affected IHD, blood pressure, and diabetes. METHODS: A separate sample instrumental variable analysis with genetic instruments was used to obtain unconfounded estimates using genetic variants strongly (P < 5 × 10(-8)) and solely associated with glutamate or aspartate applied to an IHD case (n ≤76,014)-control (n ≤ 264,785) study (based on a meta-analysis of CARDIoGRAMplusC4D 1000 Genomes, UK Biobank CAD SOFT GWAS and Myocardial Infarction Genetics and CARDIoGRAM Exome), blood pressure from the UK Biobank (n ≤ 361,194), and the DIAbetes Genetics Replication And Meta-analysis diabetes case (n = 26,676)-control (n = 132,532) study. A weighted median and MR-Egger were used for a sensitivity analysis. RESULTS: Glutamate was not associated with IHD, blood pressure, or diabetes after correction for multiple comparisons. Aspartate was inversely associated with IHD (odds ratio (OR) 0.92 per log-transformed standard deviation (SD); 95% confidence interval (CI) 0.88, 0.96) and diastolic blood pressure (-0.03; 95% CI -0.04, -0.02) using inverse variance weighting, but not diabetes (OR 1.00; 95% CI 0.91, 1.09). Associations were robust to the sensitivity analysis. CONCLUSIONS: Our findings suggest aspartate may play a role in IHD and blood pressure, potentially underlying cardiovascular benefits of soy. Clarifying the mechanisms would be valuable for IHD prevention and for defining a healthy diet.