Review of Case Reports on Adverse Events Related to Pre-workout Supplements Containing Synephrine.

The use of pre-workout supplements has become increasingly popular, including the use of supplements containing synephrine. Synephrine might stimulate weight loss and improve sports performance by its proposed adrenergic properties. However, with its increasing popularity, numerous cases of adverse events related to synephrine use have been reported. This study provides a comprehensive overview and analysis of current case reports related to the supplemental use of synephrine. The scientific literature on cases of adverse events related to synephrine intake was collected through August 2021 using Pubmed and Google Scholar and subsequently reviewed and analysed. We obtained 30 case reports describing a total of 35 patients who suffered from medical complaints following use of synephrine-containing supplements. The patients most often presented with chest pain, palpitations, syncope and dizziness. Commonly raised diagnoses were ischaemic heart disease, cardiac arrhythmias and cerebrovascular disease. Five patients were left disabled or remained on medication at last follow-up. We here show an association between the use of pre-workout supplements containing synephrine and adverse events, mainly related to the cardiovascular system. However, we cannot exclude a role of possible confounding factors such as caffeine. Thus, the use of pre-workout supplements containing synephrine may lead to serious adverse health events, and therefore, caution is needed.

Trends in the Prevalence and Incidence of Opium Abuse and its Association with Coronary Artery Risk Factors in Adult Population in Iran: Findings from Kerman Coronary Artery Disease Risk Factors Study.

Background: The prevalence of opium addiction in Iran is high probably due to the belief that opium has preventive effects against cardiovascular diseases. In the second phase of Kerman coronary artery disease risk factors study, the prevalence, incidence rate, and the association between opium use and other coronary artery disease risk factors (CADRFs) were assessed. Methods: In a cross-sectional study (2014-2018), 9996 inhabitants of Kerman, southeastern Iran, aged 15-80 years were recruited to the study. After taking fasting blood samples, the participants were examined or interviewed for demographic data and CADRFs, including opium use. The participants were categorized into "never", "occasional", and "dependent" users. The association between opium use and CADRFs was assessed with adjusted regression analysis (Stata v.11 software). Results: The overall prevalence of opium consumption was lower than that of five years earlier (P<0.01). The prevalence was currently higher in men than women and decreased in men between the two phases (P<0.001). There was a positive correlation between opium use and depression (P<0.001), anxiety (P<0.05), and a negative association with the level of physical activity (P<0.001). The five-year incident rate of dependent and occasional opium use was 4.2 and 3.9 persons/100 person-years, respectively. The incidence of opium use was higher in diabetic, hypertensive, depressed, anxious, and obese subjects. Conclusion: The study did not demonstrate any protective effects of opium on CADRFs. Considering the higher rate of opium use in subjects with hypertension, diabetes, obesity, and psychological disorders, the health authorities should implement educational programs to warn and correct the unsafe belief.

Associations of Coffee, Tea, and Caffeine Intake with Coronary Artery Calcification and Cardiovascular Events.

BACKGROUND: Coffee and tea are 2 of the most commonly consumed beverages in the world. The association of coffee and tea intake with coronary artery calcium and major adverse cardiovascular events remains uncertain. METHODS: We examined 6508 ethnically diverse participants with available coffee and tea data from the Multi-Ethnic Study of Atherosclerosis. Intake for each was classified as never, occasional (<1 cup per day), and regular (≥1 cup per day). A coronary artery calcium progression ratio was derived from mixed effect regression models using loge(calcium score+1) as the outcome, with coefficients exponentiated to reflect coronary artery calcium progression ratio versus the reference. Cox proportional hazards analyses were used to evaluate the association between beverage intake and incident cardiovascular events. RESULTS: Over a median follow-up of 5.3 years for coronary artery calcium and 11.1 years for cardiovascular events, participants who regularly drank tea (≥1 cup per day) had a slower progression of coronary artery calcium compared with never drinkers after multivariable adjustment. This correlated with a statistically significant lower incidence of cardiovascular events for ≥1 cup per day tea drinkers (adjusted hazard ratio 0.71; 95% confidence interval 0.53-0.95). Compared with never coffee drinkers, regular coffee intake (≥1 cup per day) was not statistically associated with coronary artery calcium progression or cardiovascular events (adjusted hazard ratio 0.97; 95% confidence interval 0.78-1.20). Caffeine intake was marginally inversely associated with coronary artery calcium progression. CONCLUSIONS: Moderate tea drinkers had slower progression of coronary artery calcium and reduced risk for cardiovascular events. Future research is needed to understand the potentially protective nature of moderate tea intake.

High dose and long-term statin therapy accelerate coronary artery calcification.

BACKGROUND: In randomized clinical trials statins and placebo treated patients showed the same degree of coronary artery calcium (CAC) progression. We reanalyzed data from two clinical trials to further investigate the time and dose dependent effects of statins on CAC. Additionally, we investigated whether CAC progression was associated with incident cardiovascular events. METHODS AND RESULTS: Data were pooled from two clinical trials: St. Francis Heart Study (SFHS) (419 and 432 patients treated with placebo and 20 mg atorvastatin daily, respectively) and EBEAT Study (164 and 179 patients respectively treated with 10 mg and 80 mg atorvastatin daily). CAC scores were assessed at baseline, 2 years and 4-6 years in SFHS; in EBEAT they were measured at baseline and 12 months. After a short-term follow-up (12 to 24 months) placebo and low dose atorvastatin showed a similar CAC increase, although 80 mg/daily atorvastatin increased CAC an additional 12-14% over placebo (p<0.001). In the long-term, atorvastatin caused a greater progression of CAC compared to placebo (additional 1.1%, p=0.04). In SFHS 42 cardiovascular events occurred after the second CT scan. The baseline and progression of CAC were greater in patients with events. However, only baseline CAC and family history of premature cardiovascular disease but not CAC progression were independent predictors of events. CONCLUSIONS: Despite a greater CAC increase with high dose and long-term statin therapy, events did not occur more frequently in statin treated patients. This suggests that CAC growth under treatment with statins represents plaque repair rather than continuing plaque expansion.

Opium consumption and coronary atherosclerosis in diabetic patients: a propensity score-matched study.

There is a traditional belief among Eastern people that opium may have ameliorating effects on cardiovascular risk factors, especially diabetes; thus, it is widely used among diabetic patients. We attempted to investigate the association of opium consumption with coronary artery disease (CAD) in diabetic patients. A cross-sectional study was conducted on diabetic patients undergoing coronary angiography in our center. Out of 1925 diabetic patients included in the study, 228 were opium users, and the remaining 1697 non-opium users were used as a pool of potential comparators. Propensity scores were used to match the 228 opium consumers with 228 matched comparators for age, sex, and smoking status. The Gensini score and extent score were respectively used to assess the angiographic severity and extent of CAD. The mean Gensini score (86.9 ± 62.7 vs. 59.6 ± 43.4, p < 0.0001) and extent score (7.1 ± 2.9 vs. 5.9 ± 2.9, p < 0.0001) were significantly higher in opium user diabetic patients than in non-opium users. After adjustment for potential confounders, a dose-response relationship was observed between dose of opium and the Gensini score ( ß = 0.27, p = 0.04). There were no significant differences between the routes of opium administration (inhalation vs. oral) regarding the severity and extent of CAD. In conclusion, exposure to opium in diabetic patients may be positively associated with the risk of CAD, and with the angiographically determined severity and extent of the disease. Furthermore, dosage of opium consumption may correlate with severity of CAD.

Effects of hormone therapy and dietary soy on myocardial ischemia/reperfusion injury in ovariectomized atherosclerotic monkeys.

OBJECTIVE: Hormone therapy (HT) and dietary soy (Soy) inhibit myocardial ischemia/reperfusion (I/R) injury in nonatherosclerotic animals. The aim of this study was to determine their independent and interactive effects on I/R in monkeys previously fed an atherogenic diet for 15 months. DESIGN: Ovariectomized atherosclerotic monkeys (n = 40) were divided into one of four dietary treatment groups: (1) casein as the protein source, (2) casein and added HT (the equivalent of 5 mug ethinyl estradiol + 1 mg norethindrone acetate daily), (3) Soy protein providing 141 mg total isoflavones daily, or (4) Soy + HT. After 12 months monkeys were anesthetized, and their left anterior descending coronary artery was occluded for 1 hour and reperfused for 4 hours. Infarct size was the percentage of the area at risk not staining with triphenyltetrazolium chloride. Additional measures were myocardial blood flow, stroke volume, coronary output, myeloperoxidase, and malondialdehyde. RESULTS: There was an interactive negative effect of HT + Soy to increase infarct size from approximately 30% (in other groups) to 55% (P = 0.0004). Additionally, there were negative main effects of Soy on blood flow, coronary output, and stroke volume during I/R (all P values <0.05). There were no effects of treatment on either myeloperoxidase or malondialdehyde. CONCLUSIONS: Neither HT nor Soy had beneficial effects, whereas their combination had harmful effects, on myocardial I/R injury in monkeys with preexisting atherosclerosis. The mechanism of this negative interaction remains unclear but may relate to Soy's negative effects on hemodynamics.

Ginkgolide A attenuates homocysteine-induced endothelial dysfunction in porcine coronary arteries.

BACKGROUND: Homocysteine is an independent risk factor for atherosclerosis. The objective of this study was to investigate whether ginkgolide A (GA), a major constituent of Ginkgo biloba, could block homocysteine-induced endothelial dysfunction in porcine coronary arteries. METHODS: Porcine coronary artery rings were assigned to six treatment groups: control; homocysteine (50 micromol/L); low-dose (50 micromol/L) or high-dose (100 micromol/L) GA; and homocysteine plus low-dose or high-dose GA. After 24 hours' incubation, the rings were analyzed for vasomotor function in response to a thromboxane A2 analogue (U46619), bradykinin, and sodium nitroprusside. Endothelial nitric oxide synthase (eNOS) was studied by using real-time polymerase chain reaction and immunohistochemistry analysis. Superoxide anion production was assessed by chemoluminescence analysis. RESULTS: Endothelium-dependent relaxation (bradykinin) was significantly reduced in ring segments treated with homocysteine as compared with the control (P < .05). When homocysteine was combined with either low-dose or high-dose GA, endothelium-dependent relaxation was markedly recovered. There was no significant difference in maximal contraction (U46619) or endothelium-independent relaxation (sodium nitroprusside) among all groups. In addition, superoxide anion production was increased by 113% in the homocysteine-treated group, whereas there was no statistically significant difference between the control and GA/homocysteine groups. Furthermore, eNOS messenger RNA and protein levels were substantially reduced in the homocysteine-treated group (P < .05), but not in the GA/homocysteine combined groups. CONCLUSIONS: Homocysteine significantly impairs endothelium-dependent vasorelaxation through oxidative stress and downregulation of eNOS in porcine coronary arteries. GA effectively prevents homocysteine-induced endothelial dysfunction and molecular changes in porcine coronary arteries. This study underscores the potential clinical benefits and applications of GA in controlling homocysteine-associated vascular injury and cardiovascular disease. CLINICAL RELEVANCE: Homocysteine is an independent risk factor for atherosclerosis. This study showed that ginkgolide A, a major constituent of Ginkgo biloba, effectively prevents homocysteine-induced endothelial dysfunction and molecular changes in porcine coronary arteries. This study underscores potential clinical benefits and applications of ginkgolide A in controlling homocysteine-associated vascular injury and cardiovascular disease.

Calcium-containing phosphate binder use associated with accelerated atherosclerotic coronary calcification.

OBJECTIVE: To report parameters and outcomes of phosphorus management in a maintenance hemodialysis patient who experienced atherosclerotic coronary calcification leading to myocardial infarction; to evaluate the role that high calcium intake over 6 years may have played in his coronary artery disease before the dangers of excess calcium intake in phosphorus management were recognized; and to describe an optimized therapeutic approach that provided improved mineral control. DESIGN: Case study. SETTING: A large outpatient in-center hemodialysis treatment unit. MAIN OUTCOME MEASURES: Serum calcium, serum phosphorus, Ca x P product. RESULTS: The year before his cardiac event, the patient's mean serum calcium was 9.6 mg/dL, mean serum phosphorus was 5.9 mg/dL, and mean Ca x P product was 57 mg2/dL2. Serum calcium peaked at 10.8 mg/dL shortly before his cardiac event. Treatment phases included high-dose calcium acetate (10 g Ca/day), low-dose calcium acetate (4 g Ca/day), low-dose calcium acetate plus low-dose sevelamer hydrochloride (4 g Ca/day plus 2.4 to 4.8 g sevelamer/day), and low-dose calcium acetate plus higher-dose sevelamer hydrochloride (4 g Ca/day plus 4.0 to 12.0 g sevelamer/day). With calcium acetate and sevelamer doses optimized, serum phosphorus levels and Ca x P products continued decreasing, with mean values of 5.99 mg/dL and 50.7 mg2/dL2, respectively, and serum calcium remained stable at a mean of 8.5 mg/dL. The patient has had no further myocardial infarctions. CONCLUSIONS: This case illustrates how our growing understanding of phosphorus management and the addition of a calcium-free binder to our therapeutic armamentarium have improved phosphorus and calcium balance, reducing the risk of cardiovascular calcification.

Antiinflammatory and antiarteriosclerotic effects of pioglitazone.

Peroxisome proliferator-activated receptor-gamma (PPARgamma) ligands are widely used in patients with insulin resistance and diabetes. Because coronary artery disease is a major complication for such patients, it is important to determine the effects of PPARgamma activation on arteriosclerosis. Long-term inhibition of endothelial NO synthesis by administration of N(omega)-nitro-L-arginine methyl ester (L-NAME) to rats induces coronary vascular inflammation (monocyte infiltration, monocyte chemoattractant protein-1 [MCP-1] expression) and subsequent arteriosclerosis. We examined the effects of pioglitazone (a PPARgamma ligand) in this rat model to determine whether PPARgamma activation with pioglitazone inhibits arteriosclerosis by its indirect effects on metabolic conditions or by direct effects on the cells participating to the pathogenesis of arteriosclerosis. We found that pioglitazone did not affect metabolic states, systolic blood pressure, or serum NO levels, but did prevent the L-NAME-induced coronary inflammation and arteriosclerosis. Pioglitazone did not reduce local expression of MCP-1 but markedly attenuated increased expression of the MCP-1 receptor C-C chemokine receptor 2 (CCR2) in lesional and circulating monocytes. PPARgamma activation with pioglitazone prevented coronary arteriosclerosis, possibly by its antiinflammatory effects (downregulation of CCR2 in circulating monocytes). Inhibition of the CCR2-mediated inflammation may represent novel antiinflammatory actions of pioglitazone beyond improvement of metabolic state.

Keishi-bukuryo-gan preserves the endothelium dependent relaxation of thoracic aorta in cholesterol-fed rabbit by limiting superoxide generation.

Formerly, we have reported that keishi-bukuryo-gan prevents the progression of atherosclerosis in cholesterol-fed rabbits and inhibits the free radical-induced RBC haemolysis in rats. The present study was performed to investigate how keishi-bukuryo-gan (KBG) inhibits the early stage of atherosclerosis. Plasma lipid concentration and hydroxyl radical generation during respiratory burst in neutrophils were evaluated at the start and end of the study. The protective effect of KBG against endothelium disorder due to hypercholesterolaemia was examined. Twelve male Japanese white rabbits (2 kg body weight) were divided into two groups. Group A (n = 6) was fed standard rabbit chow containing 1% cholesterol for 4 weeks. Group B (n = 6) was fed standard rabbit chow containing 1% cholesterol and 1% KBG for 4 weeks. In the plasma lipid concentration, only the lipid peroxide concentration of group A was significantly higher than that of group B. At the end of the study, DMPO-OH, the spin-trapped adduct of hydroxyl radicals generated by neutrophils, was increased in both groups, and this increase was marked in group B. Endothelium-dependent vasodilatation by acetylcholine increased significantly in group B compared with group A. Thus, KBG protects the vascular endothelium function by its antioxidative effect and by inhibiting the release of free radicals from neutrophils in vivo.

Long-term treatment with N(omega)-nitro-L-arginine methyl ester causes arteriosclerotic coronary lesions in endothelial nitric oxide synthase-deficient mice.

BACKGROUND: N(omega)-nitro-L-arginine methyl ester (l-NAME) is widely used to inhibit endothelial synthesis of NO in vivo. However, it is controversial whether the long-term vascular effects of l-NAME are mediated primarily by inhibition of endothelial NO synthesis. We addressed this point in mice that are deficient in the endothelial NO synthase gene (eNOS-KO mice). METHODS AND RESULTS: Wild-type and eNOS-KO mice received l-NAME in drinking water for 8 weeks. In wild-type mice, long-term treatment with l-NAME caused significant medial thickening and perivascular fibrosis in coronary microvessels but not in large coronary arteries. Importantly, in eNOS-KO mice, treatment with l-NAME also caused an extent of medial thickening and perivascular fibrosis in coronary microvessels that was comparable to that in wild-type mice and that was not prevented by supplementation of L-arginine. Vascular NO and cGMP levels were not significantly reduced by l-NAME treatment, and no expression of inducible or neuronal NO synthase was noted in microvessels of eNOS-KO mice, suggesting an involvement of NO-independent mechanisms. Treatment with l-NAME caused an upregulation of vascular ACE and an increase in cardiac lucigenin chemiluminescence that were comparable in both strains and that were abolished by simultaneous treatment with temocapril (ACE inhibitor) or CS866 (angiotensin II type 1 receptor antagonist) along with the suppression of vascular lesion formation. CONCLUSIONS: These results provide the first direct evidence that the long-term vascular effects of l-NAME are not mediated by simple inhibition of endothelial NO synthesis. Direct upregulation of local ACE and increased oxidative stress appear to be involved in the long-term vascular effects of l-NAME in vivo.

Effects of immunosuppressants on platelet-derived growth factor-A chain mRNA expression and coronary arteriosclerosis in rat cardiac allografts.

Graft coronary arteriosclerosis (GCA) that results in proliferative and obstructive lesions limits the long-term success of cardiac transplantation. Despite extensive study, the pathogenic mechanisms underlying GCA are still unclear and therapeutic strategies for this condition have been inadequate. In this study, we compared the therapeutic effectiveness of cyclosporine A (CsA), 15-deoxyspergualin (DSG), and Multiglycosidorum tripterygii (MT) on GCA. In addition, we studied the correlation between the extent of GCA and the degree of platelet-derived growth facter (PDGF)-A chain mRNA expression in cardiac grafts. Lewis rats receiving heterotropic heart transplants from Wistar King donors were treated with 10 mg kg(-1) day(-1) of CsA (n=7), 5 mg kg(-1) day(-1) of DSG (n=7) or 30 mg kg(-1) day(-1) of MT (n=7) respectively. Histological evaluation of coronary arteriosclerosis and Northern blot analysis of cardiac allograft PDGF-A chain mRNA expression were conducted on day 60 after transplantation. Varying levels of GCA were observed in the 21 transplanted hearts. Significant differences in both the degree of PDGF-A mRNA expression and the extent of GCA were found among the 3 groups. GCA was significantly reduced in allografts treated with MT or DSG in comparison with the level seen in CsA-treated grafts. A significant correlation was found between PDGF-A chain mRNA expression and the grade of arterial intimal thickening (r=0.76, p<0.05) as well as with the incidence of diseased vessels (r=0.82, p<0.01). Our results indicate that both MT and DSG are more effective in the treatment of GCA than CsA. In our cardiac allografts, the degree of PDGF-A chain mRNA expression correlated well with the extent of GCA, suggesting that PDGF-A may play an important role in the development of transplant-related GCA.

Therapeutic approaches to the control of coronary atherosclerosis.

Atherosclerosis is a multifactorial disease which culminates in the ruptured plaque seen at autopsy. Hypercholesterolaemia, subintimal accumulation of lipid, monocyte adhesion followed by penetration across the endothelium, the conversion of monocytes to macrophages and smooth muscle cell proliferation and migration are some of the events involved in the early stages of lesion formation. Late events include the formation of excess ground substance and collagen, and the formation of the fibrotic cap. Young lesions tend to be more fragile than "old" calcified lesions, and it is these young lesions which rupture, haemorrhage and provide anchor points for platelets. Therapeutic interventions aimed at controlling lesion formation include those which reduce risk factors, including hypertension as well as those which interfere with the cascade of events involved in lesion formation. Agents which lower plasma cholesterol provide one approach. Another approach is to use calcium antagonists which not only lower blood pressure, but also directly interfere with some of the metabolic events involved in lesion formation.