Vasoconstriction Of Coronary Arteries Research Articles

Emerging therapeutic options for acute migraine: focus on the potential of lasmiditan.

The serotonin receptor agonist triptan drugs (5-HT1B/1D receptor agonists) have been in use for over 20 years in the abortive management of migraine. Although clearly effective, their ability to produce vasoconstriction in cerebral and coronary arteries, thought to be mediated by their high affinity for the 5-HT1B receptor, has been a limitation to their use in certain patient populations. Variable potency triptan binding at the 5-HT1F receptor occurs in addition to binding at the 5-HT1B and 5-HT1D receptors. A more selective serotonin agonist without 5-HT1B-mediated vasoconstriction might prove efficacious yet safer. The 5-HT1F receptor has been targeted as a site of action for such a drug. In experimental models, 5-HT1F receptor agonists have been shown to block neurogenic inflammation and c-Fos expression in neural tissue and, as well, show no evidence of vasoconstriction in vascular tissue models in vitro. In clinical trials, efficacy in the abortive management of migraine has been established. Lasmiditan (LY573144), a selective 5-HT1F receptor agonist (K1=2.21 μM), showed efficacy in its primary endpoint, with a 2-hour placebo-subtracted headache response of 28.8%, though with frequent reports of dizziness, paresthesias, and vertigo. Study results support an emerging central neuronal mechanism of migraine pathophysiology. This review traces the history and use of 5-HT1F receptor agonists, now referred to as neurally acting anti-migraine agents in migraine management.

Coronary artery spasm: review and update.

Coronary artery spasm (CAS), an intense vasoconstriction of coronary arteries that causes total or subtotal vessel occlusion, plays an important role in myocardial ischemic syndromes including stable and unstable angina, acute myocardial infarction, and sudden cardiac death. Coronary angiography and provocative testing usually is required to establish a definitive diagnosis. While the mechanisms underlying the development of CAS are still poorly understood, CAS appears to be a multifactorial disease but is not associated with the traditional risk factors for coronary artery disease. The diagnosis of CAS has important therapeutic implications, as calcium antagonists, not β-blockers, are the cornerstone of medical treatment. The prognosis is generally considered benign; however, recurrent episodes of angina are frequently observed. We provide a review of the literature and summarize the current state of knowledge regarding the pathogenesis of CAS.

Clinical Implications

HomeHypertensionVol. 62, No. 5Clinical Implications Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBClinical Implications Originally published1 Nov 2013https://doi.org/10.1161/01.hyp.0000436210.57019.2eHypertension. 2013;62:809HT/PET-MPs (Gestational Hypertension and Preeclampsia/Toxemia-Microparticles) Affect Trophoblast and Endothelial Function (page 893)Hypertensive disorders of pregnancy are common vascular pathologies having severe implications for maternal and fetal health. Unraveling the complex pathogenesis of gestational vascular complications is crucial for their prevention and improved management.Previously, microvesicles (MVs) were shown to affect coagulation and inflammation in pregnancy. Our study demonstrates that MVs obtained from women with gestational hypertension and preeclampsia present higher levels of antiangiogenic proteins and proinflammatory cytokines. The present study shows that in contrast to MVs of healthy pregnant women, gestational vascular complication MVs do not induce early stage trophoblast migration (Figure S5), inhibit endothelial tube formation, and cause massive apoptosis in term trophoblasts. This indicates the involvement of MVs in placental development at early gestational ages and in placental health at late stages of pregnancy.Recent studies suggested that LMWH (low molecular weight heparin) could improve the outcome of women with gestational vascular complications. The mechanisms through which LMWH exert its effect are multifaceted, involving maternal and placental anticoagulation, as well as anti-inflammatory and complement pathway activity. The findings of the current study highlight that MVs are a new critical player participating in physiological mechanisms of placental development and in the pathology of hypertensive disease in pregnancy. Furthermore, these data could foster our understanding of LMWH effects in this challenging clinical setting.Download figureDownload PowerPointAmyloid-β Peptides (page 966)Alzheimer disease (AD) is the most common form of dementia with 27 million known cases worldwide. Its incidence is rapidly increasing, and there are no effective treatments. The cause is essentially unknown. Initially, defective cholinergic signaling was implicated. Subsequently, the role of amyloid deposits and the amyloid precursor protein was added to the picture. Amyloid-β (Aβ) is a peptide of 36 to 43 amino acids that is processed from amyloid precursor protein. A specific isoform of apolipoprotein, APOE4, is a major genetic risk factor for AD. Apolipoproteins enhance the breakdown of Aβ, but APOE4 is not very effective, leading to an excess amyloid buildup in the brain. Tau proteins stabilize microtubules. They are abundant in neurons of the central nervous system. Hyperphosphorylated tau pairs with other threads of tau eventually forming neurofibrillary tangles inside nerve cell bodies. Viruses, prions, oxidative stress, biometal biology, and numerous other factors are also implicated in AD including small-vessel vascular disease. Could AD be in part a vascular disorder? Indeed, amyloid can cause abnormal vascular reactivity. We found that Aβ induced vasoconstriction of coronary arteries in Langendorff-perfused rat hearts. Aβ bound to the α1 adrenoreceptor, thereby inducing a signal-transduction cascade with cytosolic calcium and extracellular-related kinase phosphorylation in vascular smooth muscle cells. Thus, Aβ itself could be a vascular signaling molecule. Aβ induced vasoconstriction, decreased coronary blood flow, and exhibited α1 adrenoreceptor–mediated signaling. Nonetheless, an in vivo model is necessary to pursue translation of our findings. The implications from our work are that successful therapies directed at AD will probably contain a component addressing the participation of blood vessels. The α1 adrenoreceptor has appeal as a target because the compounds are clinically in use. Furthermore, our notion could be investigated epidemiologically.Download figureDownload PowerPointHypoxia and Development of Nephropathy (page 914)It is well established that kidney hypoxia is present in diseases closely associated with development of nephropathy, such as diabetes mellitus and hypertension. The hypothesis that chronic kidney hypoxia results in the development of nephropathy was originally proposed in 1998 and has since gained increasing support. However, the specific contribution of kidney hypoxia for the development of nephropathy is difficult to determine because of the presence of confounding factors, such as hyperglycemia, hypertension, and oxidative stress. To identify the specific role of kidney hypoxia, Friederich-Persson et al treated normoglycemic control rats with dinitrophenol, a mitochondrial uncoupler, which increases the mitochondrial oxygen consumption. Consequently, treatment with dinitrophenol increased total kidney oxygen consumption and resulted in kidney hypoxia. Interestingly, this resulted in nephropathy evidenced as increased protein excretion and tubulointerstitial damage. Importantly, there was no hyperglycemia, hypertension, or increased oxidative stress levels after dinitrophenol treatment. Thus, the main conclusion was that kidney tissue hypoxia is an independent pathway for the development of nephropathy. Being able to detect and target early alterations in intrarenal oxygen metabolism may be important for patients at risk of developing nephropathy. As such, interventions to prevent excessive kidney oxygen consumption or to restore kidney tissue oxygen availability may prove beneficial in preventing nephropathy in patients.Download figureDownload PowerPoint Previous Back to top Next FiguresReferencesRelatedDetails November 2013Vol 62, Issue 5 Advertisement Article InformationMetrics © 2013 American Heart Association, Inc.https://doi.org/10.1161/01.hyp.0000436210.57019.2e Originally publishedNovember 1, 2013 PDF download Advertisement

Abstract 391: Enhanced Coronary Vasoconstriction in Western Diet-Induced Obesity is Associated with Alterations in NHE1, SERCA2a and 3

Cardiovascular disease (CVD) remains a major risk factor and cause of mortality in type 2 diabetes but, the effect of western diet (WD) on coronary artery vasoconstriction has not been well characterized. Therefore, the purpose of this study was to identify potential calcium (Ca 2+ ) molecular mechanism(s) underlying alterations in coronary constriction in WD-induced obesity. C57Bl/6J mice were fed a WD or control diet for 16wks. Coronary vascular function was assessed with wire myography and human coronary vascular smooth muscle cells (VSMC) were cultured. WD enhanced coronary constriction to the thromboxane analog U46619. This was associated with increased coronary VSMC expression of sodium-hydrogen exchanger 1 (NHE1) and SERCA3 with decreased expression of SERCA2a. Oxidation of SERCA2a cysteine-674, a signal for SERCA2a degradation, was increased in WD coronary VSMC. Exposure of cultured human coronary VSMC to hyperinsulinemic conditions elicited similar changes in SERCA2a, 3 and NHE1. This study suggests that enhanced thromboxane-mediated coronary constriction in WD and insulin resistance/hyperinsulinemia may result from NHE1-dependent changes in intracellular pH and/or impaired Ca 2+ handling at the level of the sarcoplasmic reticulum.

Abstract 459: Vasoactivity of the Alzheimer ß-Amyloid Peptides is Mediated by an Activation of the a 1 -Adrenoreceptor

Alzheimer disease (AD) features β-amyloid peptide (Aβ) deposition in brain and blood vessels and is associated with hypertension. Aβ can cause vasoconstriction and endothelial dysfunction. Recently, we could show that Aβ peptides elicit a signal transduction pathway in vascular smooth muscle cells and cardiomyocytes, induced by α 1 -adrenergic receptor activation. We hypothesized that the Aβ vasoactivity is also induced by activation of the α 1 -adrenoreceptor. Mouse aortic Rings were incubated for 24 h with 1 μmol/l Aβ (25-35). The influence of Aβ (25-35) on vasoconstriction of mouse aortic rings was studied in the additional presence and absence of α 1 -adrenergic receptor blocker prazosin. Vasoactivity in isolated aortic rings was measured using an isometric myograph. Vasoconstriction to 5-hydroxytryptamine was significantly increased (P≤0.001) in aortic rings by Aβ (25-35) pretreatment. This vasoactive effect was improved by the presence of α 1 -adrenergic receptor blocker during the Aβ (25-35) pretreatment. Rat middle cerebral artery (MCA) segments were treated with either 0.1μmol/L Aβ (25-35) or 0.1μmol/L of a negative control peptide with a reverse amino acid sequence (Aβ rev.) of Aβ (25-35) for 4h. Constriction of the middle cerebral artery was measured in dual vessel chamber. Incubation with Aβ (25-35) significantly enhanced (P≤0.0005) response of middle cerebral artery segments to the α 1 -agonist phenylephrine induced contractions. In a further ex vivo model of Langendorff-perfused rat hearts Aβ (25-35) also induced vasoconstriction of coronary arteries that resulted in decreased coronary flow. These effects could also be reversed by α 1 -adrenergic receptor blockade. Furthermore we analyzed the brain of hypertensive dTGR animals and in human arteriosclerotic plaques for the presence of Aβ amyloid. Amyloid deposits are present in cerebral cortex of hypertensive dTGR animals with damaged blood-brain barrier and in human arteriosclerotic plaques. Our data are relevant to the association between AD and hypertension. They may serve to explain impaired of vascular responses by Aβ and could have therapeutic implications.

Enhanced coronary vasoconstriction in western diet‐induced obesity is associated with alterations in NHE1, SERCA2a and 3

Cardiovascular disease (CVD) remains a major risk factor and cause of mortality in type 2 diabetes but, the effect of western diet (WD) on coronary artery vasoconstriction has not been well characterized. Therefore, the purpose of this study was to identify potential calcium (Ca2+) molecular mechanisms underlying alterations in coronary constriction in WD‐induced obesity. C57Bl/6J mice were fed a WD or control diet for 16wks. Coronary vascular function was assessed with wire myography and human coronary vascular smooth muscle cells (VSMC) were cultured. WD enhanced coronary constriction to the thromboxane analog U46619. This was associated with increased coronary VSMC expression of sodium‐hydrogen exchanger 1 (NHE1) and SERCA3 with decreased expression of SERCA2a. Oxidation of SERCA2a cysteine‐674, a signal for SERCA2a degradation, was increased in WD coronary VSMC. Exposure of cultured human coronary VSMC to hyperinsulinemic conditions elicited similar changes in SERCA2a, 3 and NHE1. This study suggests that enhanced thromboxane‐mediated coronary constriction in WD and insulin resistance/hyperinsulinemia may result from NHE1‐dependent changes in intracellular pH and/or impaired Ca2+ handling at the level of the SR. Supported by NIH HL107910, HL073101, and VA Merit Review 0018.

Effect of a flavonoid‐rich cacao extract on vascular reactivity in a mouse model

BackgroundCardiovascular disease (CVD) is the second leading cause of death in Mexico in both women and men. Evidence based on epidemiological studies suggests that consumption of flavanolrich foods is inversely related to the development of CVD. It has been suggested that cacao flavonoids has positive effects on vascular system, and more specifically at the endothelial level.ObjectivesTo determine whether a treatment based on a flavonoid‐rich extract from Theobroma cacao beans could contribute to decrease the number of vasoconstrictions and improve vasodilator response in old mice.Materials and MethodsWe conducted an experimental, comparative, cross‐sectional study. Firstly ethanolic extraction was performed from Mexican Theobroma cacao beans, which was used for the experiments. We made two groups of mice (treated, untreated). Vascular reactivity was assessed with two experimental strategies: 1) Quantifying the presence of coronary artery vasoconstriction in both groups and 2) Evaluating the relaxant response to acetylcholine in an organ‐isolated system.ResultsThere were more vasoconstriction in the placebo group (no extract), and although there was no statistically significant difference (p = 0.4596), there was almost 50% less vasoconstrictions in mice treated with the extract. In evaluating the relaxant response to acetylcholine, the mice receiving the extract showed a relaxant concentration‐response that was significant at higher concentrations (p<0.01), unlike control mice.ConclusionsThrough the ethanolic extraction from Theobroma cacao beans we could obtain an extract rich in flavonoids. The administration of this extract improves endothelium‐dependent relaxant response in this animal model.Source of research support:CONACYT

Signaling pathways involved in the H2O2-induced vasoconstriction of rat coronary arteries

Hydrogen peroxide (H2O2) is an endogenous endothelium-derived hyperpolarizing factor released by flow and involved in the regulation of coronary blood flow. Because opposing vasoactive effects have been reported for H2O2 depending on the vascular bed and experimental conditions, the aim of this study was to assess whether H2O2 may act as a coronary vasoconstrictor and if so to determine the underlying signaling mechanisms. Intramyocardial arteries from male Wistar rats were mounted on microvascular myographs for simultaneous measurements of intracellular Ca2+ ([Ca2+]i) and tension. On coronary arteries precontracted with the thromboxane A2 (TxA2) analogue U46619, H2O2 (1–300μM) elicited further moderate contractions in the proximal arterial segments and relaxed the more distal coronary branches, the contractions being markedly augmented in arteries depolarized by raising extracellular K+. H2O2-elicited vasoconstriction on K+30-precontracted coronary arteries was blunted by catalase and significantly reduced by endothelial cell removal and by inhibitors of cyclooxygenase (COX) and of the TxA2 receptor (TP). H2O2 (50μM) increased by about 10-fold basal superoxide anion (O2−) production in coronary arteries measured by lucigenin-enhanced chemiluminescence, and H2O2-elicited contractions were reduced by the superoxide dismutase mimetic tempol and by NADPH oxidase inhibition. Furthermore, blockade of the ERK and p38 mitogen-activated protein (MAP) kinases significantly reduced the contractions elicited by high and low concentrations of peroxide, respectively, whereas Rho kinase inhibition nearly abolished these responses. H2O2 (50μM) elicited simultaneous and similar sustained increases in [Ca2+]i and tension that were blunted by blockade of voltage-dependent L-type channels, but resistant to the nonselective Ca2+ channel blocker 2-aminoethoxydiphenyl borate. Moreover, endothelial cell removal reduced the increases in [Ca2+]i and contraction elicited by peroxide. The present data demonstrate that H2O2 is an endothelium-dependent vasoconstrictor in rat coronary arteries that activates smooth muscle Ca2+ entry through L-type and non-L-type channels and various intracellular signaling pathways including the release of a COX-derived TP agonist, stimulation of the MAP and Rho kinase pathways, and production of NADPH oxidase-derived superoxide.

Endothelin A-receptors and the coronary circulation

We review the role of endothelin (ET) A-receptors (R) on the coronary circulation. ET-1 maintains the normal coronary artery tone. ET-1 plasma levels are increased during and after coronary angioplasty and this increase is related to myocardial ischaemia rather than to mechanical artery injury. ETAR antagonists inhibit coronary artery vasoconstriction induced by ET release after coronary angioplasty in humans. ET promotes neointimal formation and ETAR antagonism has been shown to inhibit restenosis after angioplasty in the animal model but not in humans. ETAR blockade increases coronary blood flow, dilates distal coronary arterial segments and decreases coronary vascular resistance. Coronary collaterals are less sensitive than other coronary vessels to ET-1. ETAR blockade decreases collateral blood flow and, consequently, perfusion of the ischemic myocardium.

Abstract 18566: How is the Presence of Obstructive Sleep Apnea Associated with Vasospastic Angina?

Background: Vasospastic angina (VSA) is characterized by transient vasoconstriction of the epicardial coronary arteries leading to myocardial ischemia. It characteristically occurs from midnight to early morning. Obstructive sleep apnea (OSA) is caused by obstruction of the upper air passage during sleep, which leads to hypopnea. Although OSA may have an influence on VSA, the association between these two conditions remains unclear. To clarify this relationship, the frequency of OSA (Study 1) and the association between OSA and anginal attacks (Study 2) were investigated. Methods: (Study 1) Eighty-seven patients (41 men, mean age 67 years) were included in whom spasm-provocation testing for evaluation of chest symptoms was performed. VSA was defined as >90% narrowing of the epicardial coronary arteries on the angiogram during a spasm-provocation test, accompanied by chest pain and/or ST-segment deviation on ECG. Polysomnography (PSG) was performed in all patients. The presence of OSA was verified using the apnea hypopnea index (AHI) >15/h. The frequency of OSA in VSA patients (VSA group, n = 58) was compared with that in patients in whom negative spasm-provocation testing (non-VSA group, n = 29) was performed. (Study 2) Seventy-seven VSA outpatients were examined in whom PSG was performed (45 OSA, 32 non-OSA), and these patients followed up for at least a year. The number of anginal attacks per month was evaluated. The presence of intractable VSA was defined as uncontrollable angina even after administration of two types of coronary vasodilators. Results: (Study 1) No difference was observed in AHI (VSA group: 15.2 ± 1.3/h, non-VSA group: 12.8 ± 1.8/h) and the frequency of OSA (VSA group: 25/58, 43%, non-VSA group: 9/29, 31%) between the two groups. (Study 2) The number of anginal attacks tended to be higher in the OSA group (2.9 ± 0.6/months) than in the non-OSA group (1.3 ± 0.8/months, p = 0.09). The frequency of intractable VSA was higher in the OSA group (47%) than in the non-OSA group (19%, p < 0.05). Logistic regression analysis demonstrated that the presence of OSA was the significant factor responsible for intractable VSA. Conclusions: These results suggest that although OSA may not be involved in the pathogenesis of VSA, it may be a deteriorating factor of VSA.

Cocaine cardiotoxicity: a review of the pathophysiology, pathology, and treatment options.

Cocaine is a powerful stimulant that gives users a temporary sense of euphoria, mental alertness, talkativeness, and a decreased need for food and sleep. Cocaine intoxication is the most frequent cause of drug-related death reported by medical examiners in the US, and these events are most often related to the cardiovascular manifestations of the drug. Once playing a vital role in medicine as a local anesthetic, decades of research have established that cocaine has the ability to cause irreversible structural damage to the heart, greatly accelerate cardiovascular disease, and initiate sudden cardiac death. Although pathologic findings are often reported in the literature, few images are available to support these findings, and reviews of cocaine cardiopathology are rare. We describe the major pathologic findings linked to cocaine abuse in earlier research, their underlying mechanisms, and the treatment approaches currently being used in this patient population. A MEDLINE search was conducted to identify all English language articles from January 2000 to June 2008 with the subject headings and key words 'cocaine', 'heart', 'toxicity', and 'cardiotoxicity'. Epidemiologic, laboratory, and clinical studies on the pathology, pathophysiology, and pharmacology of the effects of cocaine on the heart were reviewed, along with relevant treatment options. Reference lists were used to identify earlier studies on these topics, and related articles from Google Scholar were also included. There is an established connection between cocaine use and myocardial infarction (MI), arrhythmia, heart failure, and sudden cardiac death. Numerous mechanisms have been postulated to explain how cocaine contributes to these conditions. Among these, cocaine may lead to MI by causing coronary artery vasoconstriction and accelerated atherosclerosis, and by initiating thrombus formation. Cocaine has also been shown to block K+ channels, increase L-type Ca2+ channel current, and inhibit Na+ influx during depolarization, all possible causes for arrhythmia. Additionally, cocaine use has been associated with left ventricular hypertrophy, myocarditis, and dilated cardiomyopathy, which can lead to heart failure if drug use is continued. Certain diagnostic tools, including ECG and serial cardiac markers, are not as accurate in identifying MI in cocaine users experiencing chest pain. As a result, clinicians should be suspicious of cocaine use in their differential diagnosis of chest pain, especially in the younger male population, and proceed more cautiously when use is suspected. Treatment for cocaine-related cardiovascular disease is in many ways similar to treatment for traditional cardiovascular disease. However use of beta-receptor antagonists and class Ia and III anti-arrhythmics is strongly discouraged if the patient is likely to continue cocaine use, because of documented adverse effects. The medical community is in urgent need of a pharmacologic adjunct to cocaine-dependence treatment that can deter relapse and reduce the risks associated with cardiovascular disease in these patients.

Response to Letters Regarding Article, “Acute Coronary Syndrome and Khat Herbal Amphetamine Use: An Observational Report”

We appreciate the insightful comments in the 3 accompanying letters regarding our recent article.1 The letters highlight important issues with regard to khat and acute cardiac events. In the first letter, we thank Drs Aleryani and Al-akwa for suggesting potentially additional mechanisms whereby khat chewing has cardiovascular effects in addition to those already described in our article, which are coronary artery vasoconstriction, elevation in blood pressure, and possibly hypercoagulable state. The authors suggest khat-induced oxidative stress and apoptosis as well as pesticide exposure of khat before it is “freshly” chewed as possibly contributing to these detrimental effects. Although to date there is lack of definitive data linking pesticides exposure to acute coronary syndrome risk, we concur with the authors that further studies evaluating the various aspects of khat use and its cardiovascular effects are urgently needed. We also concur with the authors that although Cathinone, the main active substance in khat, is very similar to amphetamine; however, it is not identical to it. The term “herbal or natural amphetamine” we used for khat was first introduced in the literature by Kalix et al2 in 1991, to highlight its similarity to amphetamine. In the second letter, we appreciate Dr Burrilo-Putze's description of the clinical impact of khat use in Europe. Indeed, cardiovascular complications of khat use have been reported in Europe and more recently in Australia,3; …

Low-dose celecoxib improves coronary function after acute myocardial ischaemia in rabbits

The role of celecoxib in cardiovascular events remains contentious. The aim of the present study was to investigate the effects of celecoxib in acute myocardial ischaemia (AMI) in rabbits in comparison with those of another non-steroidal anti-inflammatory drug, namely aspirin. Male New Zealand white rabbits were divided into four groups: (i) a sham-operated group; (ii) an AMI group, in which the left anterior descending coronary arteries were occluded for 60min; (iii) the celecoxib+AMI group, pretreated with 3mg/kg celecoxib, twice a day, for 3days before AMI induction; and (iv) the aspirin+AMI group, pretreated with 12.5mg/kg aspirin, twice a day, for 3days before AMI induction. Haemodynamic parameters were monitored using a multichannel physiological recorder. Serum levels of creatine kinase (CK), malondialdehyde (MDA), cyclo-oxygenase-2 (COX-2), tumour necrosis factor (TNF)-α, total nitrate/nitrite (NO(x) ), nitric oxide synthase (NOS) and myocardial infarct size were determined. Changes in isometric tension of isolated coronary rings were recorded by a myograph system. Compared with the sham group, the AMI group had lower blood pressure, higher left ventricular (LV) end-diastolic pressure, depressed maximum dP/dt of LV pressure, a larger infarct size and higher CK and MDA levels. Celecoxib, but not aspirin, pretreatment significantly ameliorated these effects of AMI. Celecoxib reversed AMI-induced increases in COX-2 levels to a similar extent as aspirin. Pretreatment with celecoxib resulted in a significant reduction in TNF-α levels and an increase in NO(x) and NOS levels compared with the AMI group. The dysfunctional vasoconstriction and vasodilation of coronary arteries were ameliorated by celecoxib administration. 4. In conclusion, the experimental evidence suggests that celecoxib exerts its protective effects in a COX-independent manner.

Endothelial and Smooth Muscle Cells Dysfunction Distal to Recanalized Chronic Total Coronary Occlusions and the Relationship With the Collateral Connection Grade

This study sought to assess the vascular function in patients with chronic total coronary occlusions (CTO) immediately after successful percutaneous recanalization and its relation with the pre-existing collateral circulation. CTOs represent a long-acting occlusion of a coronary vessel, in which the progressively developed collateral circulation may limit ischemia and symptoms. However, it is unknown if the coronary segment distal to the occlusion has a preserved vascular function. We prospectively enrolled 19 consecutive patients, after percutaneous coronary intervention of a CTO. Luminal diameter, measured by quantitative coronary angiography, and coronary blood flow at level of epicardial coronary artery distal to the treated CTO was assessed before and after administration of acetylcholine (Ach), adenosine, and nitroglycerin (NTG). Collaterals were assessed angiographically by grading of Rentrop and of collateral connections (CC1: threadlike continuous connection; CC2: side branch-like connection). Overall, Ach and adenosine caused coronary artery vasoconstriction (p=0.001 and p=0.004, respectively), whereas NTG failed to induce vasodilation (p=0.084). Coronary blood flow significantly decreased with Ach (p=0.005), significantly increased with NTG (p=0.035), and did not change with adenosine (p=0.470). Patients with CC2 collaterals (n=8) had less vasoconstriction response and reduction in coronary blood flow after Ach (p=0.005 and p=0.008, respectively), and better vasomotor response to NTG (p=0.029) than patients with CC1 collaterals (n=11). Significant endothelial and smooth muscle dysfunction is present in the distal segments of successfully recanalized CTOs, and that seems to be more pronounced in the presence of a low grading of collateral circulation.

A Case of Caffeine-Induced Coronary Artery Vasospasm of a 17-Year-Old Male

The intentional consumption and use of stimulants, such as caffeine, are known to have numerous interactions with the human cardiovascular system. Ex vivo studies have shown caffeine-induced vasoconstriction of coronary arteries (Forman et al. in Ann Emerg Med 29:178-180, 1997). We report on a case of a 17-year-old male who presented with angina and an abnormal electrocardiogram (ECG) concerning for ST elevation myocardial infarct. He was found to have diffuse ECG changes and markedly elevated cardiac enzymes. A transthoracic echocardiogram revealed a reduced left ventricular (LV) systolic function as well as segmental wall motion abnormalities consistent with an ischemic insult. The patient admitted to consuming near lethal doses of caffeine immediately preceding his angina. He was diagnosed with coronary vasospasms as a result of stimulant use. During hospitalization, ECG changes resolved, cardiac enzymes started trending downward, and LV systolic function returned to normal, all consistent with stunned myocardium that fully recovered. This case strongly suggests that overuse of stimulants, such as caffeine, should be considered in patients presenting with coronary vasospasms, particularly in teenagers and young adults.

Urotensin-II Signaling Mechanism in Rat Coronary Artery

Human urotensin-II (UII) is considered the most potentendogenous vasoconstrictor discovered to date, although the precise mechanism activated downstream of its receptor UTS2R in blood vessels remains elusive. The aim of this study was to determine the role of the store operated Ca(2+) entry (SOCE) signaling pathway in UII-induced coronary artery vasoconstriction. We used a combination of isometric tension measurement, Ca(2+) imaging, pharmacology, and molecular approaches to study UII-mediated rat coronary artery vasoconstriction and intracellular Ca(2+) mobilization in coronary smooth muscle cells. We found that UII promoted dose-dependent vasoconstriction and elicited Ca(2+) and Mn(2+) influx, which were sensitive to classical SOCE inhibitors. In addition, knockdown of either STIM1 or Orai1 essentially inhibited UII-mediated SOCE and prevented UII but not high-KCL evoked contraction in transfected coronary artery. Moreover, we found that Ca(2+)-independent phospholipase A(2)β was involved in UII effects and that is colocalized with STIM1 in different submembrane compartments. Importantly, STIM1 but not Orai1 downregulation inhibits significantly independent phospholipase A(2) activation. Furthermore, lysophosphatidylcholine, an independent phospholipase A(2) product, activated Orai1 but not STIM1-dependent contraction and SOCE. Here, we demonstrated that different critical players of SOCE signaling pathway are required for UII-induced vasoconstriction of rat coronary artery.

Mechanisms of Coronary Artery Spasm

The term coronary artery spasm (CAS) refers to a sudden, intense vasoconstriction of an epicardial coronary artery that causes vessel occlusion or near occlusion. Although CAS may be involved in other coronary syndromes, it represents the usual cause of variant angina. The variant form of angina was first described in 1959 by Prinzmetal et al,1 who used this term to indicate that angina attacks, unlike the most common form of effort angina, occurred at rest and were associated with ST-segment elevation, rather than ST-segment depression, on the ECG (Figure 1). Because myocardial ischemia occurred in the absence of any change in myocardial oxygen demand, the authors hypothesized that it was caused by an increased tonus of vessels at the level of coronary stenoses.1 Figure 1. (Top) ST-segment elevation in anterior leads, with reciprocal mild ST-segment depression in inferior leads and V6, during an angina attack in a patient with variant angina. (Bottom) Normalization of the ECG after spontaneous resolution of chest pain. Some years later, in fact, coronary angiography, performed during spontaneous angina attacks, demonstrated that CAS is the usual cause of variant angina.2–4 Coronary angiography also showed that CAS could occur at the site of a stenosis (either minor or severe) or in angiographically normal coronary arteries,5 usually at a localized segment of an epicardial artery (focal spasm) (Figure 2).6 However, sometimes CAS involves 2 or more segments of the same (multifocal spasm) or of different (multivessel spasm) epicardial coronary arteries, or may also involve diffusely one or multiple coronary branches.7 Figure 2. Occlusive spasm of the left circumflex coronary artery and near occlusive spasm of the left anterior descending coronary artery (arrows) during coronary angiography (left, top), associated with dramatic ST-segment elevation at monitoring ECG leads (left, bottom). Complete resolution of spasm (right, …

Invited Commentary

Invited Commentary

Coronary microvascular dysfunction. An update

Several studies in the last years have shown that a dysfunction of coronary microcirculation may be responsible for abnormalities in coronary blood flow and some clinical pictures. Coronary microvascular dysfunction, in absence of other coronary artery abnormalities, can cause anginal symptoms, resulting in a condition named microvascular angina (MVA). MVA can occur in a chronic form, predominantly related to effort (stable MVA), more frequently referred as cardiac syndrome X, or in an acute form, most frequently ensuing at rest, which simulates an acute coronary syndrome (unstable MVA). The main abnormalities characterizing these two forms of MVA consist of an impaired vasodilation and an increased vasoconstriction of small resistive coronary arteries, respectively. The mechanisms responsible for stable MVA are still unclear, but seem to include, together with the known traditional cardiovascular risk factors, an abnormally increased cardiac adrenergic activity. The prognosis of stable MVA is good, but some patients have progressive worsening of symptoms. Clinical outcome of patients with unstable MVA is substantially unknown, as there are no specific studies about this population. Treatment of stable MVA includes traditional anti-ischemic drugs as first step; in case of persisting symptoms several other drugs have been proposed, including xanthine derivatives, ACE-inhibitors, statins and, in women, estrogens. Severe forms of intense constriction (or spasm) of small coronary arteries may cause transmural myocardial ischemia, as the microvascular form of variant angina and the tako-tsubo syndrome.

Cardiovascular Effects of Cocaine

The use of cocaine has evolved from chewing the leaves of the Erythroxylon coca bush thousands of years ago, to purification of cocaine hydrochloride over 100 years ago and its use in tonics and elixirs (at one time in popular cola drinks), to insufflating and injecting the fine, white, water-soluble, powder form, to a smokable freebase form called “crack,” which became popular in the 1980s.1 In 2007, 2.1 million Americans had recent cocaine use; 1.6 million met criteria for cocaine dependence or abuse.1 Cocaine accounted for 31% of all visits to the emergency department related to drug misuse or abuse.1 From 1971 to 1987, the incidence of deaths caused by cocaine overdose increased 20-fold in Dade County, Florida.2 In a consecutive series of 233 emergency visits by cocaine-using patients, 56% presented with cardiovascular complaints, including 40% with chest pain.3 A minority of these patients have acute myocardial infarction (MI) (≈6%),4,–,7 and overall mortality is low (<1%).3,–,5,8,–,10 However, cocaine is associated with a number of cardiovascular diseases, including MI, heart failure, cardiomyopathies, arrhythmias, aortic dissection, and endocarditis. Identifying patients with acute disease is challenging. This review describes the relationship between cocaine and various cardiovascular diseases, as well as appropriate diagnostic evaluation and therapies. ### Molecular Cocaine stimulates the sympathetic nervous system by inhibiting catecholamine reuptake at sympathetic nerve terminals,11,12 stimulating central sympathetic outflow,11 and increasing the sensitivity of adrenergic nerve endings to norepinephrine (Figure 1).12 Cocaine also acts like a class I antiarrhythmic agent (local anesthetic) by blocking sodium and potassium channels, which depresses cardiovascular parameters.13 Of these 2 primary, opposing actions, enhanced sympathetic activity predominates at low cocaine doses, whereas the local anesthetic actions …