Ischemia In Man Research Articles

Associations Among Cardiorespiratory Fitness, Framingham Risk Score and Myocardial Ischemia

Cardiorespiratory fitness (CRF), Framingham risk score (FRS) and myocardial ischemia are all associated with coronary heart disease (CHD) risk. However, the interrelationships among these risk indicators are less understood. PURPOSE: To examine the associations among CRF, FRS, and the presence of inducible myocardial ischemia. METHODS: Participants were 379 men (mean ± SD, age 57 ± 9 years) who were free of known CHD and who completed a maximal exercise test, an electron beam tomography scan and myocardial perfusion imaging between 1998 and 2004. These tests were conducted within 180 days (median=1 day, 25th%, 75th% =0-12 days) of each other. MET levels of CRF were based on a symptom-limited maximal exercise test. CRF was denned as low (≤ 8.4 METs) or moderate-high (>8.4 METs). FRS was based on measured clinical data and was categorized as low (<10%) and moderate-high (≥ 10%) risk. Inducible myocardial ischemia was denned as the presence of reversible perfusion defects. RESULTS: Approximately 12% (n=45) of all participants had inducible myocardial ischemia. The prevalence of myocardial ischemia was higher in men with low compared with moderate-high CRF (26% vs. 9.5%, p <0.001) and in men with a moderate-high FRS compared with a low FRS (15% vs. 7.8%, p = 0.03). Logistic regression analysis showed that after adjusting for differences in baseline examination year, the presence of coronary artery calcium and family history of CHD, the relative odds (95% CI) of inducible ischemia were 0.24 (0.11–0.55) in men with moderate-high CRF compared to those with low CRF. The inverse relation between CRF and inducible ischemia tended to exist regardless of FRS. In men with low FRS, the odds ratio (95% CI) for inducible ischemia in men with moderate-high CRF was 0.35 (0.07–1.6) compared to men with low CRF. In men with moderate-high FRS, the odds ratio (95% CI) for inducible ischemia in men with moderate-high CRF was 0.20 (0.07–0.55) compared to men with low CRF. CONCLUSION: CRF, a surrogate measure of cardiac function, is inversely associated with inducible myocardial ischemia, independent of FRS. Promoting CRF appears to have effects beyond its benefits on the various components of Framingham risk analysis.

Point: The muscle metaboreflex does restore blood flow to contracting muscles

Imposed reductions in oxygen delivery to active skeletal muscle during dynamic exercise in conscious dogs evoke a powerful pressor response, termed the muscle metaboreflex. During submaximal work rates, the major mechanism used by this reflex is to increase cardiac output (CO), which generates a

Family History of Stroke Does Not Predict Risk of Stroke After Transient Ischemic Attack

Animal models suggest a genetic contribution to cerebral susceptibility to ischemia. Family history of stroke (FHxstroke) is a risk factor for ischemic stroke, but there is significant confounding by heritability of hypertension and other intermediate phenotypes, and it is uncertain whether genetic factors have a direct independent influence on cerebral susceptibility to ischemia in man. We related detailed FHxstroke to baseline characteristics and subsequent risk of stroke in 2 population-based incidence studies and a consecutive hospital-referred series of patients with recent transient ischemic attack (TIA). In none of the cohorts or the pooled data (757 patients; 5515 patient years follow-up; 200 ischemic strokes; 126 myocardial infarctions [MIs]) did FHxstroke predict ischemic stroke (odds ratio [OR], 0.87; 95% CI, 0.57 to 1.32). No associations were revealed by analyses stratified by age or hypertension in the proband, FHx(stroke) in parents versus siblings, number of affected relatives, or their age at stroke. FHxstroke was unrelated to presence of ischemic lesions on baseline computed tomography (OR, 0.96; 0.52 to 1.76) or risk of MI during follow-up. There was no bias attributable to any relationship between FHxstroke and risk factor control or medication. Family history of stroke does not predict risk of ischemic stroke after TIA.

Induced skeletal muscel ischemia in man. Edited by D. H. Lewis. 225 × 155 mm. Pp. 180. Illustrated. 1980. Basel: Karger. $69.00

Induced skeletal muscel ischemia in man. Edited by D. H. Lewis. 225 × 155 mm. Pp. 180. Illustrated. 1980. Basel: Karger. $69.00 Get access Induced skeletal muscel ischemia in man. Edited by D H Lewis. 225 × 155 mm. Pp. 180. Illustrated. 1980. Basel: Karger. $69.00 K Burnand K Burnand Search for other works by this author on: Oxford Academic Google Scholar British Journal of Surgery, Volume 70, Issue 3, March 1983, Page 191, https://doi.org/10.1002/bjs.1800700324 Published: 07 December 2005

Total hepatic ischaemia in the Rhesus monkey

During operations for major hepatic trauma it may be necessary temporarily to deprive the liver of its blood supply by occlusion of the hepatic artery and portal vein. The maximum 'safe period' of total hepatic ischaemia in man is unknown. In the monkey the ischaemic liver 'leaks' potassium, and levels of this element in the hepatic veins rise during ischaemia reaching a peak immediately after blood supply to the liver is restored. However, critical systemic levels of potassium are never reached and severe biochemical disturbance does not occur until 2 h following revascularization in animals having experienced ischaemic periods of longer than 20 min.

Actin Redistribution Underlies the Sparing Effect of Mild Hypothermia on Dendritic Spine Morphology after in Vitro Ischemia

Brain hypothermia is at present the most effective neuroprotective treatment against brain ischemia in man. Ischemia induces a redistribution of proteins involved in synaptic functions, which is markedly diminished by therapeutic hypothermia (33 degrees C). Dendritic spines at excitatory synapses are motile and show both shape changes and rearrangement of synaptic proteins as a consequence of neuronal activity. We investigated the effect of reduced temperature (33 degrees C and 27 degrees C compared with 37 degrees C), on spine motility, length and morphology by studying the distribution of GFP-actin before, during and after induction of in vitro ischemia. Because high-concentration actin filaments are located inside spines, dissociated hippocampal neurons (7-11 DIV) from transgenic mice expressing GFP-actin were used in this study. The movement of the spines and the distribution of GFP-actin were recorded using time-lapse fluorescence microscopy. Under normal conditions rapid rearrangement of GFP-actin was seen in dendritic spines, indicating highly motile spines at 37 degrees C. Decreasing the incubation temperature to 33 degrees C or 27 degrees C, dramatically reduces actin dynamics (spine motility) by approximately 50% and 70%, respectively. In addition, the length of the spine shaft was reduced by 20%. We propose that decreasing the temperature from 37 degrees C to 33 degrees C during ischemia decreases the neuronal actin polymerization rate, which reduces spine calcium kinetics, disrupts detrimental cell signaling and protects neurons against damage.

Erectile dysfunction in patients with coronary artery disease

Recent studies suggest that erectile dysfunction (ED) may be an early marker of endothelial dysfunction and coronary artery disease (CAD). Conversely, patients with CAD commonly have ED. The phosphodiesterase 5 (PDE5) inhibitors are very effective for the treatment of ED in patients with CAD. Numerous studies show that this class of drugs is in general safe in patients with stable CAD and these agents do not exacerbate ischemia in men with CAD undergoing exercise stress testing. Analysis of placebo-controlled trials did not show an increase in cardiovascular events among men receiving PDE5 inhibitors, and post-marketing surveillance studies with sildenafil did not observe an increase in cardiovascular events compared to expected age-matched rates. Organic nitrates remain a contraindication for PDE5 inhibitors and alpha blockers have precautions/contraindications depending upon specific drugs. The Princeton Consensus Guidelines (soon to be updated) suggest a logical approach to the patient with CAD seeking therapy for sexual dysfunction.

Testosterone and Atherosclerosis in Aging Men

Two of the strongest independent risk factors for coronary heart disease (CHD) are increasing age and male sex. Despite a wide variance in CHD mortality between countries, men are consistently twice as likely to die from CHD than their female counterparts. This sex difference has been attributed to a protective effect of female sex hormones, and a deleterious effect of male sex hormones, upon the cardiovascular system. However, little evidence suggests that testosterone exerts cardiovascular harm. In fact, serum levels of testosterone decline with age, and low testosterone is positively associated with other cardiovascular risk factors. Furthermore, testosterone exhibits a number of potential cardioprotective actions. For example, testosterone treatment is reported to reduce serum levels of the pro-inflammatory cytokines interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha, and to increase levels of the anti-inflammatory cytokine IL-10; to reduce vascular cell adhesion molecule (VCAM)-1 expression in aortic endothelial cells; to promote vascular smooth muscle and endothelial cell proliferation; to induce vasodilatation and to improve vascular reactivity, to reduce serum levels of the pro-thrombotic factors plasminogen activator inhibitor (PAI)-1 and fibrinogen; to reduce low-density lipoprotein-cholesterol (LDL-C); to improve insulin sensitivity; and to reduce body mass index and visceral fat mass. These actions of testosterone may confer cardiovascular benefit since testosterone therapy reduces atheroma formation in cholesterol-fed animal models, and reduces myocardial ischemia in men with CHD. Consequently, an alternative hypothesis is that an age-related decline in testosterone contributes to the atherosclerotic process. This is supported by recent findings, which suggest that as many as one in four men with CHD have serum levels of testosterone within the clinically hypogonadal range. Consequently, restoration of serum levels of testosterone via testosterone replacement therapy could offer cardiovascular, as well as other, clinical advantages to these individuals.

Testosterone-induced coronary vasodilatation occurs via a non-genomic mechanism: evidence of a direct calcium antagonism action.

Testosterone decreases myocardial ischaemia in men with coronary artery disease via a coronary vasodilatory action. However, long-term therapy may increase the risk of prostatic carcinoma via activation of the nuclear AR (androgen receptor). In the present study, we have investigated the mechanism of testosterone-induced vasodilatation using isolated rat coronary arteries and thoracic aortae from control and AR-deficient testicular-feminized mice. Vasodilatation induced by testosterone, T-3-OCMO [testosterone 3-(O-carboxymethyl)oxime] or T-3-OCMO conjugated to BSA was initially measured in preconstricted vessels that had undergone endothelial denudation or incubation with flutamide (10 microM). Cellular fluorescence was also measured in primary aortic SMCs (smooth muscle cells) following exposure to the above fluorescent-labelled agents. Subsequently, vessels were incubated with testosterone (100 microM) or vehicle prior to constriction with KCl (1-100 mM). Testosterone-induced vasodilatation was unaffected by endothelial denudation, flutamide treatment, AR deficiency or conjugation to BSA. Cells exposed to T-3-OCMO-BSA (10 microM) had a higher fluorescence than control cells (32.8+/-4.5 compared with 14.5+/-1.8 arbitrary units respectively; P<0.01). Incubation with testosterone (100 microM) reversibly attenuated coronary vasoconstriction to KCl (1-100 mM; 0.08+/-0.09 compared with 0.79+/-0.08 mN/mm respectively; P<0.0001). Testosterone-induced vasodilatation is independent of the vascular endothelium and nuclear AR, and is initiated at the SMC membrane, which contains testosterone binding sites. A direct calcium antagonistic action is implicated.

A rise in systolic blood pressure during adenosine stress myocardial perfusion imaging does not increase the likelihood of an abnormal scan

Background: The normal physiologic response to vasodilators, such as adenosine, is a fall in systolic blood pressure (SBP). However, in some cases, a patient's SBP rises rather than falls during adenosine stress myocardial perfusion imaging (MPI). It has been anecdotally suggested that this paradoxical response may result from a heightened adrenergic state due to adenosine-induced ischemia. We sought to assess whether ischemia is more common among patients whose SBP rises during adenosine stress MPI. Methods: Scan findings and SBP responses for 866 consecutive patients (age = 65.7±12.6 years; 356 men) undergoing adenosine stress MPI were assessed. Adenosine (140 μg/kg/min) was infused for six minutes (no concomitant exercise). MPI was performed using either a 201Tl stress / redistribution or a dual isotope ( 201Tl rest / 99mTc stress) protocol. Scans were interpreted by experienced readers. Results: A rise in SBP ≥10 mmHg was seen in 61 (7%) patients, while 227 (26%) had a flat response (ΔSBP <10 mmHg) and 578 (67%) had a drop in SBP ≥10 mmHg. The ratio of ischemic to non-ischemic scans in women was the same, irrespective of SBP response. In men there was a trend toward fewer ischemic scans among patients whose SBP rose compared with those whose SBP fell during testing (p = 0.08). Men with a flat SBP response had an intermediate scan ratio. MPI Result SBP Decreased SBP Flat SBP Increased Male Female Male Female Male Female % with any ischemia 42 29 34 25 29 27 % with no ischemia 58 71 66 75 71 73 Conclusion: A rise in SBP during adenosine infusion is not associated with a higher likelihood of ischemia in patients undergoing adenosine stress MPI. In fact, there is a trend toward less ischemia among men who demonstrate such a paradoxical response. It is unlikely that a rise in SBP during adenosine stress MPI is due to an adrenergic surge in response to ischemia. The finding of more ischemia in men with a fall in SBP may help to account for the observation that men with exaggerated SBP responses to adenosine have a higher risk of cardiac death.

The influence of testosterone upon vascular reactivity.

Recent clinical studies have reported that testosterone therapy reduces myocardial ischaemia in men with coronary artery disease, and the beneficial modulation of coronary vascular tone by testosterone has been proposed as an effector mechanism. Maintenance of a correct response to vasoconstrictive and vasodilatory agents is essential in the control of vascular tone. Endothelial dysfunction, most commonly manifested through an elevation in vascular tone, is implicated as an initiating factor in conditions such as hypertension and atherosclerosis. Increased sensitivity to vasoconstrictive stimuli is also proposed in the development of heart failure and hypertensive vascular remodelling, while increased coronary vascular reactivity to vasoconstrictive factors is likely further to restrict coronary blood flow through the partially occluded atherosclerotic vessel. Reduced vasodilatation and enhanced vasoconstriction can also lead to vasospasm and exacerbation of anginal symptoms. Testosterone is well known to elicit direct vasodilatation, but its influence upon responses induced by other vasoactive agents is less coherent, and may depend upon the underlying pathogenic process or gender. The aim of this review is to present the data obtained from both the patient and animal studies conducted to date, to ascertain any influence testosterone may have upon the regulation of vascular tone.

Testosterone is a potent inhibitor of L-type Ca 2+ channels

Testosterone administration is beneficial in alleviating myocardial ischaemia in men with significant coronary artery disease (CAD), a condition which is associated with hypotestosteronaemia. Infusion of physiological concentrations of testosterone into coronary arteries at angiography results in rapid vasodilatation in patients with CAD. Whilst the cardiovascular benefits of testosterone have long been documented, the underlying mechanism(s) have not yet been revealed. Here, we have investigated whether testosterone might act like widely prescribed antihypertensive dihydropyridines, as an endogenous Ca 2+ channel antagonist. To do this, we used the whole-cell patch-clamp technique to record Ca 2+ currents from the A7r5 smooth muscle cell line and HEK 293 cells stably expressing either L- or T-type Ca 2+ channels. We demonstrate that testosterone directly inhibited both native and human recombinant vascular L-type Ca 2+ channels in a manner that was voltage-independent and, crucially, displayed an IC 50 value of 38 nM, a value within the physiological range. At higher (supraphysiological) concentrations both native and human recombinant T-type channels were also inhibited by testosterone. Our data indicate that testosterone acts like widely prescribed antihypertensive dihydropyridines to reduce Ca 2+ influx into vascular smooth muscle and so promote vasodilation. This effect is likely to account for its beneficial cardiovascular actions.

Periodontal disease as a risk factor for ischemic stroke.

Chronic infectious diseases may increase the risk of stroke. We investigated whether periodontal disease, including periodontitis and gingivitis, is a risk factor for cerebral ischemia. We performed a case-control study with 303 patients examined within 7 days after acute ischemic stroke or transient ischemic attack, 300 population controls, and 168 hospital controls with nonvascular and noninflammatory neurological diseases. All subjects received a complete clinical and radiographic dental examination. The individual mean clinical attachment loss measured at 4 sites per tooth served as the main indicator for periodontitis. Patients had higher clinical attachment loss than population (P<0.001) and hospital (P=0.010) controls. After adjustment for age, sex, number of teeth, vascular risk factors and diseases, childhood and adult socioeconomic conditions, and lifestyle factors, the risk of cerebral ischemia increased with more severe periodontitis. Subjects with severe periodontitis (mean clinical attachment loss >6 mm) had a 4.3-times-higher (95% confidence interval, 1.85 to 10.2) risk of cerebral ischemia than subjects with mild or without periodontitis (<or=3 mm). Severe periodontitis was a risk factor in men but not women and in younger (<60 years) but not older subjects. Periodontitis increased the risk of cerebral ischemia caused by large-artery atherosclerosis, cardioembolism, and cryptogenic etiology. Gingivitis and severe radiologic bone loss were also independently associated with the risk of cerebral ischemia, whereas caries was not. Our study indicates that periodontal disease, a treatable condition, is an independent risk factor for cerebral ischemia in men and younger subjects.

Neuronal expression of cell cycle-related proteins after brain ischaemia in man

The death of neurons after brain ischaemia may be associated with activation of cyclin-dependent kinases (CDKs) and upregulation of cyclins, reflecting aberrant entry of neurons into the cell cycle. Little has been published on the expression of cell cycle proteins after brain ischaemia in man. Well-characterized antisera were therefore used to examine the neuronal expression of CDK2, CDK4 and cyclins A, D1 and E in sections of brain from patients who had experienced cardiac arrest or focal brain infarction, and died 3.5 h to 9 days later. Scattered neurons contained elevated levels of cyclin D1, CDK2 and, to a lesser extent, CDK4, but little or no cyclin A or E. Present findings indicate that brain ischaemia induces the entry of some neurons from G0 into the G1 phase of the cell cycle, and suggest a potential therapeutic role for CDK inhibitors in ischaemic stroke.

Neuronal expression of cell cycle-related proteins after brain ischaemia in man

The death of neurons after brain ischaemia may be associated with activation of cyclin-dependent kinases (CDKs) and upregulation of cyclins, reflecting aberrant entry of neurons into the cell cycle. Little has been published on the expression of cell cycle proteins after brain ischaemia in man. Well-characterized antisera were therefore used to examine the neuronal expression of CDK2, CDK4 and cyclins A, D1 and E in sections of brain from patients who had experienced cardiac arrest or focal brain infarction, and died 3.5 h to 9 days later. Scattered neurons contained elevated levels of cyclin D1, CDK2 and, to a lesser extent, CDK4, but little or no cyclin A or E. Present findings indicate that brain ischaemia induces the entry of some neurons from G0 into the G1 phase of the cell cycle, and suggest a potential therapeutic role for CDK inhibitors in ischaemic stroke.

Evidence for the involvement of endothelin-1 but not urotensin-II in chronic lower limb ischaemia in man

Background: endogenous vasoconstrictor peptides may play a role in the pathophysiology of critical limb ischaemia (CLI). This study investigated endothelin-1 (ET-1) and urotensin-II (U-II) mRNA expression, peptide distribution and ET receptor subtype binding in chronically ischaemic muscle. Methods: open muscle biopsies were taken from patients undergoing amputations for CLI and from patients undergoing coronary artery bypass surgery (controls). ET-1 and U-II mRNA expression in muscle biopsies was studied using real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). ET-1 and U-II immunohistochemistry was performed on muscle sections and ET receptor binding studied using in vitro autoradiography. Results: ET-1 mRNA expression was significantly increased in CLI compared to controls (p < 0.05) whilst no significant change in U-II expression occurred. ET-1 immunoreactivity was also increased in CLI with no difference in U-II immunostaining observed. ETB receptor binding was significantly increased in CLI (median 4, range 1-8 vs 2, range 1-3, dpm × 103/mm2, p = 0.01, Mann-Whitney test) whilst ETA receptor binding was not significantly raised. Binding was associated with microvessels and macrophages. Conclusions: in CLI, the ET-1 pathway is upregulated but U-II is unaffected. ET-1 may vasoconstrict microvessels and mediate inflammation in chronically ischaemic muscle. ET-1 binding to ETB receptors in particular may play an important role in the pathophysiology of CLI underscoring the therapeutic potential of ETB receptor antagonists in the management of CLI.Eur J Vasc Endovasc Surg 25, 443-450 (2003)

The vasodilatory action of testosterone: a potassium-channel opening or a calcium antagonistic action?

British Journal of Pharmacology (2003) 138, 733–744. doi:10.1038/sj.bjp.0705141

Testosterone supplementation therapy for older men: potential benefits and risks.

Serum testosterone levels decline gradually and progressively with aging in men. Many manifestations associated with aging in men, including muscle atrophy and weakness, osteoporosis, reduced sexual functioning, and increased fat mass, are similar to changes associated with testosterone deficiency in young men. These similarities suggest that testosterone supplementation may prevent or reverse the effects of aging. A MEDLINE search was performed to identify studies of testosterone supplementation therapy in older men. A structured, qualitative review was performed of placebo-controlled trials that included men aged 60 and older and evaluated one or more physical, cognitive, affective, functional, or quality-of-life outcomes. Studies focusing on patients with severe systemic diseases and hormone deficiencies related to specific diseases were excluded. In healthy older men with low-normal to mildly decreased testosterone levels, testosterone supplementation increased lean body mass and decreased fat mass. Upper and lower body strength, functional performance, sexual functioning, and mood were improved or unchanged with testosterone replacement. Variable effects on cognitive function were reported, with improvements in some cognitive domains (e.g., spatial, working, and verbal memory). Testosterone supplementation improved exercise-induced coronary ischemia in men with coronary heart disease, whereas angina pectoris was improved or unchanged. In a few studies, men with low testosterone levels were more likely to experience improvements in lumbar bone mineral density, self-perceived functional status, libido, erectile function, and exercise-induced coronary ischemia with testosterone replacement than men with less marked testosterone deficiency. No major unfavorable effects on lipids were reported, but hematocrit and prostate specific antigen levels often increased. Based on these results, testosterone supplementation cannot be recommended at this time for older men with normal or low-normal testosterone levels and no clinical manifestations of hypogonadism. However, testosterone replacement may be warranted in older men with markedly decreased testosterone levels, regardless of symptoms, and in men with mildly decreased testosterone levels and symptoms or signs suggesting hypogonadism. The long-term safety and efficacy of testosterone supplementation remain uncertain. Establishment of evidence-based indications will depend on further demonstrations of favorable clinical outcomes and symptomatic, functional, and quality-of-life benefits in carefully performed, long-term, randomized, placebo-controlled clinical trials.

Implications of Vascular Endothelial Growth Factor, sFlt-1, and sTie-2 in Plasma, Serum and Cerebrospinal Fluid During Cerebral Ischemia in Man

Implications of Vascular Endothelial Growth Factor, sFlt-1, and sTie-2 in Plasma, Serum and Cerebrospinal Fluid During Cerebral Ischemia in Man

Implications of vascular endothelial growth factor, sFlt-1, and sTie-2 in plasma, serum and cerebrospinal fluid during cerebral ischemia in man.

The relation between cerebral ischemia and local release of angiogenic factors was investigated after subarachnoid hemorrhage (SAH) in humans. Time-dependent concentration-changes of vascular endothelial growth factor (VEGF), sFlt-1 and sTie-2 extracted from plasma, serum, and cerebrospinal fluid (ventricular, cisternal, and lumbar) were analyzed in 15 patients surgically treated for ruptured aneurysms of the anterior circulation (Hunt and Hess grades I-V). Data were related to brain Po2 (Pbro2) and cerebral energy metabolites (extracellular lactate, pyruvate, glutamate, and glycerin concentrations) as well as clinical and radiologic reference data. Delayed impairment of cerebral perfusion secondary to progressive microcirculatory alterations was associated with reduced local Pbro2 and energy metabolism (increased lactate-pyruvate ratio, glutamate and glycerine levels). Elevated serum/plasma and CSF concentrations of VEGF, sFlt-1, and sTie-2 matched the scale of ischemic tissue hypoxia. Excessive VEGF/sFlt-1 and sTie-2 levels were related to Pbro2 values consistently less than 5 mm Hg, glutamate concentrations greater than 300 micromol/L, lactate-pyruvate ratio greater than 300, cerebral infarction, and reduced outcome (P < 0.01). Delayed microcirculatory impairment was mirrored by distinct elevation of cisternal and arterial VEGF and sFlt-1 concentrations, suggesting local induction of angiogenesis. Arterial levels of VEGF, sFlt-1, and sTie-2 reflect both extent and time course of compensatory, yet clinically inefficient, angiogenesis in the absence of general hypoxia.