ABSTRACT
We aimed to determine clinical outcomes 1 year after successful chronic total occlusion (CTO) PCI and, in particular, whether use of dissection and re-entry strategies affects clinical outcomes. Hybrid approaches have increased the procedural success of CTO percutaneous coronary intervention (PCI) but longer-term outcomes are unknown, particularly in relation to dissection and re-entry techniques. Data were collected for consecutive CTO PCIs performed by hybrid-trained operators from 7 United Kingdom (UK) centres between 2012 and 2014. The primary endpoint (death, myocardial infarction, unplanned target vessel revascularization) was measured at 12 months along with angina status. One-year follow up data were available for 96% of successful cases (n = 805). In total, 85% of patients had a CCS angina class of 2-4 prior to CTO PCI. Final successful procedural strategy was antegrade wire escalation 48%; antegrade dissection and re-entry (ADR) 21%; retrograde wire escalation 5%; retrograde dissection and re-entry (RDR) 26%. Overall, 47% of CTOs were recanalized using dissection and re-entry strategies. During a mean follow up of 11.5 ± 3.8 months, the primary endpoint occurred in 8.6% (n = 69) of patients (10.3% (n = 39/375) in DART group and 7.0% (n = 30/430) in wire-based cases). The majority of patients (88%) had no or minimal angina (CCS class 0 or 1). ADR and RDR were used more frequently in more complex cases with greater disease burden, however, the only independent predictor of the primary endpoint was lesion length. CTO PCI in complex lesions using the hybrid approach is safe, effective and has a low one-year adverse event rate. The method used to recanalize arteries was not associated with adverse outcomes. © 2017 Wiley Periodicals, Inc.
Subject(s)
Angina Pectoris/therapy , Coronary Occlusion/therapy , Percutaneous Coronary Intervention/methods , Aged , Angina Pectoris/diagnostic imaging , Angina Pectoris/mortality , Chi-Square Distribution , Chronic Disease , Coronary Angiography , Coronary Occlusion/diagnostic imaging , Coronary Occlusion/mortality , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Multivariate Analysis , Myocardial Infarction/etiology , Odds Ratio , Percutaneous Coronary Intervention/adverse effects , Percutaneous Coronary Intervention/instrumentation , Percutaneous Coronary Intervention/mortality , Propensity Score , Proportional Hazards Models , Registries , Risk Factors , Stents , Time Factors , Treatment Outcome , United KingdomABSTRACT
OBJECTIVES: Treatment options for coronary chronic total occlusions (CTO) are limited, with low historical success rates from percutaneous coronary intervention (PCI). We report procedural outcomes of CTO PCI from 7 centres with dedicated CTO operators trained in hybrid approaches comprising antegrade/retrograde wire escalation (AWE/RWE) and dissection re-entry (ADR/RDR) techniques. METHODS: Clinical and procedural data were collected from consecutive unselected patients with CTO between 2012 and 2014. Lesion complexity was graded by the Multicentre CTO Registry of Japan (J-CTO) score, with ≥2 defined as complex. Success was defined as thrombolysis in myocardial infarction 3 flow with <30% residual stenosis, subclassified as at first attempt or overall. Inhospital complications and 30-day major adverse cardiovascular events (MACEs, death/myocardial infarction/unplanned target vessel revascularisation) were recorded. RESULTS: 1156 patients were included. Despite high complexity (mean J-CTO score 2.5±1.3), success rates were 79% (first attempt) and 90% (overall) with 30-day MACE of 1.6%. AWE was highly effective in less complex lesions (J-CTO ≤1 94% success vs 79% in J-CTO score ≥2). ADR/RDR was used more commonly in complex lesions (J-CTO≤1 15% vs J-CTO ≥2 56%). Need for multiple approaches during each attempt increased with lesion complexity (17% J-CTO ≤1 vs 48% J-CTO ≥2). Lesion modification ('investment procedures') at the end of unsuccessful first attempts increased the chance of subsequent success (96% vs 71%). CONCLUSIONS: Hybrid-trained operators can achieve overall success rates of 90% in real world practice with acceptable MACE. Use of dissection re-entry and investment procedures maintains high success rates in complex lesions. The hybrid approach represents a significant advance in CTO treatment.
Subject(s)
Coronary Occlusion/therapy , Percutaneous Coronary Intervention/methods , Aged , Chronic Disease , Collateral Circulation , Coronary Angiography , Coronary Circulation , Coronary Occlusion/diagnostic imaging , Coronary Occlusion/mortality , Coronary Occlusion/physiopathology , Female , Humans , Male , Middle Aged , Percutaneous Coronary Intervention/adverse effects , Percutaneous Coronary Intervention/mortality , Registries , Risk Factors , Time Factors , Treatment Outcome , United Kingdom , Vascular PatencyABSTRACT
OBJECTIVE: To assess the impact of proctoring for chronic total occlusion (CTO) percutaneous coronary intervention (PCI) in six UK centres. METHODS: We retrospectively analysed 587 CTO procedures from six UK centres and compared success rates of operators who had received proctorship with success rates of the same operators before proctorship (pre-proctored) and operators in the same institutions who had not been proctored (non-proctored). There were 232 patients in the pre-proctored/non-proctored group and 355 patients in the post-proctored group. Complexity was assessed by calculating the Japanese CTO (JCTO) score for each case. RESULTS: CTO PCI success was greater in the post-proctored compared with the pre-proctored/non-proctored group (77.5% vs 62.1%, p<0.0001). In more complex cases where JCTO≥2, the difference in success was greater (70.7% vs 49.5%, p=0.0003). After proctoring, there was an increase in CTO PCI activity in centres from 2.5% to 3.5%, p<0.0001 (as a proportion of total PCI), and the proportion of very difficult cases with JCTO score ≥3 increased from 15.3% (35/229) to 29.7% (105/354), p<0.0001. CONCLUSIONS: Proctoring resulted in an increase in procedural success for CTO PCI, an increase in complex CTO PCI and an increase in total CTO PCI activity. Proctoring may be a valuable way to improve access to CTO PCI and the likelihood of procedural success.
ABSTRACT
AIMS: To evaluate the effects of the intravenous administration of the nitric oxide synthesis inhibitor N(g)nitro-L-arginine methyl ester (L-NAME) in healthy volunteers. METHODS: L-NAME (0.25, 0.5 and 0.75 mg/kg over 8 min) was infused in 13 healthy male volunteers. Finally, subjects were infused with either L- or D-arginine. RESULTS: L-NAME resulted in dose-dependent falls in heart rate 60 bpm (55-64 bpm) to 49 bpm (46-52 bpm) (P<0.01) and increased mean arterial pressure 77.0 mmHg (73.2-80.8 mmHg) to 90.0 mmHg (87.1-92.8 mmHg) (P<0.01). The cardiac output was significantly reduced after each L-NAME infusion, and systemic vascular resistance increased linearly over the dosage range. Cardiac stroke volume was significantly reduced only following 0.75 mg/kg/min L-NAME: from 100 ml (91.3-108.7 ml) to 83 ml (74.7-91.4 ml); P<0.01. Forearm blood flow was unchanged at any dosage. L-arginine but not D-arginine infusion reversed the haemodynamic effects of L-NAME. CONCLUSIONS: Contrasting with the profound dose-dependent effects of L-NAME had significant effects on central haemodynamics but no discernible effects on peripheral blood flow.
Subject(s)
Hemodynamics/drug effects , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide/antagonists & inhibitors , Dose-Response Relationship, Drug , Forearm/blood supply , Forearm/diagnostic imaging , Hemodynamics/physiology , Humans , Infusions, Intravenous , Male , NG-Nitroarginine Methyl Ester/administration & dosage , Nitric Oxide/physiology , Regional Blood Flow/drug effects , Regional Blood Flow/physiology , UltrasonographyABSTRACT
The embryological development of the superior vena cava (SVC) is complex. If the left common cardinal vein fails to occlude it can, along with the left duct of Cuvier form a left SVC, which frequently drains into the coronary sinus. This may result in abnormalities in the anatomy of this structure. A persistent left SVC occurs in 0.5% of the normal population, and 3% to 4.3% of patients with congenital heart anomalies. The pacemaking tissue of the heart is derived from two sites near the progenitors of the superior vena cava. The right-sided site forms the sinoatrial node, the left-sided site is normally carried down to an area near the coronary sinus. Out of 300 patients with cardiac rhythm abnormalities, who have undergone electrophysiological studies (EPS), or permanent pacemaker insertion (PPI), we identified 12 patients with cardiac conduction abnormalities and anomalies of venous drainage. Anomalies of the coronary sinus may be associated with abnormalities of the conduction system of the heart. This may be due to the close proximity of the coronary sinus to the final position of the left-sided primitive pacemaking tissue. In our series of 300 patients, 4% had an associated left SVC, a similar incidence to that found in previous studies of congenital heart disease.
Subject(s)
Arrhythmias, Cardiac/complications , Coronary Vessel Anomalies/complications , Heart Conduction System/abnormalities , Vena Cava, Superior/abnormalities , Adult , Aged , Coronary Vessels/embryology , Female , Humans , Male , Middle AgedABSTRACT
Heightened systemic oxidative stress is increasingly recognized as a feature of cystic fibrosis (CF). The consequences of long-term exposure to free radical attack include a predisposition to diseases such as cancer and atherosclerosis. An increased incidence of malignancy among adult patients with CF has been reported, but the absence of atherosclerotic disease is well described. The aim of the present study was to assess endothelial function in vivo and relate this to the potential of serum from patients with CF to induce oxidative-mediated damage in cultured human endothelial cells. A group of 11 CF patients was matched with a group of healthy volunteers with regard to age and sex. Endothelial function was assessed as endothelium-dependent and -independent vasodilation by measuring forearm blood flow in response to infused acetylcholine and sodium nitroprusside respectively. Confluent monolayers of cultured human endothelial cells were exposed to serum from CF patients and control subjects. Following exposure, cell death was assessed by lactate dehydrogenase release, and the degree of lipid peroxidation in the membrane was assessed by measuring the content of lipid hydroperoxides, malondialdehyde and 4-hydroxynonenal. Endothelial monolayers exposed to serum from CF patients released significantly less lactate dehydrogenase following exposure than those exposed to serum from healthy controls (1.8% and 3.0% respectively; mean difference -1.2%; 95% confidence intervals -1.9% to -0.1%; P<0.05) and contained significantly less 4-hydroxynonenal (0.75 and 3.41 micromol/g of protein respectively; mean difference -2.66 micromol/g; 95% confidence intervals -5.10 to -0.22 micromol/g; P<0.05). There was no significant difference between patients and controls in the extent of serum-induced membrane peroxidation, as assessed by malondialdehyde or lipid hydroperoxides, or in endothelial function, as assessed by forearm blood flow. In conclusion, despite evidence for heightened systemic oxidative stress in CF, patients displayed no impairment of endothelial function, and their serum caused significantly less damage to human endothelial cells than that from matched controls.
Subject(s)
Cystic Fibrosis/physiopathology , Endothelium, Vascular/physiopathology , Oxidative Stress/physiology , Adolescent , Adult , Aorta/pathology , Area Under Curve , Case-Control Studies , Cells, Cultured , Chromatography, High Pressure Liquid , Culture Media , Cystic Fibrosis/blood , Cystic Fibrosis/pathology , Endothelium, Vascular/cytology , Humans , L-Lactate Dehydrogenase/metabolism , Lipid Peroxidation/physiology , Male , Plethysmography , Spectrophotometry , Statistics, Nonparametric , Vitamin E/bloodSubject(s)
Angioplasty, Balloon, Coronary , Whole Blood Coagulation Time , Angioplasty, Balloon, Coronary/adverse effects , Body Weight , Clinical Trials as Topic , Confounding Factors, Epidemiologic , Data Interpretation, Statistical , Dose-Response Relationship, Drug , Heparin/therapeutic use , Humans , Meta-Analysis as Topic , Postoperative Complications/prevention & control , Reproducibility of ResultsABSTRACT
BACKGROUND: Manipulation of total homocysteine concentration with oral methionine is associated with impairment of endothelial-dependent vasodilation. This may be caused by increased oxidative stress. Vitamin C is an aqueous phase antioxidant vitamin and free radical scavenger. We hypothesised that if the impairment of endothelial function related to experimental hyperhomocysteinaemia was free radically mediated then co-administration of vitamin C should prevent this. METHODS: Ten healthy adults took part in this crossover study. Endothelial function was determined by measuring forearm blood flow (FBF) in response to intra-arterial infusion of acetylcholine (endothelial-dependent) and sodium nitroprusside (endothelial-independent). Subjects received methionine (100 mg/Kg) plus placebo tablets, methionine plus vitamin C (2 g orally) or placebo drink plus placebo tablets. Study drugs were administered at 9 am on each study date, a minimum of two weeks passed between each study. Homocysteine (tHcy) concentration was determined at baseline and after 4 hours. Endothelial function was determined at 4 hours. Responses to the vasoactive substances are expressed as the area under the curve of change in FBF from baseline. Data are mean plus 95% Confidence Intervals. RESULTS: Following oral methionine tHcy concentration increased significantly versus placebo. At this time endothelial-dependent responses were significantly reduced compared to placebo (31.2 units [22.1-40.3] vs. 46.4 units [42.0-50.8], p < 0.05 vs. Placebo). Endothelial-independent responses were unchanged. Co-administration of vitamin C did not alter the increase in homocysteine or prevent the impairment of endothelial-dependent responses (31.4 [19.5-43.3] vs. 46.4 units [42.0-50.8], p < 0.05 vs. Placebo) CONCLUSIONS: This study demonstrates that methionine increased tHcy with impairment of the endothelial-dependent vasomotor responses. Administration of vitamin C did not prevent this impairment and our results do not support the hypothesis that the endothelial impairment is mediated by adverse oxidative stress.
Subject(s)
Ascorbic Acid/pharmacology , Endothelium, Vascular/drug effects , Hyperhomocysteinemia/physiopathology , Methionine/pharmacology , Acetylcholine/administration & dosage , Administration, Oral , Adult , Area Under Curve , Ascorbic Acid/administration & dosage , Cross-Over Studies , Endothelium, Vascular/physiology , Forearm/blood supply , Homocysteine/blood , Humans , Hyperhomocysteinemia/chemically induced , Hyperhomocysteinemia/complications , Injections, Intra-Arterial , Male , Methionine/administration & dosage , Oxidative Stress , Plethysmography , Regional Blood Flow , Single-Blind Method , Vasodilation/physiologyABSTRACT
Traditionally, nitric oxide-mediated alteration in blood vessel tone has been inferred from changes in flow in response to physical and pharmacological interventions using plethysmographic or ultrasonic techniques. We hypothesized that alteration in pulsatile arterial function may represent a more sensitive measure to detect and monitor nitric oxide-mediated modulation of arterial smooth muscle tone. Healthy male volunteers (n = 15) had radial artery pressure pulse waveforms recorded using a calibrated tonometer device. A computer-based assessment of the diastolic pressure decay was employed to quantify changes in arterial waveform morphology in terms of altered pulsatile (arterial compliance) and steady-state (peripheral resistance) haemodynamics. N(G)-nitro-L-arginine methyl ester (L-NAME), a stereospecific inhibitor of nitric oxide synthesis, was infused intravenously in incrementally increasing doses of 0.25, 0.5 and 0.75 mg/kg for 8 min each. Subjects then received either L-arginine or D-arginine (200 mg/kg over 15 min) intravenously in a blinded fashion. On a separate day, subjects had radial artery pressure pulse waveforms recorded before and after the sublingual administration of glyceryl trinitrate, an exogenous donor of nitric oxide. Cardiac output and heart rate decreased and mean arterial blood pressure increased significantly (P < 0.01 for all) in response to the incremental intravenous infusion of L-NAME. Small artery compliance decreased, whereas systemic vascular resistance increased in response to nitric oxide synthesis inhibition (P < 0.01 for both). The intravenous infusion of L-arginine restored the pulsatile and steady-state haemodynamic parameters to pre-treatment values, whereas D-arginine had no effect. Sublingual glyceryl trinitrate decreased systemic vascular resistance by 11%, whereas large artery- and small artery-compliance increased by 25% and 44% respectively. Pressure pulse contour analysis represents a sensitive and convenient technique capable of tracking changes in the pulsatile function of arteries accompanying nitric oxide-mediated alteration in arterial smooth muscle tone.
Subject(s)
Nitric Oxide/physiology , Pulsatile Flow/physiology , Vascular Resistance/physiology , Adult , Compliance/drug effects , Endothelium, Vascular/physiology , Enzyme Inhibitors/pharmacology , Hemodynamics/drug effects , Humans , Male , Middle Aged , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Pulsatile Flow/drug effects , Radial Artery/physiology , Vascular Resistance/drug effectsABSTRACT
BACKGROUND: Raised homocysteine is a risk factor for vascular disease. Homocysteine is formed from methionine, and dietary manipulation of homocysteine in primates and humans with oral methionine is associated with endothelial dysfunction. A cause-effect relation has not been clearly established. AIM: To study the effect of oral methionine and then oral homocysteine on endothelial function. METHODS: 22 healthy adults were recruited for two randomised crossover studies, each containing 11 subjects. Endothelial function was determined by measuring forearm blood flow in response to intra-arterial infusion of acetylcholine (endothelium dependent) and sodium nitroprusside (endothelium independent). Subjects received methionine or placebo (study 1), or homocysteine or placebo (study 2). Methionine and homocysteine were determined at baseline and t = 4 hours. Endothelial function was determined at four hours. The responses to the vasoactive substances are expressed as the area under the curve of change in forearm blood flow from baseline. RESULTS: Study 1: plasma methionine and homocysteine concentrations increased significantly versus placebo. The increases were associated with a reduction of endothelium dependent responses (mean (95% confidence interval), arbitrary units), from 48.8 (95% CI 36.4 to 61.2) to 29.9 (95% CI 18.0 to 41.1), p < 0.04; endothelium independent responses were unchanged. Study 2: homocysteine concentration increased significantly while methionine remained unchanged. Endothelium dependent responses were reduced from 34.6 (95% CI 20.6 to 48.6) to 22.8 (95% CI 12.0 to 33.6), p < 0.03. CONCLUSIONS: Homocysteine and not methionine is responsible for the changes in endothelial function. This supports the hypothesis that homocysteine promotes atherosclerosis by inducing endothelial dysfunction.
Subject(s)
Brachial Artery/drug effects , Endothelium, Vascular/drug effects , Homocysteine/pharmacology , Methionine/pharmacology , Administration, Oral , Adult , Area Under Curve , Brachial Artery/physiology , Cross-Over Studies , Female , Forearm/blood supply , Homocysteine/blood , Humans , Male , Methionine/blood , Plethysmography , Regional Blood FlowABSTRACT
A mild to moderate elevation of the total homocysteine concentration (tHcy) is now recognized as a risk factor for vascular disease. It is also associated with endothelial dysfunction in middle-aged and elderly individuals without overt atherosclerotic vascular disease. This is important, as endothelial dysfunction is a well recognized early and potentially reversible marker of the atherosclerotic process. We investigated whether mild hyperhomocysteinaemia was associated with endothelial dysfunction in otherwise healthy young males. We compared endothelial function, by measuring forearm blood flow, in 17 males with mild hyperhomocysteinaemia (defined as tHcy >10 micromol/l) and 14 controls with low tHcy (defined as <5 micromol/l). Forearm blood flow was measured in response to the intra-arterial infusion of acetylcholine (endothelial-dependent response) or sodium nitroprusside (endothelial-independent response). Responses to the vasoactive substances were expressed as the area under the curve of the change in forearm blood flow from baseline. Data are given as mean (95% confidence interval). The two groups were well matched for age, body mass index, pulse rate and blood pressure. tHcy was significantly different between the groups [12.3 (10.4-14.2) micromol/l compared with 4.9 (4.6-5.1) micromol/l; P<0.001]. Concentrations of vitamin B(12) and folate were significantly higher in the control group. There was no difference in basal forearm blood flow between the group with mild hyperhomocysteinaemia and the controls, and both the endothelial-dependent [37.5 (26.2-38.8) and 35.3 (26.1-44.4) arbitrary units respectively] and -independent [26.1 (22.2-29.9) and 25.9 (21.0-30.8) units respectively] responses were not significantly different between the groups. Thus the present study demonstrates that, in healthy adults, mild elevation of tHcy was not associated with impaired endothelial-dependent vasodilation. These data suggest an age effect with regard to homocysteine and endothelial dysfunction. The development of vascular disease in individuals with hyperhomocysteinaemia may only result with higher concentrations or after prolonged exposure.
Subject(s)
Endothelium, Vascular/physiopathology , Hyperhomocysteinemia/physiopathology , Vasodilation/physiology , Acetylcholine , Adult , Forearm/blood supply , Humans , Male , Nitroprusside , Regional Blood Flow/drug effects , Regional Blood Flow/physiology , Vasodilator AgentsABSTRACT
This article compares different methods of scatterplot analysis to assess the optimal methodology. The scatterplot (Poincaré plot) is a nonlinear heart rate variability method where a "return map" is constructed by plotting each current cycle against the previous beat (RR vs. RR(n-1)). Geometric analysis of the scatterplot allows short-term and long-term heart rate variability (HRV) to be assessed. A three-dimensional construct is also possible, where the third axis represents the density of values, at any given RR vs. RR(n-1) intersection. Topological methods of analysis can compute the density distribution function or compactness of a dataset. Scatterplots that otherwise appear very similar in the two-dimensional plot may be clearly differentiated using this approach. Correct characterization may improve the ability of scatterplot analysis to predict outcomes in cardiovascular disease. We have assessed two computational approaches that take account of scatterplot density, namely, the heart rate variability fraction and the compactness measure. Scatterplots were constructed from three double-blind and randomized placebo controlled studies conducted in a total of 49 healthy subjects. Single oral doses of antagonists (atenolol 50 mg [beta-1], propranolol 160 mg [beta-1 and beta-2], and ICI 118,551 25 mg [beta-2]) or agonists (xamoterol 200 mg [beta-1], salbutamol 8 mg [beta-2], prenalterol 50 mg [beta-1 and beta-2], and pindolol 10 mg [mainly beta-2] of the cardiac beta-adrenoceptor were studied. Salbutamol, pindolol, and xamoterol increased compactness and reduced HRV fraction significantly compared with placebo. However, when compared with the more conventional scatterplot parameters, these newer density methods were found to be less discriminating. An alternative approach to improve scatterplot discrimination, using the combination of several scatterplot features, is under investigation.
Subject(s)
Adrenergic beta-Agonists/pharmacology , Adrenergic beta-Antagonists/pharmacology , Heart Rate/drug effects , Adult , Albuterol/pharmacology , Analysis of Variance , Atenolol/pharmacology , Double-Blind Method , Humans , Male , Pindolol/pharmacology , Propranolol/pharmacology , Randomized Controlled Trials as TopicABSTRACT
Digoxin remains one of the most commonly prescribed of all cardiac medications. The main indications for digoxin usage include atrial fibrillation and heart failure; both these conditions are more prevalent in older patients. Given the aging population and the increasing incidence of heart failure we would expect prescribing of digoxin to remain as frequent or to even increase in older patients. Older patients are also more likely to develop toxicity and diagnosis of digoxin toxicity can be difficult in this group. Numerous components contribute to the development of toxicity in older patients, ranging from aging-related changes in renal function or body mass to polypharmacy and possible interactions with digoxin. It is therefore important to understand how the pharmacokinetics of digoxin may be altered in the older population. Application of basic pharmacological principles may be helpful in anticipating these problems. This review describes the pharmacokinetics of digoxin, the changes in pharmacokinetics with increasing age and how concomitant disease states or drug interactions may affect the pharmacokinetics of digoxin. Greater knowledge about the causes and prevention of digoxin toxicity should further reduce the morbidity and mortality arising from digoxin toxicity, especially in the elderly population.
Subject(s)
Aging/metabolism , Cardiotonic Agents/pharmacokinetics , Digoxin/pharmacokinetics , Absorption , Aged , Biological Availability , Drug Interactions , Geriatric Assessment , Humans , Tissue DistributionABSTRACT
BACKGROUND: Acetaminophen (paracetamol) poisoning is a major source of morbidity and mortality. It has been proposed that methionine be incorporated into acetaminophen tablets routinely as a protective mechanism. Methionine has been shown to be effective in the treatment of acetaminophen toxicity and a combination preparation of acetaminophen and methionine may prevent toxicity. However, there has been some concern that chronic methionine supplementation may be associated with vascular disease. The aim of the study was to investigate if methionine supplementation causes changes in endothelial function, plasma homocysteine, or lipid peroxidation which may be associated with atherosclerosis. METHODS: Sixteen healthy volunteers were studied. Forearm blood flow in response to local intra-arterial infusion of acetylcholine to assess endothelium-dependent vasodilatation and sodium nitroprusside to assess endothelium-independent vasodilatation was measured by venous occlusion plethysmography. Plasma homocysteine and lipid peroxidation, measured as thiobarbituric acid reactive substances, were measured using high-performance liquid chromatography. Forearm vascular responses, plasma homocysteine concentrations, and thiobarbituric acid reactive substances were measured at baseline and following methionine supplementation. RESULTS: There was no significant difference in endothelial-dependent vascular responses after acute (methionine 250 mg orally, p > 0.05), 1 month of low-dose (methionine 250 mg daily, p > 0.05), or 1 week of high-dose (methionine 100 mg/kg daily, p > 0.05) methionine administration. There was no significant difference in plasma homocysteine concentrations after acute (p > 0.05) or 1 month of low-dose (p > 0.05) methionine administration. However, 1 week of high-dose methionine (100 mg/kg) administration daily significantly increased homocysteine concentrations (p < 0.0015). Thiobarbituric acid reactive substances were unchanged during the period of study (p > 0.05). CONCLUSIONS: Methionine supplementation does not impair endothelial-dependent vascular responses in healthy volunteers. Although high-dose methionine administration causes elevation of plasma homocysteine concentrations, doses similar to those used in combination preparations with acetaminophen do not affect plasma homocysteine concentrations.
Subject(s)
Dietary Supplements/adverse effects , Endothelium, Vascular/drug effects , Homocysteine/blood , Lipid Peroxidation/drug effects , Methionine/pharmacology , Acetylcholine/pharmacology , Adult , Chromatography, High Pressure Liquid , Dose-Response Relationship, Drug , Female , Forearm/blood supply , Humans , Male , Methionine/administration & dosage , Nitric Oxide/metabolism , Nitroprusside/pharmacology , Plethysmography , Thiobarbituric Acid Reactive Substances/analysisABSTRACT
Full antagonists of the cardiac beta-adrenoceptor improve heart-rate variability (HRV) in humans; however, partial agonism at the beta2-adrenoceptor has been suggested to decrease HRV. We therefore studied the HRV effects of some partial agonists of the beta1- and beta2-adrenoceptors in normal volunteers. Under double-blind and randomised conditions (Latin square design), eight healthy volunteers received placebo; xamoterol, 200 mg (beta1-adrenoceptor partial agonist); prenalterol, 50 mg (beta1- and beta2-adrenoceptor partial agonist); salbutamol, 8 mg (beta2-adrenoceptor partial agonist); ICI 118,551, 25 mg (selective beta2-adrenoceptor antagonist); and combinations of each partial agonist with ICI 118,551. Single oral doses of medication (at weekly intervals) were administered at 22:30 h with HRV assessed from the overnight sleeping heart rates. HRV was determined by using standard time-domain summary statistics and two nonlinear methods, the Poincaré plot (scatterplot) and cardiac sequence analysis. On placebo, the sleeping heart rate decreased significantly, between 2 and 8 h after dosing. The heart rate with ICI 118,551 was unaltered. Xamoterol, prenalterol, and salbutamol increased the sleeping heart rate. ICI 118,551 blocked the heart-rate effects of salbutamol, attenuated those of prenalterol, but did not influence the xamoterol heart rate. The scatterplot (Poincaré) area was reduced by beta1-adrenoceptor (xamoterol), beta2-adrenoceptor (salbutamol), and combined beta1- and beta2-adrenoceptor (prenalterol) agonism. A reduction in scatterplot length followed salbutamol, prenalterol alone, and prenalterol in combination with ICI 118,551. The geometric analysis of the scatterplots allowed width assessment (i.e., dispersion) at fixed RR intervals. At higher heart rates (i.e., 25 and 50% of RR scatterplot length), dispersion was decreased after xamoterol, prenalterol, and prenalterol/ICI 118,551. Cardiac sequence analysis (differences between three adjacent beats; deltaRR vs. deltaRRn+1) assessed the short-term patterns of cardiac acceleration and deceleration; four patterns were identified: +/+ (a lengthening sequencing), +/- or -/+ (balanced sequences), and finally -/- (a shortening sequence). Cardiac acceleration or deceleration episodes (i.e., number of times deltaRR and deltaRRn+1 were altered in the same direction) were increased after salbutamol and prenalterol. In conclusion, partial agonism at either the cardiac beta1-adrenoceptor (xamoterol), beta2-adrenoceptor (salbutamol), and beta1- plus beta2-adrenoceptors (prenalterol) altered the autonomic balance toward sympathetic dominance in healthy volunteers; blockade of the beta2-adrenoceptor with the highly selective beta2-antagonist ICI 118,551 prevented the effects of salbutamol on HRV, attenuated the HRV effects of prenalterol, but had no effect on the actions of xamoterol. Agonism at both the beta1- and beta2-adrenoceptor reduced HRV in healthy subjects; the implications for the preventive use of the beta-adrenoceptor compounds in cardiovascular disease warrant further investigation.
Subject(s)
Adrenergic beta-Agonists/pharmacology , Heart Rate/drug effects , Adult , Albuterol/pharmacology , Double-Blind Method , Drug Interactions , Humans , Male , Prenalterol/pharmacology , Sleep/drug effects , Statistics as Topic , Xamoterol/pharmacologyABSTRACT
AIMS: To examine the impact on heart rate variability (HRV), of agonism or antagonism at the cardiac beta2-adrenoceptor in healthy volunteers, using standard time-domain summary statistics and non-linear methods (scatterplot and quadrant analysis). METHODS: Under double-blind and randomised conditions (Latin square design), 17 normal volunteers received placebo, salbutamol (beta2-adrenoceptor partial agonist), ICI 118,551 (specific beta2-adrenoceptor antagonist), or salbutamol plus ICI 118,551. Single oral doses of medication (at weekly intervals) were administered at 22.30 h, with HRV assessed from the sleeping heart rates. RESULTS: Salbutamol reduced the long-term (SDNN: 135 ms [120, 156], SDANN: 107 ms [89, 124]) time-domain indicators of HRV compared with placebo (SDNN: 39 [24, 55], SDANN 42 [29, 56], [mean difference [95% confidence intervals of difference]]). Alone, ICI 118,551 did not effect HRV, but in combination blocked the actions of salbutamol. Scatterplot length (944 ms [869, 1019]) and area (222*10(3) ms2 [191, 253]) were reduced by salbutamol compared with placebo; (length difference (164 [98, 230]) and area difference 59 [36, 83]). Scatterplot width (dispersion) was lower at both low (width RR-1 25% salbutamol 277 ms [261, 293]: salbutamol minus placebo 14 ms [0, 28]) and high (width 75% salbutamol 417 [391, 443]: salbutamol minus placebo 41 [20, 62]) heart rates. ICI 118,551 alone did not alter scatterplot parameters but in combination blocked the effect of salbutamol. Cardiac acceleration episodes (i.e. consecutive deltaRR and deltaRRn+1 shorten) were increased following salbutamol 7288 [6089, 8486] compared with placebo -1890 [-2600, -1179]; the beat-to beat difference (deltaRRn+1) was reduced after salbutamol compared with the other treatments. ICI 118,551 did not effect acceleration episodes but reduced the effect of salbutamol when used in combination. CONCLUSIONS: Agonism at the cardiac beta2-adrenoceptor in healthy volunteers with salbutamol altered autonomic balance towards sympathetic dominance; this re-balancing was blocked by ICI 118,551 given in combination with salbutamol. However antagonism at the beta2-adrenoceptor with ICI 118,551 alone did not significantly alter the HRV. The beta2-adrenoceptor modulates HRV in healthy volunteers; the implications of agonism and antagonism at the beta2-adrenoceptor in cardiovascular disease states warrants further investigation.
Subject(s)
Adrenergic beta-Agonists/pharmacology , Adrenergic beta-Antagonists/pharmacology , Albuterol/pharmacology , Heart Rate/drug effects , Propanolamines/pharmacology , Adult , Double-Blind Method , Drug Interactions , Humans , Male , Placebos , Sleep , Statistics as TopicABSTRACT
Spontaneous coronary artery dissection is a rare cause of myocardial ischaemia. Typically it affects young, apparently healthy females, and may result in significant myocardial loss or even death. Due to the rarity of the condition there are no clear guidelines for its management. We describe two cases of spontaneous coronary artery dissection and report successful coronary stenting of the affected artery in one patient. We believe that this interventional technique may be the treatment of choice in selected patients with this condition.