Medical management of anginal symptoms in women with stable angina pectoris: A systematic review of randomised controlled trials.

BACKGROUND: Medical therapies are used to improve stable anginal symptoms and quality of life in clinical practice however the evidence for the use of antianginal medication in women is largely unknown. We conducted a systematic review to investigate the extent of the evidence-base for the medical management of anginal symptoms in women with stable angina. METHODS: MEDLINE, EMBASE, Cochrane and ClinicalTrials.gov databases were searched to the end of December 2019. Retrieved papers were hand searched. Included were randomised controlled trials with at least one week of follow-up that included women with stable angina pectoris, with or without significant coronary atherosclerosis, randomised to conventional antianginal medication or/and a comparator, with a primary or secondary endpoint of angina frequency or glyceryl trinitrate (GTN) consumption. RESULTS: A total of 397 eligible publications were included in a qualitative analysis, with women comprising up to 20-30% of the study populations. No publication that included women and men reported all data separately for each sex. Twenty-six publications reported any female data separately from male data but only 18 reported angina data for women, 12 of which included fewer than 10 women. CONCLUSIONS: Substantially fewer women than men were included in randomised trials of antianginal medications reporting effects on anginal symptoms, and reporting of data by sex was infrequent. As a result, there is little evidence on which to base treatment recommendations for anginal symptoms in women. Our results provide a platform for future studies to fill this void in the evidence.

Angiographic Outcome of Coronary Artery Bypass Grafts: The Radial Artery Database International Alliance.

BACKGROUND: We used a large patient-level data set including 6 angiographic randomized controlled trials (RCTs) on coronary artery bypass conduits to explore incidence and determinants of coronary graft failure. METHODS: Patient-level angiographic data of 6 RCTs comparing long-term outcomes of the radial artery and other conduits were joined. Primary outcome was graft occlusion at maximum follow-up. The analysis was divided as (1) left anterior descending coronary (LAD) distribution and (2) non-LAD distribution (circumflex and right coronary artery). Mixed-model multivariable Cox regression including all baseline characteristics with stratification by individual trials was used to identify predictors of graft occlusion. RESULTS: Included were 1091 patients and 2281 grafts, consisting of 921 left internal mammary arteries, 74 right internal mammary arteries, 710 radial arteries, and 576 saphenous veins. All left internal mammary arteries were used on the LAD, the other conduits were used on the non-LAD distribution. Mean angiographic follow up was 65 ± 29 months. Occlusion rates were 2.3% for the left internal mammary arteries, 13.5% for the left internal mammary arteries, 9.4% for the right internal mammary arteries, and 17.5% for the saphenous veins. At multivariable analysis, type of conduit used, age, female sex, left ventricular ejection fraction of less than 0.50, and use of the Y graft were significantly associated with graft occlusion in the non-LAD distribution. CONCLUSIONS: Our analyses showed that failure of the left internal mammary arteries-to-LAD bypass is a very uncommon event. For the non-LAD distribution, the nonuse of radial artery, age, female sex, left ventricular ejection fraction of less than 0.50, and use of the Y graft configuration were significantly associated with midterm graft failure.

Long-term performance of an external stent for saphenous vein grafts: the VEST IV trial.

BACKGROUND: Externally stenting saphenous vein grafts reduces intimal hyperplasia, improves lumen uniformity and reduces oscillatory shear stress 1 year following surgery. The present study is the first to present the longer-term (4.5 years) performance and biomechanical effects of externally stented saphenous vein grafts. METHODS: Thirty patients previously implanted with the VEST external stent in the randomized, within-patient-controlled VEST I study were followed up for adverse events; 21 of these were available to undergo coronary angiography and intravascular ultrasound. RESULTS: Twenty-one stented and 29 nonstented saphenous vein grafts were evaluated by angiography and ultrasound at 4.5 ± 0.3 years. Vein graft failure rates were comparable between stented and nonstented grafts (30 and 23% respectively; p = 0.42). All failures were apparent at 1 year except for one additional nonstented failure at 4.5 years. In patent vein grafts, Fitzgibbon perfect patency remained significantly higher in the stented versus nonstented vein grafts (81 and 48% respectively, p = 0.002), while intimal hyperplasia area (4.27 mm2 ± 1.27 mm2 and 5.23 mm2 ± 1.83 mm2 respectively, p < 0.001) and thickness (0.36 mm ± 0.09 mm and 0.42 mm ± 0.11 mm respectively, p < 0.001) were significantly reduced. Intimal hyperplasia proliferation correlated with lumen uniformity and with the distance between the stent and the lumen (p = 0.04 and p < 0.001 respectively). CONCLUSIONS: External stenting mitigates saphenous vein graft remodeling and significantly reduces diffuse intimal hyperplasia and the development of lumen irregularities 4.5 years after coronary artery bypass surgery. Close conformity of the stent to the vessel wall appears to be an important factor. TRIAL REGISTRATION: NCT01415245 . Registered 11 August 2011.

OCT imaging of aorto-coronary vein graft pathology modified by external stenting: 1-year post-surgery.

AIMS: The Venous External Support Trial (VEST) evaluated whether a novel external stent attenuated saphenous vein graft (SVG) disease assessed with intravascular ultrasound 1 year following coronary artery bypass graft (CABG) surgery. This sub-study assessed SVGs with and without external stenting using optical coherence tomography (OCT). The aim of this study was to accurately compare quantitative and qualitative features of SVGs with and without a novel external stent using OCT. METHODS AND RESULTS: Twenty-four of 30 patients (65 ± 8 years) enrolled in VEST underwent coronary angiography with OCT imaging using a non-occlusive technique. Quantitative analysis of lumen area was performed in one frame every 10 mm along the length of the graft, from distal to proximal anastomosis, and pathological features within the lumen were noted. Mean cross-sectional area was greater in unstented vs. stented grafts (8.4 ± 3 vs. 7.6 ± 2.7 mm; P = 0.005). The lumen of the stented grafts was more homogeneous (difference between maximum and minimum lumen diameter was significantly smaller in stented compared with unstented grafts, 0.28 ± 0.19 vs. 0.33 ± 0.23 mm, respectively, P = 0.006), and more circular (mean eccentricity index 0.08 ± 0.06 vs. 0.10 ± 0.06, stented vs. unstented; P = 0.019). Adherent thrombus was identified in three grafts (all unstented). CONCLUSION: Our findings highlight the early changes occurring in SVGs after implantation of aorto-coronary bypass conduits, changes that may accelerate vein graft failure. External stenting resulted in a more homogeneous and less eccentric lumen with no thrombus formation.

Cardiac rehabilitation to improve physical functioning in refractory angina: a pilot study.

OBJECTIVES: Refractory angina patients suffer debilitating chest pain despite optimal medical therapy and previous cardiovascular intervention. Cardiac rehabilitation is often not prescribed due to a lack of evidence regarding potential efficacy and patient suitability. A randomised controlled study was undertaken to explore the impact of cardiac rehabilitation on cardiovascular risk factors, physical ability, quality of life and psychological morbidity among refractory angina sufferers. METHODS: Forty-two refractory angina patients (65.1 ± 7.3 years) were randomly assigned to an 8-week Phase III cardiac rehabilitation program or symptom diary control. Physical assessment, Progressive Shuttle Walk test, Hospital Anxiety and Depression Scale, Health Anxiety Questionnaire, the York Angina Beliefs scale, ENRICHD Social Support Instrument and SF-36 were completed before and after intervention and at 8-week follow-up. RESULTS: Following cardiac rehabilitation, patients demonstrated improved physical ability compared with controls in Progressive Shuttle Walk level attainment (p = 0.005) and total distance covered (p = 0.015). Angina frequency and severity remained unchanged in both groups, with the control demonstrating worsening SF-36 pain scale (63.43 ± 22.28 vs. 55.46 ± 23.98, p = 0.025). Cardiac rehabilitation participants showed improved Health Anxiety Questionnaire reassurance (1.71 ± 1.72 vs. 1.14 ± 1.23, p = 0.026) and York Beliefs anginal threat perception (12.42 ± 4.58 vs. 14.35 ± 4.73, p = 0.05) after cardiac rehabilitation. Physical measures were broadly unaffected. CONCLUSIONS: Cardiac rehabilitation can be prescribed to improve physical ability without affecting angina frequency or severity among patients with refractory angina.

Vascular reactivity and flow characteristics of radial artery and long saphenous vein coronary bypass grafts: a 5-year follow-up.

BACKGROUND: Radial artery (RA) aortocoronary bypass grafts anastomosed to a branch of the circumflex coronary artery have significantly better patency rates than saphenous vein (SV) grafts at 5 years, but the physiological characteristics and mechanisms involved are not clearly defined. We compared RA and SV graft vasomotor and flow responses to endothelium-dependent and -independent stimuli 5 years after surgery in a subgroup of patients enrolled in the Radial artery versus Saphenous Vein Patency (RSVP) trial. METHODS AND RESULTS: Twenty-seven patients were included in the study (RA, n=15; SV, n=12). Graft blood flow was calculated from flow velocity, measured by intracoronary Doppler, and luminal diameter, measured by quantitative coronary angiography, before and after intragraft infusions of adenosine, acetylcholine, and isosorbide dinitrate. At rest, RA luminal diameters were significantly smaller than SV luminal diameters (P=0.029), blood flow velocity was greater in RA than SV (P=0.008), and volume blood flows were similar. RA but not SV dilated in response to adenosine and isosorbide dinitrate (all P<0.05, RA versus SV, percent change from baseline), and there were no significant differences in the diameter responses to acetylcholine. Volume blood flow responses to adenosine, acetylcholine, and isosorbide dinitrate were comparable. CONCLUSIONS: Five years after surgery, RA coronary bypass conduits grafted to a single coronary territory demonstrated preserved flow-mediated vasodilatation, whereas SV grafts did not. Our results may provide insight into the more favorable patency of RA grafts over SV grafts. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT00139399.

Testosterone and coronary artery disease in men.

Coronary artery disease (CAD) is the leading cardiovascular cause of death, and in men, endogenous testosterone concentrations are inversely related to the extent and severity of CAD. Testosterone is known to affect a number of risk factors for CAD and has effects on vascular tone, vasoreactivity and blood flow of blood vessels beyond the reproductive system, indicating that testosterone may be involved in the pathogenesis of CAD. In this review we will present and discuss the actions of endogenous testosterone and testosterone treatment on risk factors for CAD, on the blood vessel wall and blood flow, and on atheroma development and progression, and discuss the potential for testosterone use in men with CAD.

Radial artery versus saphenous vein patency randomized trial: five-year angiographic follow-up.

BACKGROUND: Graft patency is a fundamental predictor of long-term survival after coronary artery bypass surgery. Left and right internal thoracic artery (arterial) graft patency has been shown to be superior to that of saphenous vein grafts. More recently, the radial artery has been used as an aortocoronary graft, but little is known about the midterm and long-term patency of this conduit. We performed a single-center prospective randomized trial comparing the angiographic patency of radial artery and saphenous vein aortocoronary bypass grafts at 5 years after surgery. METHODS AND RESULTS: We enrolled 142 patients randomized at a single center to have either the radial artery or saphenous vein grafted to a stenosed branch of the native left circumflex coronary artery. The primary end point was angiographic graft patency 5 years postoperatively. At 5 years, 134 patients were alive and eligible for reangiography (5-year survival, 94.4%). Angiography was performed in 103 patients (77%); 98.3% of radial artery grafts and 86.4% of saphenous vein grafts were patent (P=0.04). Graft narrowing occurred in 10% of patent radial artery grafts and 23% of patent saphenous vein grafts (P=0.01). CONCLUSIONS: Radial artery aortocoronary bypass grafts to a stenosed branch of the circumflex coronary artery have an excellent patency rate at 5 years. This was significantly better than the patency rate for saphenous vein grafts and comparable to reported patency rates for internal thoracic artery grafts.

Coronary vasomotor and blood flow responses to isoflavone-intact soya protein in subjects with coronary heart disease or risk factors for coronary heart disease.

Results in animals suggest favourable coronary vasomotor actions of isoflavones; however, the effects of isoflavones on the human coronary circulation have not been determined. In the present study, we therefore investigated the effects of short-term isoflavone-intact soya protein ingestion on basal coronary arterial tone and stimulated vasoreactivity and blood flow in patients with CHD (coronary heart disease) or risk factors for CHD. Seventy-one subjects were randomized, double-blind, to isoflavone-intact soya protein [active; n=33, aged 58+/-8 years (mean+/-S.D.)] or isoflavone-free placebo (n=38, aged 61+/-8 years) for 5 days prior to coronary angiography. In 25 of these subjects, stimulated coronary blood flow was calculated from flow velocity, measured using intracoronary Doppler and coronary luminal diameter before and after intracoronary adenosine, ACh (acetylcholine) and ISDN (isosorbide dinitrate) infusions. Basal and stimulated coronary artery luminal diameters were measured using quantitative coronary angiography. Serum concentrations of the isoflavones genistein, daidzein and equol were increased by active treatment (P<0.001, P<0.001 and P=0.03 respectively). Basal mean luminal diameter was not significantly different between groups (active compared with placebo: 2.9+/-0.7 compared with 2.73+/-0.44 mm, P=0.31). There was no difference in luminal diameter, flow velocity and volume flow responses to adenosine, ACh or ISDN between groups. Active supplement had no effect on basal coronary artery tone or stimulated coronary vasoreactivity or blood flow compared with placebo. Our results suggest that short-term consumption of isoflavone-intact soya protein is neither harmful nor beneficial to the coronary circulation of humans with CHD or risk factors for CHD. These results are consistent with recent cautions placed on the purported health benefits of plant sterols.

Effects of oral testosterone treatment on myocardial perfusion and vascular function in men with low plasma testosterone and coronary heart disease.

Intracoronary testosterone infusions induce coronary vasodilatation and increase coronary blood flow. Longer term testosterone supplementation favorably affected signs of myocardial ischemia in men with low plasma testosterone and coronary heart disease. However, the effects on myocardial perfusion are unknown. Effects of longer term testosterone treatment on myocardial perfusion and vascular function were investigated in men with CHD and low plasma testosterone. Twenty-two men (mean age 57 +/- 9 [SD] years) were randomly assigned to oral testosterone undecanoate (TU; 80 mg twice daily) or placebo in a crossover study design. After each 8-week period, subjects underwent at rest and adenosine-stress first-pass myocardial perfusion cardiovascular magnetic resonance, pulse-wave analysis, and endothelial function measurements using radial artery tonometry, blood sampling, anthropomorphic measurements, and quality-of-life assessment. Although no difference was found in global myocardial perfusion after TU compared with placebo, myocardium supplied by unobstructed coronary arteries showed increased perfusion (1.83 +/- 0.9 vs 1.52 +/- 0.65; p = 0.037). TU decreased basal radial and aortic augmentation indexes (p = 0.03 and p = 0.02, respectively), indicating decreased arterial stiffness, but there was no effect on endothelial function. TU significantly decreased high-density lipoprotein cholesterol and increased hip circumference, but had no effect on hemostatic factors, quality of life, and angina symptoms. In conclusion, oral TU had selective and modest enhancing effects on perfusion in myocardium supplied by unobstructed coronary arteries, in line with previous intracoronary findings. The TU-related decrease in basal arterial stiffness may partly explain previously shown effects of exogenous testosterone on signs of exercise-induced myocardial ischemia.

Comparison of flow characteristics and vascular reactivity of radial artery and long saphenous vein grafts [NCT00139399].

BACKGROUND: The morphological and functional differences between arteries and veins may have implications on coronary artery bypass graft (CABG) survival. Although subjective differences have been observed between radial artery (RA) and long saphenous venous (LSV) grafts, these have not been quantified. This study assessed and compared the flow characteristics and in-vivo graft flow responses of RA and LSV aorto-coronary grafts. METHODS: Angiograms from 52 males taken 3.7 +/- 1.0 months after CABG surgery were analyzed using adjusted Thrombolysis in Myocardial Infarction (TIMI) frame count. Graft and target coronary artery dimensions were measured using quantitative coronary angiography. Estimated TIMI velocity (V(E)) and volume flow (F(E)) were then calculated. A further 7 patients underwent in-vivo graft flow responses assessments to adenosine, acetylcholine and isosorbide dinitrate (ISDN) using intravascular Doppler. RESULTS: The V(E) for RA grafts was significantly greater than LSV grafts (P = 0.002), however there was no difference in volume F(E) (P = 0.20). RA grafts showed positive endothelium-dependent and -independent vasodilatation, and LSV grafts showed no statistically significant response to adenosine and acetylcholine. There was no difference in flow velocity or volume responses. Seven RA grafts (11%) had compromised patency (4 (6%) > or = 50% stenosis in the proximal/distal anastomoses, and 3 (5%) diffuse narrowing). Thirty-seven (95%) LSV grafts achieved perfect patency and 2 (5%) were occluded. CONCLUSION: The flow characteristics and flow responses of the RA graft suggest that it is a more physiological conduit than the LSV graft. The clinical relevance of the balance between imperfect patency versus the more physiological vascular function in the RA graft may be revealed by the 5-year angiographic follow-up of this trial.

Normal coronary physiology assessed by intracoronary Doppler ultrasound.

There is a natural need to measure flow in normal as well as diseased coronary arteries since the reestablishment of normal flow is the aim of most coronary interventions. Miniaturization has enabled positioning both proximal and distal within the coronary anatomy and improved accuracy of Doppler velocity measurements. Measurement of coronary flow reserve adds functional data to coronary angiographic anatomic description, and quantitation of flow, achieved by combining Doppler velocity. Although new techniques involving transthoracic Doppler and magnetic resonance imaging are currently being developed and refined to measure coronary flow velocity and volume flow noninvasively, the role of intracoronary Doppler remains secure particularly for the coronary interventional physician.

Long-term use of contraceptive depot medroxyprogesterone acetate in young women impairs arterial endothelial function assessed by cardiovascular magnetic resonance.

BACKGROUND: Depot medroxyprogesterone acetate (DMPA) inhibits proliferation of ovarian follicles, resulting in anovulation and a decrease in circulating estrogen; the latter action is potentially disadvantageous to cardiovascular health. We therefore investigated the vascular effects of long-term contraceptive DMPA in young women. METHODS AND RESULTS: Endothelium-dependent (hyperemia-induced flow-mediated dilatation [FMD]) and -independent (glyceryl trinitrate [GTN]) changes in brachial artery area were measured using cardiovascular magnetic resonance in 13 amenorrheic DMPA users (>1 year use; mean age 29+/-4 years) and in 10 controls (mean age 30+/-4 years, P=0.25) with regular menstrual cycles after validation of the technique. FMD and GTN responses were measured just before repeat MPA injection and 48 hours later (n=12) in DMPA users and during menstruation and midcycle (n=9) in controls. Serum-estradiol levels (S-estradiol) were measured at both visits. FMD was reduced in DMPA users compared with controls during menstruation (1.1% versus 8.0%, respectively P<0.01) without differences in GTN responses. S-estradiol levels in DMPA users were significantly lower than in controls during menstruation (58 versus 96 pmol/L, P<0.01). High levels of circulating MPA 48 hours after injection were not linked to an additional impairment in FMD (2.0% versus 3.1%, P=0.23). Estradiol levels were significantly correlated to FMD (r=0.43, P<0.01). CONCLUSIONS: Endothelium-dependent arterial function measured by cardiovascular magnetic resonance is impaired in chronic users of DMPA, and hypoestrogenism may be the mechanism of action. DMPA might adversely affect cardiovascular health, and in particular its use in women with cardiovascular disease should be additionally evaluated.

A comparison of brachial artery reactivity measured by external and intravascular ultrasound.

External ultrasound (US), EXUS, is widely used to measure brachial artery (BA) diameter changes in the assessment of vascular function; however, it has not been compared with other imaging modalities. We simultaneously measured BA diameter responses to hyperaemic flow and nitrate using EXUS and intravascular ultrasound (US), IVUS, in 10 patients. Mean diameters measured across all time periods correlated closely (r = 0.67, p < 0.001). Percent diameter change to hyperaemia and nitrate also correlated well (r = 0.67, p < 0.01). IVUS cross-sectional area (CSA) was significantly different from that calculated from EXUS using pir(2) (23.95 +/- 4.89 vs. 20.35 +/- 4.51 mm(2), respectively, p < 0.001). Orthogonal diameters measured by IVUS were significantly different (5.45 +/- 0.85 vs. 5.17 +/- 0.79 mm, respectively, p < 0.005). In conclusion, EXUS and IVUS BA diameter measurements correlated well; however, discrepancies in absolute measurements were revealed. The cross-section of the BA is oval; therefore, deriving CSA by pir(2) is inaccurate.

Assessment of endothelial function using peripheral waveform analysis: a clinical application.

OBJECTIVES: The study was done to determine whether radial artery applanation tonometry can be used as a noninvasive method of assessing global endothelial function. BACKGROUND; It is known that beta(2)-receptor stimulation results in endothelial release of nitric oxide. Furthermore, for over a century glyceryl trinitrate (GTN) has been known to markedly affect the arterial pressure waveform, even in the absence of significant blood pressure (BP) changes. Therefore, it was hypothesized that the change in the peripheral pressure waveform, as measured using tonometry and quantified using the augmentation index (AIx) and in response to Salbutamol (Salb), would allow assessment of global endothelial function. METHODS: The study contained three parts. In the first study, Salb (400 microg) was administered to 11 healthy subjects via inhalation after either intravenous N-omega-nitro-monomethyl-L-arginine (L-NMMA) (3 mg/kg over 5 min) or control solution (normal saline) in the supine, rested, fasted condition. The BP, heart rate and waveform responses were recorded each 5 min following Salb for 20 min. Next, GTN was given and responses recorded 5 min later. In the second study, both the reproducibility of Salb and the GTN responses were assessed in 9 subjects studied twice on separate days. In the third study, the Salb and GTN responses of 12 subjects with angiographic coronary artery disease (CAD) were compared with 10 age-matched control subjects with no atherosclerotic risk factors. RESULTS: After control infusion, AIx decreased following Salb, from 50.8 +/- 4.3% to 44.8 +/- 4.2%, a change of -11.8 +/- 3.7%, p < 0.01. After L-NMMA, AIx did not significantly change following Salb (54.2 +/- 5.1% vs. 52.9 +/- 5.3%, -2.0 +/- 3.1%). The GTN-induced decreases in AIx were similar after either infusion (35.1 +/- 3.3% vs. 36.5 +/- 3.3%). Reproducibility of Salb-induced changes in AIx between studies performed on separate days was good (r = 0.80, p < 0.01). Salb-induced changes in AIx in CAD patients were significantly less compared to control subjects (-2.4 +/- 1.9% vs. -13.2 +/- 2.4%, respectively, p < 0.002). The GTN-induced changes were not significantly different (-27.6 +/- 4.2 vs. -38.9 +/- 4.4%, p = 0.07). CONCLUSIONS: The peripheral arterial pressure waveform is sensitive to beta(2)-stimulation. Changes are related to nitric oxide release, are reproducible and can distinguish between clinical subject groups. Arterial waveform changes following Salb may thus provide a noninvasive method of measuring "global" arterial endothelial function.