'Legacy publication of a 2009 validation of the Riester Big Ben Square Desk aneroid device for blood pressure measurement according to the European Society of Hypertension International Protocol for validation of blood pressure measuring devices in adults (2002)'.

OBJECTIVE: To report a validation of the Riester Big Ben Square Desk Aneroid Sphygmomanometer according to the international protocol developed by the Working Group on Blood Pressure Monitoring of the European Society of Hypertension 2002 (ESH-IP 2002) in the interest of transparency. This legacy publication is intended to assure users that the device satisfied the requirements in place at that time. METHODS: Performance of the device was assessed by participants' age, sex, arm circumference and entry SBP/DBP. Validation was performed in 33 participants. The sphygmomanometer was assessed according to the ESH-IP, which defines zones of accuracy compared to the mercury standard as ≤5, ≤10, ≤15 mmHg or more. RESULTS: The mean (± SD) age was 50.5 ±â€…13.0 years, range 29-71 years, entry SBP 142.6 ±â€…23.7 mmHg, entry DBP 89.0 ±â€…17.8 mmHg. The device passed all the requirements listed and the validation protocol. The Riester Big Ben Square Desk aneroid sphygmomanometer slightly underestimated the observer-measured SBP, yet slightly overestimated DBP. The observer-device disagreement was -0.8 ±â€…6.4 mmHg SBP and +0.6 ±â€…4.0 mmHg DBP. CONCLUSION: These data show that the Riester Big Ben Square Desk aneroid sphygmomanometer fulfilled the ESH-IP 2002 requirements for the validation of BP monitors. It was on this basis that the British and Irish Hypertension Society recommended it for clinical use in the adult population.

The Effect of a Neuronal Nitric Oxide Synthase Inhibitor on Neurovascular Regulation in Humans.

BACKGROUND: Neurovascular coupling (NVC) is a key process in cerebral blood flow regulation. NVC ensures adequate brain perfusion to changes in local metabolic demands. Neuronal nitric oxide synthase (nNOS) is suspected to be involved in NVC; however, this has not been tested in humans. Our objective was to investigate the effects of nNOS inhibition on NVC in humans. METHODS: We performed a 3-visit partially randomized, double-blinded, placebo-controlled, crossover study in 12 healthy subjects. On each visit, subjects received an intravenous infusion of either S-methyl-L-thiocitrulline (a selective nNOS-inhibitor), 0.9% saline (placebo control), or phenylephrine (pressor control). The NVC assessment involved eliciting posterior circulation hyperemia through visual stimulation while measuring posterior and middle cerebral arteries blood velocity. RESULTS: nNOS inhibition blunted the rapidity of the NVC response versus pressor control, evidenced by a reduced initial rise in mean posterior cerebral artery velocity (-3.3% [-6.5, -0.01], P=0.049), and a reduced rate of increase (ie, acceleration) in posterior cerebral artery velocity (slope reduced -4.3% [-8.5, -0.1], P=0.045). The overall magnitude of posterior cerebral artery response relative to placebo control or pressor control was not affected. Changes in BP parameters were well-matched between the S-methyl-L-thiocitrulline and pressor control arms. CONCLUSIONS: Neuronal NOS plays a role in dynamic cerebral blood flow control in healthy adults, particularly the rapidity of the NVC response to visual stimulation. This work opens the way to further investigation of the role of nNOS in conditions of impaired NVC, potentially revealing a therapeutic target.

Lifestyle intervention in obese pregnancy and cardiac remodelling in 3-year olds: children of the UPBEAT RCT.

BACKGROUND/OBJECTIVES: Obesity in pregnancy has been associated with increased childhood cardiometabolic risk and reduced life expectancy. The UK UPBEAT multicentre randomised control trial was a lifestyle intervention of diet and physical activity in pregnant women with obesity. We hypothesised that the 3-year-old children of women with obesity would have heightened cardiovascular risk compared to children of normal BMI women, and that the UPBEAT intervention would mitigate this risk. SUBJECTS/METHODS: Children were recruited from one UPBEAT trial centre. Cardiovascular measures included blood pressure, echocardiographic assessment of cardiac function and dimensions, carotid intima-media thickness and heart rate variability (HRV) by electrocardiogram. RESULTS: Compared to offspring of normal BMI women (n = 51), children of women with obesity from the trial standard care arm (n = 39) had evidence of cardiac remodelling including increased interventricular septum (IVS; mean difference 0.04 cm; 95% CI: 0.018 to 0.067), posterior wall (PW; 0.03 cm; 0.006 to 0.062) and relative wall thicknesses (RWT; 0.03 cm; 0.01 to 0.05) following adjustment. Randomisation of women with obesity to the intervention arm (n = 31) prevented this cardiac remodelling (intervention effect; mean difference IVS -0.03 cm (-0.05 to -0.008); PW -0.03 cm (-0.05 to -0.01); RWT -0.02 cm (-0.04 to -0.005)). Children of women with obesity (standard care arm) compared to women of normal BMI also had elevated minimum heart rate (7 bpm; 1.41 to 13.34) evidence of early diastolic dysfunction (e prime) and increased sympathetic nerve activity index by HRV analysis. CONCLUSIONS: Maternal obesity was associated with left ventricular concentric remodelling in 3-year-old offspring. Absence of remodelling following the maternal intervention infers in utero origins of cardiac remodelling. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: The UPBEAT trial is registered with Current Controlled Trials, ISRCTN89971375.

Neuronal nitric oxide synthase regulates regional brain perfusion in healthy humans.

AIMS: Neuronal nitric oxide synthase (nNOS) is highly expressed within the cardiovascular and nervous systems. Studies in genetically modified mice suggest roles in brain blood flow regulation while dysfunctional nNOS signalling is implicated in cerebrovascular ischaemia and migraine. Previous human studies have investigated the effects of non-selective NOS inhibition but there has been no direct investigation of the role of nNOS in human cerebrovascular regulation. We hypothesized that inhibition of the tonic effects of nNOS would result in global or localized changes in cerebral blood flow (CBF), as well as changes in functional brain connectivity. METHODS AND RESULTS: We investigated the acute effects of a selective nNOS inhibitor, S-methyl-L-thiocitrulline (SMTC), on CBF and brain functional connectivity in healthy human volunteers (n = 19). We performed a randomized, placebo-controlled, crossover study with either intravenous SMTC or placebo, using magnetic resonance imaging protocols with arterial spin labelling and functional resting state neuroimaging. SMTC infusion induced an ∼4% decrease in resting global CBF [-2.3 (-0.3, -4.2) mL/100g/min, mean (95% confidence interval, CI), P = 0.02]. In a whole-brain voxel-wise factorial-design comparison of CBF maps, we identified a localized decrease in regional blood flow in the right hippocampus and parahippocampal gyrus following SMTC vs. placebo (2921 voxels; T = 7.0; x = 36; y = -32; z = -12; P < 0.001). This was accompanied by a decrease in functional connectivity to the left superior parietal lobule vs. placebo (484 voxels; T = 5.02; x = -14; y = -56; z = 74; P = 0.009). These analyses adjusted for the modest changes in mean arterial blood pressure induced by SMTC as compared to placebo [+8.7 mmHg (+1.8, +15.6), mean (95% CI), P = 0.009]. CONCLUSIONS: These data suggest a fundamental physiological role of nNOS in regulating regional CBF and functional connectivity in the human hippocampus. Our findings have relevance to the role of nNOS in the regulation of cerebral perfusion in health and disease.

Effect of diuretics on plasma aldosterone and potassium in primary hypertension: A systematic review and meta-analysis.

AIM: By contrast with drugs inhibiting the renin-angiotensin-aldosterone system (RAAS), diuretics stimulate renin release by the kidneys. Although plasma aldosterone (PA) is thought to be mainly regulated by RAAS activity, serum potassium has been shown to be an important factor in animal models and humans. Here we perform a systematic review and meta-analysis of randomised controlled trials (RCT) in hypertension investigating the effects of diuretic therapy on PA and the correlation of change in PA with that of potassium and blood pressure (BP). METHODS: Three databases were searched: MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL). Titles were first screened by title and abstract for relevance before full-text articles were assessed for eligibility according to a predefined inclusion/exclusion criteria. RESULTS: A total of 1139 articles were retrieved, of which 42 met the prespecified inclusion/exclusion criteria. The average standardised difference in mean PA was similar for all classes of diuretic: thiazide/thiazide-like 0.299 (95% confidence interval [CI] 0.150, 0.447), loop 0.927 (0.37, 1.49), MRA/potassium-sparing 0.265 (0.173, 0.357) and combination 0.466 (0.137, 0.796), Q = 6.33, P = .097. In subjects untreated with another antihypertensive, there was a significant relationship between change in PA and change in systolic BP but no relationship with the change in potassium. CONCLUSION: In RCTs of diuretic therapy in hypertension, there is an increase in PA with all classes of diuretic and no significant between-class heterogeneity. Change in PA is not related with potassium but correlates with the change in BP in subjects untreated with another antihypertensive medication.

Dietary nitrate prevents progression of carotid subclinical atherosclerosis through blood pressure-independent mechanisms in patients with or at risk of type 2 diabetes mellitus.

AIMS: To test if 6 months' intervention with dietary nitrate and spironolactone could affect carotid subclinical atherosclerosis and stiffness, respectively, vs. placebo/doxazosin, to control for blood pressure (BP). METHODS: A subgroup of participants in our double-blind, randomized-controlled, factorial VaSera trial had carotid imaging. Patients with hypertension and with/at risk of type 2 diabetes were randomized to active nitrate-containing beetroot juice or placebo nitrate-depleted juice, and spironolactone or doxazosin. Vascular ultrasound for carotid diameter (CD, mm) and intima-media thickness (CIMT, mm) was performed at baseline, 3- and 6-months. Carotid local stiffness (CS, m/s) was estimated from aortic pulse pressure (Arteriograph) and carotid lumen area. Data were analysed by modified intention to treat and using mixed-model effect, adjusted for confounders. RESULTS: In total, 93 subjects had a baseline evaluation and 86% had follow-up data. No statistical interactions occurred between the juice and drug arms and BP was similar between the juices and between the drugs. Nitrate-containing vs. placebo juice significantly lowered CIMT (-0.06 [95% confidence interval -0.12, -0.01], P = .034), an overall difference of ~8% relative to baseline; but had no effect on CD or CS. Doxazosin appeared to reduce CS from baseline (-0.34 [-0.62, -0.06]) however, no difference was detected vs. spironolactone (-0.15 [-0.46, 0.16]). No differences were detected between spironolactone or doxazosin on CIMT and CD. CONCLUSIONS: Our results show that 6 months' intervention with dietary nitrate influences vascular remodelling, but not carotid stiffness or diameter. Neither spironolactone nor doxazosin had a BP-independent effect on carotid structure and function.

Direct cardiac versus systemic effects of inorganic nitrite on human left ventricular function.

Inorganic nitrite is a source of nitric oxide (NO) and is considered as a potential therapy in settings where endogenous NO bioactivity is reduced and left ventricular (LV) function impaired. However, the effects of nitrite on human cardiac contractile function, and the extent to which these are direct or indirect, are unclear. We studied 40 patients undergoing diagnostic cardiac catheterization who had normal LV systolic function and were not found to have obstructive coronary disease. They received either an intracoronary sodium nitrite infusion (8.7-26 µmol/min, n = 20) or an intravenous sodium nitrite infusion (50 µg/kg/min, n = 20). LV pressure-volume relations were recorded. The primary end point was LV end-diastolic pressure (LVEDP). Secondary end points included indices of LV systolic and diastolic function. Intracoronary nitrite infusion induced a significant reduction in LVEDP, LV end-diastolic pressure-volume relationship (EDPVR), and the time to LV end-systole (LVEST) but had no significant effect on LV systolic function or systemic hemodynamics. Intravenous nitrite infusion induced greater effects, with significant decreases in LVEDP, EDPVR, LVEST, LV dP/dtmin, tau, and mean arterial pressure. Inorganic nitrite has modest direct effects on human LV diastolic function, independent of LV loading conditions and without affecting LV systolic properties. However, the systemic administration of nitrite has larger effects on LV diastolic function, which are related to reduction in both preload and afterload. These contractile effects of inorganic nitrite may indicate a favorable profile for conditions characterized by LV diastolic dysfunction.NEW & NOTEWORTHY This is the first study to assess the direct and indirect effects of inorganic nitrite on invasive measures of left ventricular function in humans in vivo. Inorganic nitrite has a modest direct myocardial effect, improving diastolic function. Systemic administration of nitrite has larger effects related to alterations in cardiac preload and afterload. The changes induced by nitrite appear favorable for potential use in conditions characterized by LV diastolic dysfunction.

Impact of arterio-ventricular interaction on first-phase ejection fraction in aortic stenosis.

AIMS: First-phase ejection fraction (EF1), the EF at the time to peak aortic jet velocity, has been proposed as a novel marker of peak systolic function in aortic stenosis (AS). This study aimed to explore the association of myocardial contractility and arterial load with EF1 in AS patients. METHODS AND RESULTS: Data from a prospective, cross-sectional study of 114 patients with mild, moderate, and severe AS with preserved left ventricular EF (>50%) were analysed. EF1 was measured as the volume change from end-diastole to the time that corresponded to peak aortic jet velocity. Myocardial contractility was assessed by strain rate measured by speckle tracking echocardiography. Arterial stiffness was assessed by central pulse pressure/stroke volume index ratio (PP/SVi). The total study population included 48% women, median age was 73 years, and mean peak aortic jet velocity was 3.47 m/s. In univariable linear regression analyses, lower EF1 was associated with higher age, higher peak aortic jet velocity, lower global EF, lower global longitudinal strain, lower strain rate, and higher PP/SVi. There was no significant association between EF1 and heart rate or sex. In multivariable linear regression analysis, EF1 was associated with lower strain rate and higher PP/SVi, independent of AS severity. Replacing PP/SVi by valvular impedance did not change the results. CONCLUSION: In patients with AS, reduced myocardial contractility and increased arterial load were associated with lower EF1 independent of the severity of valve stenosis.

Effect of diuretics on plasma renin activity in primary hypertension: A systematic review and meta-analysis.

AIMS: Plasma renin activity (PRA) is regarded as a marker of sodium and fluid homeostasis in patients with primary hypertension. Whether effects of diuretics on PRA differ according to class of diuretic, whether diuretics lead to a sustained increase in PRA, and whether changes in PRA relate to those in blood pressure (BP) is unknown. We performed a systematic review and meta-analysis of trials investigating the antihypertensive effects of diuretic therapy in which PRA and/or other biomarkers of fluid homeostasis were measured before and after treatment. METHODS: Three databases were searched: MEDLINE, EMBASE and The Cochrane Central Register of Controlled Trials. Titles were firstly screened by title and abstract for relevancy before full-text articles were assessed for eligibility according to a predefined inclusion/exclusion criteria. RESULTS: A total of 1684 articles were retrieved of which 61 met the prespecified inclusion/exclusion criteria. PRA was measured in 30/61 studies. Diuretics led to a sustained increase in PRA which was similar for different classes of diuretic (standardised mean difference [95% confidence interval] 0.481 [0.362, 0.601], 0.729 [0.181, 1.28], 0.541 [0.253, 0.830] and 0.548 [0.159, 0.937] for thiazide, loop, mineralocorticoid receptor antagonists/potassium-sparing and combination diuretics respectively, Q = 0.897, P = .826), and did not relate to the average decrease in blood pressure. CONCLUSION: In antihypertensive drug trials, diuretics lead to a sustained increase in average PRA, which is similar across different classes of diuretic and unrelated to the average reduction in blood pressure.

Snacking on Whole Almonds for Six Weeks Increases Heart Rate Variability during Mental Stress in Healthy Adults: A Randomized Controlled Trial.

Cardiac autonomic regulation can be indirectly measured by heart rate variability (HRV). Low HRV, which can be induced by mental stress, is a predictor of risk of sudden cardiac death. Few studies have investigated cause-and-effect relationships between diet and HRV. Nut consumption is associated with CVD risk reduction, but the impact on HRV, particularly in response to stress, is unclear. Men and women (30-70 y) with above average risk of developing CVD were randomly assigned in a 6-week randomized, controlled, parallel arm trial to consume either whole almond or isocaloric control snacks (20% of daily estimated energy requirement). Control snacks contained the average nutrient profile of UK snacks. Five-minute periods of supine heart rate (HR) and HRV were measured at resting and during mental stress (Stroop color-word test) at baseline and six weeks. High frequency (HF) power, which reflects parasympathetic regulation of HR, was increased following almonds during the mental stress task relative to control (mean difference between groups 124 ms2; 95% CI 11, 237; p = 0.031, n = 105), but other indices were unaffected. Snacking on whole almonds instead of typical snacks may reduce risk of CVD partly by ameliorating the suppression of HRV during periods of mental stress.

Snacking on whole almonds for 6 weeks improves endothelial function and lowers LDL cholesterol but does not affect liver fat and other cardiometabolic risk factors in healthy adults: the ATTIS study, a randomized controlled trial.

BACKGROUND: There is convincing evidence that daily whole almond consumption lowers blood LDL cholesterol concentrations, but effects on other cardiometabolic risk factors such as endothelial function and liver fat are still to be determined. OBJECTIVES: We aimed to investigate whether isoenergetic substitution of whole almonds for control snacks with the macronutrient profile of average snack intakes, had any impact on markers of cardiometabolic health in adults aged 30-70 y at above-average risk of cardiovascular disease (CVD). METHODS: The study was a 6-wk randomized controlled, parallel-arm trial. Following a 2-wk run-in period consuming control snacks (mini-muffins), participants consumed either whole roasted almonds (n = 51) or control snacks (n = 56), providing 20% of daily estimated energy requirements. Endothelial function (flow-mediated dilation), liver fat (MRI/magnetic resonance spectroscopy), and secondary outcomes as markers of cardiometabolic disease risk were assessed at baseline and end point. RESULTS: Almonds, compared with control, increased endothelium-dependent vasodilation (mean difference 4.1%-units of measurement; 95% CI: 2.2, 5.9), but there were no differences in liver fat between groups. Plasma LDL cholesterol concentrations decreased in the almond group relative to control (mean difference -0.25 mmol/L; 95% CI: -0.45, -0.04), but there were no group differences in triglycerides, HDL cholesterol, glucose, insulin, insulin resistance, leptin, adiponectin, resistin, liver function enzymes, fetuin-A, body composition, pancreatic fat, intramyocellular lipids, fecal SCFAs, blood pressure, or 24-h heart rate variability. However, the long-phase heart rate variability parameter, very-low-frequency power, was increased during nighttime following the almond treatment compared with control (mean difference 337 ms2; 95% CI: 12, 661), indicating greater parasympathetic regulation. CONCLUSIONS: Whole almonds consumed as snacks markedly improve endothelial function, in addition to lowering LDL cholesterol, in adults with above-average risk of CVD.This trial was registered at clinicaltrials.gov as NCT02907684.

Do anti-tumour necrosis factor-α biologics affect subclinical measures of atherosclerosis and arteriosclerosis? A systematic review.

AIMS: Inflammatory cytokines, particularly tumour necrosis factor-α (TNFα), are thought to promote arterial disease through a variety of mechanisms leading to arteriosclerosis and atherosclerosis. We reviewed the existing evidence of the effect of anti-TNFα treatment on arteriosclerosis and atherosclerosis in chronic inflammatory disease. METHODS: We performed a systematic review of studies examining effects of monoclonal antibodies against TNFα on subclinical measures of arteriosclerosis (arterial pulse wave velocity) and atherosclerosis (endothelial function measured by flow-mediated dilation or forearm blood flow responses to endothelium-dependent agonists, and common carotid intima-media thickness). RESULTS: We identified 60 studies (of 854 potential studies identified using a systematic search) in which effects of anti-TNFα biologics on these measures were assessed in patients receiving anti-TNFα therapy for a clinical indication (usually an inflammatory disease such as an inflammatory arthritis, psoriasis or inflammatory bowel disease). Of these, only 6 were randomised clinical controlled trials. Whilst many observational studies and noncontrolled studies reported positive findings, positive finding were reported in only 1 of 6 randomised clinical controlled trials. CONCLUSIONS: There is no strong evidence for an effect of anti-TNFα biologics on the subclinical measures of arteriosclerosis or atherosclerosis examined in this review. This does not exclude a positive effect of TNFα biologics on clinical outcomes through alternate pathways including those induced by remission of the primary inflammatory disease.

A review of the prescribing trend of thiazide-type and thiazide-like diuretics in hypertension: A UK perspective.

Thiazide diuretics have been the cornerstone of hypertension treatment for >5 decades. Most recent European and American guidelines recommend both thiazide-type and thiazide-like diuretics as first-line drugs for all patients with hypertension. In contrast, diuretics are not regarded as first-line treatment in the UK and in patients who are to be initiated on a diuretic treatment, thiazide-like molecules, such as chlortalidone and indapamide are the preferred option. This review examines the prescribing trend of the 4 most commonly prescribed thiazide diuretics for the treatment of hypertension in the UK. Prescription cost analysis data were obtained for both 2010 and 2016/2017 for each region of the UK to analyse the impact of the 2011 National Institute for Health and Care Excellence hypertension guidelines on the trend in thiazide diuretic prescribing. Overall, the prescriptions of thiazide diuretics declined over the years. Bendroflumethiazide is the most commonly prescribed diuretic in the UK and despite some geographical differences, thiazide-type diuretics are more widely used than thiazide-like. The use of indapamide increased significantly between 2010 and 2016/2017 while chlortalidone was rarely employed. Of the many factors affecting trends in prescriptions, clinical inertia, treatment adherence, availability of the products and the lack of fixed dose combinations may play a role.

Relation of arterial stiffness to left ventricular structure and function in healthy women.

BACKGROUND: Interactions between the left ventricular (LV) and the arterial system, (ventricular-arterial coupling) are key determinants of cardiovascular function. However, most of studies covered multiple cardiovascular risk factors, which also contributed to the morphological and functional changes of LV. The aim of this study was to examine the relationship between arterial stiffness and LV structure and function in healthy women with a low burden of risk factors. METHODS: Healthy women from the Twins UK cohort (n = 147, mean age was 54.07 ± 11.90 years) were studied. Arterial stiffness was evaluated by carotid-femoral pulse wave velocity (cf-PWV). LV structure and function were assessed by two-dimensional speckle tracking echocardiography. RESULTS: cf-PWV was significantly associated with most measures of LV geometry and function, including relative wall thickness (RWT), E/e' ratio, global circumferential and radial strain, apical rotation and LV twist (each p <  0.05), but bore no relation to global longitudinal strain. After adjustment for age, body mass index, blood pressure and heart rate, cf-PWV was significantly correlated with RWT, global circumferential strain, apical rotation and LV twist (ß = 0.011, - 0.484, 1.167 and 1.089, respectively, each p ≤  0.05). CONCLUSIONS: In healthy women with a low burden of risk factors, elevated arterial stiffness was intimately interwoven with increased LV twisting even before LV dysfunction becomes clinically evident.

The human coronary vasodilatory response to acute mental stress is mediated by neuronal nitric oxide synthase.

Mental stress-induced ischemia approximately doubles the risk of cardiac events in patients with coronary artery disease, yet the mechanisms underlying changes in coronary blood flow in response to mental stress are poorly characterized. Neuronal nitric oxide synthase (nNOS) regulates basal coronary blood flow in healthy humans and mediates mental stress-induced vasodilation in the forearm. However, its possible role in mental stress-induced increases in coronary blood flow is unknown. We studied 11 patients (6 men and 5 women, mean age: 58 ± 14 yr) undergoing elective diagnostic cardiac catheterization and assessed the vasodilator response to mental stress elicited by the Stroop color-word test. Intracoronary substance P (20 pmol/min) and isosorbide dinitrate (1 mg) were used to assess endothelium-dependent and -independent vasodilation, respectively. Coronary blood flow was estimated using intracoronary Doppler recordings and quantitative coronary angiography to measure coronary artery diameter. Mental stress increased coronary flow by 34 ± 7.0% over the preceding baseline during saline infusion (P < 0.01), and this was reduced to 26 ± 7.0% in the presence of the selective nNOS inhibitor S-methyl-l-thiocitrulline (0.625 µmol/min, P < 0.001). Mental stress increased coronary artery diameter by 6.9 ± 3.7% (P = 0.02) and 0.5 ± 2.8% (P = 0.51) in the presence of S-methyl-l-thiocitrulline. The response to substance P did not predict the response to mental stress (r2 = -0.22, P = 0.83). nNOS mediates the human coronary vasodilator response to mental stress, predominantly through actions at the level of coronary resistance vessels.NEW & NOTEWORTHY Acute mental stress induces vasodilation of the coronary microvasculature. Here, we show that this response involves neuronal nitric oxide synthase in the human coronary circulation.Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/nnos-and-coronary-flow-during-mental-stress/.

Physiology of Angina and Its Alleviation With Nitroglycerin: Insights From Invasive Catheter Laboratory Measurements During Exercise.

BACKGROUND: The mechanisms governing exercise-induced angina and its alleviation by the most commonly used antianginal drug, nitroglycerin, are incompletely understood. The purpose of this study was to develop a method by which the effects of antianginal drugs could be evaluated invasively during physiological exercise to gain further understanding of the clinical impact of angina and nitroglycerin. METHODS: Forty patients (mean age, 65.2±7.6 years) with exertional angina and coronary artery disease underwent cardiac catheterization via radial access and performed incremental exercise using a supine cycle ergometer. As they developed limiting angina, sublingual nitroglycerin was administered to half the patients, and all patients continued to exercise for 2 minutes at the same workload. Throughout exercise, distal coronary pressure and flow velocity and central aortic pressure were recorded with sensor wires. RESULTS: Patients continued to exercise after nitroglycerin administration with less ST-segment depression (P=0.003) and therefore myocardial ischemia. Significant reductions in afterload (aortic pressure, P=0.030) and myocardial oxygen demand were seen (tension-time index, P=0.024; rate-pressure product, P=0.046), as well as an increase in myocardial oxygen supply (Buckberg index, P=0.017). Exercise reduced peripheral arterial wave reflection (P<0.05), which was not further augmented by the administration of nitroglycerin (P=0.648). The observed increases in coronary pressure gradient, stenosis resistance, and flow velocity did not reach statistical significance; however, the diastolic velocity-pressure gradient relation was consistent with a significant increase in relative stenosis severity (k coefficient, P<0.0001), in keeping with exercise-induced vasoconstriction of stenosed epicardial segments and dilatation of normal segments, with trends toward reversal with nitroglycerin. CONCLUSIONS: The catheterization laboratory protocol provides a model to study myocardial ischemia and the actions of novel and established antianginal drugs. Administration of nitroglycerin causes changes in the systemic and coronary circulation that combine to reduce myocardial oxygen demand and to increase supply, thereby attenuating exercise-induced ischemia. Designing antianginal therapies that exploit these mechanisms may provide new therapeutic strategies.