Cardiovascular morbidity and mortality related to orthostatic hypotension: a meta-analysis of prospective observational studies.

BACKGROUND: Whether orthostatic hypotension (OH) is a risk factor for cardiovascular morbidity and death is uncertain. Currently available evidence derives from non-homogeneous and partly ambiguous studies. OBJECTIVE: We aimed at assessing the relationship between OH and death or major adverse cardiac and cerebrovascular events (MACCEs) by integrating results of previous studies. METHODS: We performed a meta-analysis of prospective observational studies reporting on the association between prevalent OH, mortality, and incident MACCE, published from 1966 through 2013. Mantel-Haenszel pooled estimates of relative risk (RR) and 95% confidence intervals (CIs) for all-cause death were assessed as the primary endpoint at the longest follow-up; incident coronary heart disease (CHD), heart failure (HF), and stroke were assessed as secondary endpoints. We also performed post hoc subgroup analyses stratified by age and a meta-regression analysis. RESULTS: We identified a total of 13 studies, including an overall population of 121 913 patients, with a median follow-up of 6 years. Compared with the absence of OH, the occurrence of OH was associated with a significantly increased risk of all-cause death (RR 1.50; 95% CI 1.24-1.81), incident CHD (RR 1.41; 95% CI 1.22-1.63), HF (RR 2.25; 95% CI 1.52-3.33), and stroke (RR 1.64; 95% CI 1.13-2.37). When analysed according to age, pooled estimates of RR (95% CI) for all-cause death were 1.78 (1.25-2.52) for patients <65 years old, and 1.26 (0.99-1.62) in the older subgroup. CONCLUSION: Orthostatic hypotension is associated with a significantly increased risk of all-cause death, incident CHD, HF, and stroke.

From short-term blood pressure variability to atherosclerosis: Relative roles of vascular stiffness and endothelial dysfunction.

Both arterial blood pressure (BP) average levels and short-term BP variability (BPV) relate to hypertension-mediated organ damage, in particular increased carotid artery intima-media thickness (IMT) and carotid-femoral pulse wave velocity (PWV). Endothelial dysfunction possibly mediates such damage. The authors aimed at further investigating such role in hypertensive patients. In 189 recently diagnosed, untreated hypertensive patients the authors evaluated, in a cross-sectional design, the relationships of BP average levels and short-term systolic (S) BPV (standard deviation of awake SBP or of 24-hour-weighted SBP) with IMT and PWV, and how much these relationships are explained by endothelial function parameters-brachial artery flow-mediated dilation (FMD) and digital reactive hyperemia index (RHI). Multivariable models assessed the strength of these relationships to derive a plausible pathogenetic sequence. Both average SBP values and our measures of SBPV were significantly related to IMT (24-hour mean SBP: r = .156, P = .034; 24-hour-weighted SBPV: r = .157, P = .033) and to PWV (24-hour mean SBP: r = .179, P = .015; 24-hour-weighted SBPV: r = .175; P = .018), but only poorly related to FMD or RHI (P > .05 for all). At univariable regression analysis, FMD and RHI were both related to IMT, (P < .001), but not to PWV. When FMD and RHI were added to average SBP and SBPV parameters in a multivariable model, both significantly (P < .005) contributed to predict IMT, but not PWV. Thus, endothelial dysfunction relates to IMT independently of BP parameters, but appears to play a minor role in the association between BP variability-related variables and arterial stiffening.

Awake blood pressure variability, inflammatory markers and target organ damage in newly diagnosed hypertension.

Increased blood pressure (BP) may stimulate vascular inflammation, which may itself induce pathological arterial changes. BP variability has been associated with target-organ damage and future cardiovascular complications. We hypothesized that BP variability, as derived from ambulatory BP monitoring, is related to inflammatory markers in newly diagnosed hypertension. Systolic (S) and diastolic (D) BP variabilities were assessed as the SD of 24-h pressure recordings in a cohort of 190 recently (<6 months) diagnosed, untreated hypertensive subjects. Target organ damage, assessed by measuring the carotid artery intima-media thickness, left ventricular mass index, and microalbuminuria, was related to plasma high-sensitivity C-reactive protein (hsCRP) and soluble (s) E-selectin, an endothelium-specific molecule. The patients' age (mean+/-SD) was 53.0+/-8.5 years, and 59% were male. Multivariable analysis identified awake SBP variability (95% confidence interval [CI]: 0.002-0.042, p=0.034) as an independent correlate of hsCRP and awake SBP (95% CI: 0.003-0.014, p=0.003), awake SBP variability (95% CI: 0.003-0.035, p=0.018), and microalbuminuria (95% CI: 0.075-0.280, p=0.001) as independent correlates of sE-selectin. When patients were divided into low and high awake SBP variability groups, age (p=0.001), hsCRP (p=0.0001), and sE-selectin (p=0.005) were significantly different in the two groups. After adjusting for age, these differences remained significant (p=0.022 and p=0.001 for hsCRP and sE-selectin, respectively). In recently diagnosed hypertensive subjects, hsCRP and sE-selectin levels are related to awake SBP variability. High SBP variability is likely associated with vascular inflammation in newly diagnosed hypertension, independent of SBP. (Hypertens Res 2008; 31: 2137-2146).

Genetic determinants of cognitive responses to caffeine drinking identified from a double-blind, randomized, controlled trial.

The widely observed between-subject variability in cognitive responses to coffee may have a genetic basis. We evaluated cognitive responses to caffeine throughout three complex cognitive tasks assessing different subdomains of attention, namely Alerting and Orienting (Categorical Search Task) and Executive Control (Stroop Task and Eriksen Flanker Task). We explored whether they are influenced by gene variants affecting adenosine metabolism or catecholamine receptors. We recruited 106 healthy male subjects who were administered, in a double-blind design, 40mL of either a decaffeinated coffee preparation plus 3mg/kg caffeine (caf) or the corresponding vehicle (decaf). The protocol was repeated 24h later with the alternative preparation. Cognitive tasks were performed between 30min and 2h after caf or decaf administration. Each subject underwent ambulatory blood pressure monitoring for 2h. Blood samples were collected for genetic evaluations and for plasma caffeine and catecholamines measures. We found a significant reduction of reaction times in two of the cognitive tasks (Categorical Search Task and Stroop Task) after caf compared with decaf, indicating that caffeine, on average, improved the attention level in the domains under investigation. We also found, however, a great inter-individual variability in the cognitive performance responses to caffeine. In exploring genetic sources for such variability, we found a relation between polymorphisms of adenosine A2A and the caffeine effects on the attentional domains of Orienting and Executive control. In conclusion, variability in the attentional response to coffee may be partly explained by genetic polymorphisms of adenosine and adrenergic receptors.

Increased short-term blood pressure variability is associated with early left ventricular systolic dysfunction in newly diagnosed untreated hypertensive patients.

BACKGROUND AND AIM: Twenty-four-hour blood pressure (BP) variability, by ambulatory BP monitoring (ABPM), has been related to left ventricular hypertrophy, independent of mean BP values. We tested the hypothesis that short-term BP variability (BPV) is also related to subclinical left ventricular systolic dysfunction. METHODS: We assessed 24-h SBP and DBP variabilities, quantified as standard deviation (SD) of daytime (awake) BP values and as weighted SD of 24-h BP (24-h-weighted BPV), in 309 recently (<6 months) diagnosed, prospectively recruited, and untreated hypertensive patients. Patients were included only if with normal (≥55%) left ventricular ejection fraction (LVEF). Left ventricular systolic function was assessed by echocardiography measuring midwall fractional shortening (MFS), circumferential end-systolic stress (cESS), MFS/cESS, peak systolic wall stress, left ventricular fractional shortening (LVFS), and LVEF. RESULTS: At multivariate analysis, awake and 24-h-weighted SBP variabilities (directly, P = 0.038 and P = 0.002, respectively) as well as relative wall thickness (RWT) (inversely, P = 0.001) were significantly related to cESS. Awake and 24-h SBP average values (inversely, P = 0.011 and P = 0.002, respectively), awake and 24-h-weighted SBP variabilities (inversely, P = 0.017 and P = 0.024, respectively), and RWT (directly, P = 0.001) were all significantly related to MFS/cESS. Finally, awake and 24-h average SBP (directly, P = 0.01 for both), awake and 24-h-weighted SBP variability (directly, P = 0.001 and P = 0.032, respectively), and RWT (inversely, P = 0.001) were all significantly and independently related to peak systolic wall stress. CONCLUSION: In newly diagnosed never-treated hypertensive patients, in the absence of LVEF changes and independent of left ventricular mass index, higher awake, or 24-h-weighted short-term SBP variabilities are associated with early depressed left ventricular systolic function.

A comparison of the diagnostic performance of the ST/HR hysteresis with cardiopulmonary stress testing parameters in detecting exercise-induced myocardial ischemia.

BACKGROUND: Because ST segment depression has limited diagnostic performance at exercise electrocardiography (ECG), ST segment depression/heart rate (ST/HR) hysteresis and cardiopulmonary exercise test (CPET)-derived parameters have been proposed as alternatives to diagnose exercise-induced myocardial ischemia. We compared the diagnostic performance of such parameters. METHODS: We studied 56 subjects (45 men, 11 women, age 59.7 ± 13.6 years) referred for suspected exercise-induced myocardial ischemia with an equivocal ECG exercise test. All subjects serially underwent CPET and a myocardial single-photon emission computerized tomography (SPECT) perfusion imaging (as the gold standard for ischemia). Maximum ST depression at peak exercise (ST-max), the ST/HR hysteresis, ΔVO2/ΔWR b-b1 slope, ΔVO2/ΔWR (aa1-bb1), VO2/HR flattening duration and other CPET parameters were derived in all subjects. RESULTS: On the basis of SPECT, 23 subjects (41%) were considered ischemic and 33 subjects (59%) non-ischemic. ST/HR hysteresis was higher (0.026 mV; 95% CI: 0.003 to 0.049 vs -0.016 mV; 95% CI: -0.031 to -0.001 mV) and ST-max was lower (-0.105 mV; 95% CI: -0.158 to -0.052 vs 0.032 mV; 95% CI: -0.001 to -0.066 mV) in ischemic vs non-ischemic subjects (P=0.004 and P=0.001, respectively). Among CPET parameters, ΔVO2/ΔWR b-b(1) slope was lower (9.4 ± 3.8) and ΔVO2/ΔWR (aa(1)-bb(1)) was higher (2.1 ± 2.6) in ischemic vs non-ischemic subjects (11.4 ± 2.3, P=0.005, and 1.1 ± 1.5, P=0.001, respectively). The ST/HR hysteresis had the highest area under the curve value, better (P<0.05) than any other parameters tested, thus showing the highest overall diagnostic performance. CONCLUSION: The ST/HR hysteresis is superior to CPET-derived parameters for detecting exercise-induced myocardial ischemia in patients with equivocal ECG exercise test results.

Genetic determinants of blood pressure responses to caffeine drinking.

BACKGROUND: The widely observed between-subject variability in cardiovascular responses to coffee may have a genetic basis. OBJECTIVE: We evaluated acute blood pressure (BP) responses to caffeine and explored whether they are influenced by candidate gene variants affecting caffeine metabolism (for cytochrome P450 1A2), adenosine metabolism (for adenosine receptor and AMP deaminase), or catecholamine receptors. METHODS: We recruited 110 healthy male habitual moderate coffee drinkers who refrained from drinking coffee on the day preceding the study. Each subject underwent ambulatory BP monitoring at 6-min intervals for 2 h. Each participant was administered, in a double-blind design, 40 mL of either a decaffeinated coffee preparation plus 3 mg caffeine/kg (caf) or the corresponding vehicle (decaf). The protocol was repeated 24 h later with the alternative preparation. Blood samples were collected for genetic and plasma caffeine and catecholamine evaluations. RESULTS: Compared with decaf, caf was associated with a mean (± SD) significant increase in systolic BP of 4 ± 12 mm Hg and in diastolic BP of 3 ± 10 mm Hg (P < 0.001 for both). Plasma caffeine and adrenaline increased after caf, but not after decaf. Of 11 gene polymorphisms analyzed, a relation was observed between the ADORA2A TT variant and the change in SBP peak and between the ADRA2B I variant and the changes in both SBP mean and peak; mean peak change in SBP; these variants were associated with increased SBP responses to caf. CONCLUSIONS: Variability in the acute BP response to coffee may be partly explained by genetic polymorphisms of the adenosine A2A receptors and α(2)-adrenergic receptors. This trial is registered at clinicaltrials.gov as NCT01330680.

Defective recovery of QT dispersion predicts late cardiac mortality after percutaneous coronary intervention.

BACKGROUND: It has been suggested that corrected QT dispersion (cQTD) provides a measure of repolarisation inhomogeneity; however, the existence of a relationship between cQTD and cardiac outcomes is controversial. OBJECTIVE: To assess whether changes in cQTD following percutaneous coronary intervention (PCI) predict long-term survival. DESIGN: Prospective observational study. SETTING: Single tertiary care centre. Main outcome measures Cardiac mortality. PATIENTS: 612 patients had a 12-lead ECG recorded before and 6 h after PCI, and were followed-up for 49 ± 10 months. RESULTS: PCI was associated with a significant overall reduction of cQTD at 6 h versus baseline (p < 0.001); a reduction in cQTD occurred in 343 patients (56%). During the follow-up, 46 deaths (7.5%) were recorded, 21 of which for non-cardiac and 25 for cardiac causes. At Cox regression analysis, a reduced ΔcQTD (cQTD baseline - 6 h) was an independent predictor of cardiac mortality (HR = 1.497; 95% CI 1.081 to 2.075 for each 20 ms decrease; p = 0.015), together with age (HR = 1.672; 95% CI 1.039 to 2.691 per 10 years increase; p = 0.034), diabetes (HR = 2.622; 95% CI 1.112 to 6.184; p=0.028), peak CK-MB (HR = 1.798; 95% CI 1.063 to 3.039 per each unit increase over normal level; p = 0.029), three-vessel coronary artery disease (HR=3.626; 95% CI 1.079 to 12.187; p = 0.037) and the number of treated lesions (HR=2.066; 95% CI 1.208 to 3.532; p = 0.008). Patients in the lowest tertile of ΔcQTD and having a post-procedural increase of CK-MB had a considerably higher cardiac mortality than the remaining population (14.6 vs 2.4%, p < 0.001). CONCLUSIONS: cQTD decreases after PCI. A defective cQTD recovery, suggesting the persistence of repolarisation inhomogeneities, predicts long-term cardiac mortality.

Cholesterol-lowering interventions and stroke: insights from a meta-analysis of randomized controlled trials.

OBJECTIVES: This meta-analysis was performed to determine the effects of various cholesterol-lowering treatments on the risk of stroke and its relationship with the extent of cholesterol lowering. BACKGROUND: Statins reduce the incidence of stroke, and it has been proposed that such effect is independent of cholesterol lowering and is explained by alternative mechanisms. METHODS: We performed a meta-analysis of randomized trials of cholesterol-lowering treatments in cardiovascular disease reporting on stroke, involving 266,973 patients investigated and a cumulative 946,582 person-years of exposure, and a meta-regression analysis of the extent of stroke reduction as a function of changes in total cholesterol. RESULTS: The odds ratio (OR) for the incidence of stroke in actively treated groups versus controls was 0.88 (95% confidence interval: 0.83 to 0.94, p < 0.001). No treatment affected fatal strokes. Whereas statins decreased the risk of total stroke significantly (OR: 0.85, 95% confidence interval: 0.78 to 0.92; p < 0.001), the benefit of nonstatin interventions was smaller and not statistically significant (diet OR: 0.92, fibrates OR: 0.98, other treatments OR: 0.81). We found a significant relationship between percent reduction of total (and low-density lipoprotein) cholesterol and percent reduction of total strokes (p = 0.0017), with each 1% reduction of total cholesterol predicting a 0.8% relative risk reduction of stroke. We found no significant association between stroke reduction and changes of high-density lipoprotein cholesterol levels, and inconsistent associations with reduction of triglycerides. CONCLUSIONS: Among cholesterol-lowering treatments, statins are the most effective at decreasing the risk of total stroke, but their benefit is proportional to the percent reduction of total cholesterol and low-density lipoprotein cholesterol. No lipid-lowering intervention was associated with a reduction of fatal stroke.

Awake systolic blood pressure variability correlates with target-organ damage in hypertensive subjects.

Growing evidence associates blood pressure (BP) variability with cardiovascular events in hypertensive patients. Here we tested the existence of a relationship between awake BP variability and target-organ damage in subjects referred for suspected hypertension. Systolic and diastolic BP variability were assessed as the standard deviation of the mean out of 24-hour, awake and asleep BP recordings in 180 untreated subjects, referred for suspected hypertension. Measurements were done at 15-minute intervals during daytime and 30-minute intervals during nighttime. Left ventricular mass index (by echo), intima-media thickness (by carotid ultrasonography), and microalbuminuria were assessed as indices of cardiac, vascular and renal damage, respectively. Intima-media thickness and left ventricular mass index progressively increased across tertiles of awake systolic BP variability (P for trend=0.001 and 0.003, respectively). Conversely, microalbuminuria was similar in the 3 tertiles (P=NS). Multivariable analysis identified age (P=0.0001), awake systolic BP (P=0.001), awake systolic BP variability (P=0.015) and diastolic BP load (P=0.01) as independent predictors of intima-media thickness; age (P=0.0001), male sex (P=0.012), awake systolic (P=0.0001) and diastolic BP (P=0.035), and awake systolic BP variability (P=0.028) as independent predictors of left ventricular mass index; awake systolic BP variability (P=0.01) and diastolic BP load (P=0.01) as independent predictors of microalbuminuria. Therefore, awake systolic BP variability by non-invasive ambulatory BP monitoring correlates with sub-clinical target-organ damage, independent of mean BP levels. Such relationship, found in subjects referred for recently suspected hypertension, likely appears early in the natural history of hypertension.