Extreme dipping: is the cardiovascular risk increased? An unsolved issue Extreme dipping (i.e. a marked blood pressure fall during night-time period) is an alteration of circadian blood pressure (BP) rhythm frequently observed in the setting of systemic hypertension as well as in the general population. Some reports have suggested that cardiovascular prognosis in extreme dippers (ED) is similar as in dippers, whereas other studies have documented either a better or worse prognosis in ED. Available information on clinical and prognostic implications of ED is scanty and data provided by studies are controversial. Furthermore, a comprehensive report summarizing the key features of this BP pattern is lacking. The present review focuses on a number of issues concerning ED pattern such as the prevalence and clinical correlates, mechanisms underlying this BP phenotype association with hypertension mediated organ damage (HMOD) and prognostic value in predicting cardiovascular events and all-cause mortality. The reported prevalence of this BP rhythm alteration ranges from 5% to 30%, depending on diagnostic criteria, clinical and demographic characteristics of subjects. Most studies targeting the association of this condition with HMOD failed to find consistent findings in support of an adverse impact of ED on vascular, renal of cardiac structure and function. Available data on ED as compared to low risk reference group (i.e. dippers) do not allow to conclude that high BP variability resulting from a marked BP fall at night adversely affects cardiovascular prognosis at the community level and in the general hypertensive population. Thus, further studies aimed to assess the prognostic significance of ED as well as the impact of therapeutic interventions aimed to normalize this circadian BP pattern, are highly needed.

Effects of isometric resistance training on resting blood pressure: individual participant data meta-analysis Background: Previous meta-analyses based on aggregate group-level data report antihypertensive effects of isometric resistance training (IRT). However, individual participant data meta-analyses provide more robust effect size estimates and permit examination of demographic and clinical variables on IRT effectiveness. Methods: We conducted a systematic search and individual participant data (IPD) analysis, using both a one-step and two-step approach, of controlled trials investigating at least 3 weeks of IRT on resting systolic, diastolic and mean arterial blood pressure. Results: Anonymized individual participant data were provided from 12 studies (14 intervention group comparisons) involving 326 participants (52.7% medicated for hypertension); 191 assigned to IRT and 135 controls, 25.2% of participants had diagnosed coronary artery disease. IRT intensity varied (8–30% MVC) and training duration ranged from 3 to 12 weeks. The IPD (one-step) meta-analysis showed a significant treatment effect for the exercise group participants experiencing a reduction in resting SBP of −6.22 mmHg (95% CI −7.75 to −4.68; P < 0.00001); DBP of −2.78 mmHg (95% CI −3.92 to −1.65; P = 0.002); and mean arterial blood pressure (MAP) of −4.12 mmHg (95% CI −5.39 to −2.85; P < 0.00001). The two-step approach yielded similar results for change in SBP −7.35 mmHg (−8.95 to −5.75; P < 0.00001), DBP MD −3.29 mmHg (95% CI −5.12 to −1.46; P = 0.0004) and MAP MD −4.63 mmHg (95% CI −6.18 to −3.09: P < 0.00001). Sub-analysis revealed that neither clinical, medication, nor demographic participant characteristics, or exercise program features, modified the IRT treatment effect. Conclusion: This individual patient analysis confirms a clinically meaningful and statistically significant effect of IRT on resting SBP, DBP and mean arterial blood pressure.

Effects of glucose-lowering on outcome incidence in diabetes mellitus and the modulating role of blood pressure and other clinical variables: overview, meta-analysis of randomized trials Background: Randomized controlled trials (RCTs) of antidiabetic agents started in the 1960s. Updated meta-analyses of RCTs investigating glucose-lowering in patients with type 2 diabetes mellitus are lacking. Also, no previous attempt was made to evaluate the role of blood pressure (BP) reduction and LDL cholesterol (LDL-C) change on outcome incidence following glucose-lowering. Objectives: Three main clinical questions were investigated: the extent of different outcome reductions by glucose-lowering in patients with diabetes, the proportionality of outcome reductions to glycated hemoglobin (HBA1c) reductions and whether ongoing BP and LDL-C difference in RCTs can change glucose-lowering outcome effects. Methods: PubMed between 1960 and January 2019 (any language), Cochrane Collaboration Library and previous overviews were used as data sources to identify and select all RCTs comparing the glucose-lowering drugs with placebo or less intense treatment (intentional glucose-lowering RCTs); comparing glucose-lowering drugs with placebo without glucose-lowering intention, but HBA1c difference (nonintentional glucose-lowering RCTs); enrolling type 2 diabetes mellitus patients; and reporting ongoing SBP and DBP difference. We excluded RCTs of acute care, glucose intolerance, type 1 diabetes, multiple interventions applied and glucose-lowering by lifestyle or other interventions. Risk ratios and 95% confidence intervals, of seven fatal and nonfatal outcomes and of treatment-related discontinuations were calculated (random-effects model) before and after adjustment for the ongoing BP difference, while LDL-C difference was also considered. The relationships of different outcome reductions to HBA1c reductions were investigated by meta-regressions. Results: A total of 25 RCTs (174 235 individuals, follow-up 3.5 years) were eligible, and the resulted ongoing SBP/DBP difference was −1.4/−0.4 mmHg. Both before and after adjustment for BP difference, glucose-lowering reduced CHD (coronary heart disease) and both composites of major cardiovascular events were reduced by a mean of 8 and 5%, respectively, while before BP-adjustment the risk of treatment-related discontinuations was increased by 26% and the risk of stroke and all-cause death was reduced by 7 and 6%, respectively. Logarithmic risk ratios were related to HBA1c reductions for the composite of CHD and stroke and for treatment-related discontinuations. Glucose-lowering had no differential outcome effects, before and after estimate adjustment for the ongoing BP difference, at different HBA1c thresholds and targets, as well as when both baseline BP and achieved BP, overall cardiovascular risk and diabetes mellitus duration were considered as dichotomous effect modifiers. Although heart failure incidence was found increased by 15% in the early glucose-lowering RCTs, this effect faded away in contemporary RCTs. LDL-C change was overall trivial and did not change glucose-lowering outcome effects. Conclusion: Meta-analyses of all glucose-lowering RCTs involving patients with diabetes provide precise estimates of benefits for CHD and major cardiovascular events after consideration of the resulting ongoing BP difference. No benefit or harm on mortality, heart failure and stroke were noticed, while discontinuations related to adverse events because of treatment were increased following glucose-lowering. The extent of glucose-lowering is proportionally related to changes of CHD and stroke composite, and treatment-related discontinuations.

Reviewing the effects of thiazide and thiazide-like diuretics as photosensitizing drugs on the risk of skin cancer Background: Thiazide diuretics and particularly hydrochlorothiazide were recently linked to an increased risk of skin cancer, which was attributed to the photosensitizing properties of these drugs. Given the widespread use of thiazide diuretics, a potential skin cancer promoting effect would impose an important public health concern. Objective: To critically appraise in a narrative review, the association between use of thiazide and thiazide-like diuretics and risk of skin cancer. Methods: We evaluated chemical structures and photosensitizing potential of selected thiazide and thiazide-like diuretics. Moreover, we searched PubMed up to December 2018 for observational studies assessing the association between use of thiazide or thiazide-like diuretics and risk of skin cancer. Study quality was assessed for major methodological biases. Results: Commonly used thiazide and thiazide-like diuretics carry resonating structural components, such as sulfonamide groups that contribute to their photosensitizing activity. Overall, 13 observational (9 case–control, 4 cohort) studies assessed the association between use of different thiazide or thiazide-like diuretics and risk of several skin cancer types. Of those, nine studies showed positive associations ranging from 3% increased risk for bendroflumethiazide and basal cell carcinoma to 311% increased risk for thiazide diuretics and squamous cell carcinoma. All studies had important design-related methodological limitations including potential confounding by indication, detection bias, and time-window bias. Conclusion: Commonly used thiazide and thiazide-like diuretics have photosensitizing potential, and some observational studies with important methodological limitations have linked their use to an increased risk of skin cancer. Well designed observational studies are needed to provide more solid evidence on this possible association.

The modulating effect of differences in cardiovascular risk factors on major cardiovascular outcomes in glucose-lowering trials: ‘good to know’ but not the whole story No abstract available

Diuretics and skin cancer: should a common prescription come with advice to avoid sun exposure? No abstract available

Improving intrarenal microcirculation prior to balloon angioplasty: new chances for the treatment of atherosclerotic renal artery stenosis? No abstract available

Association between invasively measured aortic pulse pressure and orthostatic hypotension in patients undergoing invasive coronary angiography Objective: Underlying pathophysiology of orthostatic hypotension has been poorly understood. We hypothesized that aortic pulse pressure (APP) reflecting aortic stiffness may be involved in the development of orthostatic hypotension. Methods: A total of 200 patients (age 64.3 ± 10.9 years, 62.5% men) who underwent invasive coronary angiography (ICA) were prospectively recruited. Orthostatic hypotension was defined as SBP drop at least 20 mmHg or DBP drop at least 10 mmHg within 3 min of the standing position compared with the supine position. Hemodynamic parameters were measured at the ascending aorta using a pig-tail catheter immediately before ICA. APP was calculated as a difference between the aortic peak systolic pressure and the end-diastolic pressure. Results: A total of 156 patients (78.0%) had obstructive coronary artery disease on ICA. Orthostatic hypotension was present in 58 patients (29.0%). Diabetes mellitus was more prevalent in patients with orthostatic hypotension than those without (48.3% vs. 23.2%; P < 0.001). Other clinical parameters including age, cardiovascular risk factors, laboratory findings and concomitant medications were not different between patients with and without orthostatic hypotension (P > 0.05 for each). In hemodynamic parameters, APP was higher in patients with orthostatic hypotension than those without (78.4 ± 25.8 vs. 68.3 ± 21.3 mmHg; P = 0.005). Higher APP was significantly associated with the presence of orthostatic hypotension even after controlling for potential confounders (odds ratio, 2.99; 95% confidence interval 1.15–7.78; P = 0.025). Conclusion: In patients undergoing ICA, APP was associated with increased risk of orthostatic hypotension. Central aortic stiffness may play a role in the development of orthostatic hypotension.

Ambulatory versus home blood pressure monitoring: frequency and determinants of blood pressure difference and diagnostic disagreement Objectives: Out-of-office blood pressure evaluation assessed using ambulatory (ABP) or home (HBP) monitoring is currently recommended for hypertension management. We evaluated the frequency and determinants of diagnostic disagreement between ABP and HBP measurements. Methods: Cross-sectional data from 1971 participants (mean age 53.8 ± 11.4 years, 52.6% men, 32% treated) from Greece, Finland and the United Kingdom were analyzed. The diagnostic disagreement between HBP and daytime ABP was regarded as certain when (i) the two methods diagnosed a different blood pressure phenotype, (ii) the absolute HBP–ABP difference was more than 10/5 mmHg (systolic/diastolic) and (iii) ABP and HBP had a more than 5 mmHg difference from the respective hypertension threshold. Results: In 1574 participants (79.9%), there was agreement between HBP and ABP in diagnosing hypertensive phenotypes (kappa 0.70). Of the remaining 397 participants (20.1%) with diagnostic disagreement, 95 had clinically irrelevant HBP–ABP differences, which reduced the disagreement to 15.3%. When cases with ABP and/or HBP differing ≤5 mmHg from the respective hypertension threshold were excluded, the certain disagreement between the two methods was reduced to 8.2%. Significant determinants of the HBP–ABP difference were age, sex, study center, BMI, cardiovascular disease history, office hypertension and antihypertensive treatment. Antihypertensive drug treatment, alcohol consumption and office normotension independently increased the odds of diagnostic disagreement. Conclusion: These data suggest that there is considerable diagnostic agreement between HBP and ABP, and that these methods are interchangeable for clinical decisions in most patients. However, considerable disagreement between the two methods occurs in an appreciable minority, most likely due to methodological and patient-related factors.