Revisiting Cardiovascular Benefits of Blood Pressure Reduction in Primary and Secondary Prevention: Focus on Targets and Residual Risk-A Systematic Review and Meta-Analysis.

BACKGROUND: Previous meta-analyses resurrected the debated statement "the lower, the better" following blood pressure (BP)-lowering treatment. We investigated the benefits of BP-lowering treatment at different BP targets by prevention category. METHODS: The meta-analysis protocol was registered at the International Prospective Register of Systematic Reviews (CRD42022379249). The database included 115 BP-lowering or comparison trials from patients with (n=241 089) or without (n=198 937) previous cardiovascular events. Prevention disease groups were stratified by in-treatment achieved BP, drug class versus placebo, and drug class versus other classes. Risk ratios and 95% CIs of major adverse cardiovascular events were calculated. RESULTS: Following a standard (10/5 mm Hg) BP reduction, major adverse cardiovascular event relative risk reductions were not different between prevention groups (primary, 25% [95% CI, 18%-31%]; secondary, 28% [95% CI, 20%-37%]). For achieved systolic BP of at least 140 mm Hg, between 130 and 140 mm Hg, and <130 mm Hg (nadir, 125 mm Hg), (1) risk ratios of major adverse cardiovascular events and absolute risk reductions were not different between prevention groups across systolic BP strata, and (2) residual risk, though 4.1× greater in secondary than primary prevention, decreased in primary prevention from higher to lower systolic BP targets. The effect of separate drugs versus others on the primary outcome was not different between prevention groups. CONCLUSIONS: BP-lowering treatment benefits did not differ by prevention group to a nadir of 125 mm Hg for systolic BP. Although residual risk in secondary prevention is higher than in primary prevention, it gradually decreases at progressively lower systolic BP targets in primary prevention. REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42022379249.

DASH vs. Mediterranean diet on a salt restriction background in adults with high normal blood pressure or grade 1 hypertension: A randomized controlled trial.

BACKGROUND & AIMS: Non-pharmacological measures are recommended as the first-line treatment for individuals with high-normal blood pressure (BP) or mild hypertension. Studies directly comparing the BP effects of the Dietary Approaches to Stop Hypertension (DASH) vs. the Mediterranean diet (MedDiet) on a salt restriction background are currently lacking. Thus, our purpose was to assess the BP effects of a 3-month intensive dietary intervention implementing salt restriction either alone or in the context of the DASH, and the MedDiet compared to no/minimal intervention in adults with high normal BP or grade 1 hypertension. METHODS: We randomly assigned never drug-treated individuals to a control group (CG, n = 60), a salt restriction group (SRG, n = 60), a DASH diet with salt restriction group (DDG, n = 60), or a MedDiet with salt restriction group (MDG, n = 60). The primary outcome was the attained office systolic BP difference among the randomized arms during follow-up. RESULTS: A total of 240 patients were enrolled, while 204 (85%) completed the study. According to the intention-to-treat analysis, compared to the CG, office and 24 h ambulatory systolic and diastolic BP were reduced in all intervention groups. A greater reduction in the mean office systolic BP was observed in the MDG compared to all other study groups (MDG vs. CG: mean difference = -15.1 mmHg; MDG vs. SRG: mean difference = -7.5 mmHg, and MDG vs. DDG: mean difference = -3.2 mmHg, all P-values <0.001). The DDG and the MDG did not differ concerning the office diastolic BP and the 24 h ambulatory systolic and diastolic BP; however, both diets were more efficient in BP-lowering compared to the SRG. CONCLUSIONS: On a background of salt restriction, the MedDiet was superior in office systolic BP-lowering, but the DASH and MedDiet reduced BP to an extent higher than salt restriction alone.

The effect of SGLT2 inhibitors on the endothelium and the microcirculation: from bench to bedside and beyond.

AIMS: The beneficial cardiovascular effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors irrespective of the presence of diabetes mellitus are nowadays well established and they already constitute a significant pillar for the management of heart failure, irrespective of the ejection fraction. The exact underlying mechanisms accountable for these effects, however, remain largely unknown. The direct effect on endothelial function and microcirculation is one of the most well studied. The broad range of studies presented in this review aims to link all available data from the bench to bedside and highlight the existing gaps as well as the future directions in the investigations concerning the effects of SGLT2 inhibitors on the endothelium and the microcirculation. METHODS AND RESULTS: An extensive search has been conducted using the MEDLINE/PubMed database in order to identify the relevant studies. Preclinical data suggest that SGLT2 inhibitors directly affect endothelial function independently of glucose and specifically via several interplaying molecular pathways, resulting in improved vasodilation, increased NO production, enhanced mitochondrial homeostasis, endothelial cell viability, and angiogenesis as well as attenuation of oxidative stress and inflammation. Clinical data systematically confirm this beneficial effect on the endothelium, whereas the evidence concerning the effect on the microcirculation is conflicting. CONCLUSION: Preclinical and clinical studies indicate that SGLT2 inhibitors attenuate endothelial and microvascular dysfunction via a combination of mechanisms, which play a role in their beneficial cardiovascular effect.

Rationale and Design of a Randomized Controlled Clinical Trial on the Safety and Efficacy of Flecainide versus Amiodarone in the Cardioversion of Atrial Fibrillation at the Emergency Department in Patients with Coronary Artery Disease (FLECA-ED).

Pharmacologic cardioversion is a well-established alternative to electric cardioversion for hemodynamically stable patients, as it skips the risks associated with anesthesia. A recent network meta-analysis identifies the most effective antiarrhythmics for pharmacologic cardioversion with flecainide exhibiting a more efficacious and safer profile towards faster cardioversion. Moreover, the meta-analysis of class Ic antiarrhythmics revealed an absence of adverse events when used for pharmacologic cardioversion of AF in the ED, including patients with structural heart disease. The primary goals of this clinical trial are to prove the superiority of flecainide over amiodarone in the successful cardioversion of paroxysmal atrial fibrillation in the Emergency Department and to prove that the safety of flecainide is non-inferior to amiodarone in patients with coronary artery disease without residual ischemia, and an ejection fraction over 35%. The secondary goals of this study are to prove the superiority of flecainide over amiodarone in the reduction in hospitalizations from the Emergency Department due to atrial fibrillation in the time taken to achieve cardioversion, and in the reduction in the need to conduct electrical cardioversion.

Sex-related cardiovascular prognosis in patients with hypertensive emergencies: a 12-month study.

Current evidence on the prognosis of patients with a hypertensive crisis and predisposing factors is limited. We registered the clinical phenotype of patients with HC admitted to the emergency department, while those with a hypertensive emergency (HE) were hospitalized. One-year outcomes, i.e., composite of death or cardiovascular hospitalizations, were determined in patients with HE after hospital discharge. Out of 38,589 patients assessed in the emergency department, 256 hypertensive urgencies and 97 HE was registered. After stratification of the HE by sex, 48 men and 46 women completed the one-year follow-up. Men had more events than women (27 vs. 13, Ηazard Ratio 2.2, 95% Confidence Interval 1.03-4.7, p = 0.042) after adjustment for age, cardiovascular or chronic kidney disease, and diabetes mellitus. Our study raises the hypothesis that the male sex is an independent risk factor for cardiovascular outcomes in HE patients. CV Cardiovascular, BP blood pressure. The diagram presents the groups of comparison, men versus women in hypertensive emergencies that completed the 1-year follow-up for outcomes, in terms of hospitalizations or deaths.

Fatty liver index and cardiovascular outcomes in never-treated hypertensive patients: a prospective cohort.

The prevalence of nonalcoholic fatty liver disease (NAFLD) has been increasing rapidly worldwide, affecting 25-30% of the population. Fatty liver index (FLI) is a validated marker of NAFLD and can be used as a screening tool for hepatic steatosis. The purpose of the study was to evaluate the relationship between FLI and the risk of major cardiovascular events in never treated hypertensive patients. We included 903 hypertensive patients without a history of cardiovascular disease (mean age 52.7 ± 11.4 years; men 55%; baseline clinic BP 149.8 ± 15.2/95.5 ± 10.1 mmHg). Participants were prospectively evaluated for a mean follow-up period of 5.2 ± 3.2 years with at least one annual visit. Patients were also categorized into two groups using an FLI of 60 units. The incidence of cardiovascular events during follow-up was 8.5% (n = 77). Patients with FLI < 60 (n = 625) had a better BP control compared to their counterparts with FLI ≥ 60 (n = 278) during follow up (43% vs 33%, p = 0.02). Cox-regression analysis indicated that FLI (Hazard Ratio [HR], 1.05; 95% Confidence Interval [CI], 1.03-1.07, p < 0.001), FLI z-scores (HR, 3.66; 95% CI, 2.22-6.04) and high-risk FLI (HR, 7.5; 95% CI, 3.12-18.04) were independent determinants of the outcome after adjustment for baseline and follow-up variables. Stratification by diabetes mellitus indicated that FLI predicted the outcome to a greater extent in those with than those without diabetes (P-interaction < 0.001). In conclusion, FLI has an independent prognostic value for the incidence of cardiovascular events in newly diagnosed, never-treated hypertensive patients. Therefore, FLI might identify higher-risk patients in the primary prevention of hypertension.

Blood pressure control measures and cardiovascular outcomes: a prospective hypertensive cohort.

PURPOSE: We investigated whether blood pressure (BP) control measures, visit-to-visit BP variability, and time in therapeutic range (TTR) are associated with future cardiovascular outcomes in hypertensive patients. MATERIALS AND METHODS: Among 1,408 hypertensive patients without cardiovascular disease, we prospectively evaluated the incident major cardiovascular events over 6 years. In newly diagnosed patients, antihypertensive drug treatment was initiated. We estimated two markers of on-treatment BP control, (1) visit-to-visit BPV as the coefficient of variation of office systolic BP (BP-CV), and (2) TTR calculated as the percentage of office systolic BP measurements within 120-140mmHg across visits. RESULTS: The hypertensive cohort (672 males, mean age 60 years, 31% newly diagnosed) had a mean systolic/diastolic BP of 142/87 mmHg. The mean number of visits was 4.9 ± 2.6, while the mean attained systolic/diastolic BP during follow-up was 137/79 mmHg using 2.7 ± 1.1 antihypertensive drugs. The BP-CV and TTR were 9.1 ± 4.1% and 45 ± 29%, respectively, and the incidence of the composite outcome was 8.3% (n = 117). After adjustment for relevant confounders and standardization to z-scores, BP-CV and TTR were associated with a 43% (95% CI, 27-62%) increase and a 33% (95% CI, 15-47%) reduction in the outcome. However, the joint evaluation of TTR and BP-CV in a common multivariable model indicated that a standardized change of TTR was associated with the outcome to a greater extent than BP-CV (mean hazard ratios of 30% vs. 24%, respectively). When combined with the higher BP standardized-CV quartile, the lower TTR quartile predicted the outcome by 2.3 times (95% CI, 1.1-5.4) compared to the inverse TTR and BP-CV quartile pattern. CONCLUSION: High BP-CV or low TTR was associated with future cardiovascular events in a cohort of treated hypertensive patients. As a determinant, the extent of TTR value appears greater than BP-CV when these measures are considered in the same multivariable model.

Common surgical masks and unattended blood pressure changes in treated hypertensive patients.

Although the effect of face masks on preventing airborne transmission of SARS-CoV-2 is well studied, no study has evaluated their effect on blood pressure (BP). Therefore, we investigated the effect of surgical masks on BP in 265 treated hypertensive patients. Following the routine mask-on office BP measurement, patients were left alone and randomized to automated office BP measurement, with measurements taken after first wearing a mask for 10 min, then without wearing the mask for 10 min, and vice versa. Among the participants, 115 were women (43.4%), the mean age was 62 ± 12 years, and the mean office BP was 134 ± 15/81 ± 12 mmHg. There was no significant difference between mask-on unattended systolic BP (133 ± 15 mmHg) and mask-off unattended systolic BP (132 ± 15 mmHg) (P = 0.13) or between mask-on unattended diastolic BP (77 ± 13 mmHg) and mask-off unattended diastolic BP (76 ± 13 mmHg) (P = 0.32). Surgical masks had no effect on BP in treated hypertensive patients.

Overview of salt restriction in the Dietary Approaches to Stop Hypertension (DASH) and the Mediterranean diet for blood pressure reduction.

Despite considerable advances in pharmacological treatments, hypertension remains a major cause of premature morbidity and mortality worldwide since elevated blood pressure (BP) adversely influences cardiovascular and renal outcomes. Accordingly, the current hypertension guidelines recommend the adoption of dietary modifications in all subjects with suboptimal BP levels. These modifications include salt intake reduction and a healthy diet, such as the Dietary Approaches to Stop Hypertension (DASH) diet or the Mediterranean diet (MedDiet), independently of the underlying antihypertensive drug treatment. However, dietary modifications for BP reduction in adults with prehypertension or hypertension are usually examined as stand-alone interventions and, to a lesser extent, in combination with other dietary changes. The purpose of the present review was to summarize the evidence regarding the BP effect of salt restriction in the context of the DASH diet and the MedDiet. We also summarize the literature regarding the effects of these dietary modifications when they are applied as the only intervention for BP reduction in adults with and without hypertension and the potent physiological mechanisms underlying their beneficial effects on BP levels. Available data of randomized controlled trials (RCTs) provided evidence about the significant BP-lowering effect of each one of these dietary strategies, especially among subjects with hypertension since they modulate various physiological mechanisms controlling BP. Salt reduction by 2.3 g per day in the DASH diet produces less than half of the effect on systolic blood pressure (SBP)/diastolic blood pressure (DBP) (-3.0/-1.6 mmHg) as it does without the DASH diet (-6.7/-3.5 mmHg). Although their combined effect is not fully additive, low sodium intake and the DASH diet produce higher SBP/DBP reduction (-8.9/-4.5 mmHg) than each of these dietary regimens alone. It is yet unsettled whether this finding is also true for salt reduction in the MedDiet.

Renal outcomes associated with glucose-lowering agents: Systematic review and meta-analysis of randomized outcome trials.

Although the clinical questions of the recent glucose-lowering trials are principally oriented towards preventing macrovascular events, an updated review regarding renal outcome prevention is lacking. We assessed the impact of different antihyperglycemic classes on kidney damage progression. A systematic review and meta-analysis was performed by searching PubMed, Cochrane Collaboration Library, Medline, and previous overviews through June 2021 (any language) for earlier and contemporary glucose-lowering trials, including patients with, but not limited to, type 2 diabetes mellitus vs. placebo or less intense treatment. Incidences of kidney function worsening and macroalbuminuria development was extracted, and risk ratios and 95% confidence intervals (CI) under the random-effects model were calculated. The association between outcome reductions and glycohemoglobin (HBA1c) reductions was investigated through the meta-regression analyses. Among 27 eligible trials (n = 198,532 patients) an averaged HBA1c reduction of 0.6 ± 0.3% was followed by a reduction of 17% (95% CI, 8-25%) in worsening of kidney function, and of 25% (95% CI, 19-32%) in macroalbuminuria. Analog of human glucagon-like peptide 1 (GLP1)-agonists, and sodium-glucose cotransporter (SGLT2)-inhibitors, considered separately, compared with placebo, were associated with a significant reduction of both renal outcomes, at variance with dipeptidyl peptidase 4 (DPP4)-inhibitors, where no outcome change was observed. Logarithmic risk ratios of macroalbuminuria were related to HBA1c reductions, in contrast to the worsening of kidney function related to systolic blood pressure reduction. Worsening of kidney function and macroalbuminuria development were reduced following glucose-lowering. GLP1 agonists and SGLPT2 inhibitors were associated with protection against both outcomes, while DPP4 inhibitors do not provide renal protection.

Left ventricular mass versus pulse wave velocity as predictors of coronary artery disease in hypertensive patients: data from a 6-year-follow-up study.

In treated hypertensive patients, there is a substantial residual cardiovascular (CV) risk that cannot be assessed by the available prediction models. This risk can be associated with subclinical organ damage, such as increased left ventricular mass (LVM) and arterial stiffness. However, it remains unknown which of these two CV markers better predicts coronary artery disease (CAD). A prospective cohort study was used to answer the above question. The study sample consisted of 1033 patients with hypertension (mean age 55.6 years, 538 males) free of CAD at baseline, who were followed for a mean period of 6 years. At baseline, all subjects underwent a complete echocardiographic study and pulse wave velocity (PWV) measurement. Hypertensive individuals who developed CAD (2.8%) compared to those without CAD at follow-up, had a higher baseline LVM index (by 16.7 g/m2, p < 0.001), higher prevalence of left ventricular hypertrophy (LVH) (21% greater, p = 0.027) and greater prevalence of high PWV levels at baseline (21% greater, p = 0.019). Multivariate Cox regression analysis revealed that baseline age >65 years (HR = 2.067, p = 0.001), male gender (HR = 3.664, p = 0.001), baseline chronic kidney disease (HR = 2.020, p = 0.026), baseline diabetes mellitus (HR = 1.952, p = 0.015) and baseline LVH (HR = 2.124 p = 0.001) turned out to be independent predictors of CAD, whereas high PWV levels were not. LVH proved to be an independent prognosticator of CAD in contrast to arterial stiffness that was not related to CAD after accounting for established confounders. Therefore, LVM can reliably help physicians to identify high-risk hypertensives in whom an intensified therapeutic management is warranted.

Net clinical benefit of direct oral anticoagulants in atrial fibrillation patients with or without diabetes mellitus: A meta-analysis of outcome trials.

AIM: To evaluate the net clinical benefit following direct oral anticoagulants (DOACs) vs warfarin by diabetes status in patients with non-valvular atrial fibrillation. METHODS: We searched 3 electronic databases through end-February 2021 to identify relevant outcome trials in patients with and without diabetes mellitus (DM). All-cause death, non-fatal stroke/systemic embolism and major bleedings defined net clinical benefit. Outcome risk ratios and 95% confidence interval (CI), and absolute risk outcome reduction per 1000 treated patients were assessed. RESULTS: Four trials of DOACs vs warfarin compared 22,087 patients with DM to 49,592 patients without DM. CHADS2 and 10-year fatal cardiovascular risk were higher in patients with vs those without DM (3.7 vs 2.5 and 28.4% vs 23.4%, respectively). DOACs were associated with more favorable net clinical benefit compared to warfarin in patients with and without DM (relative risk reduction, 0.85 [95% CI, 0.81-0.89] and 0.87 [95% CI, 0.79-0.96]; absolute risk reduction per 1000 patients treated, -33 [95% CI, -45, -21]) and -24 [95% CI, -43, -5]), but interaction test was not significant by relative and absolute numbers (P = 0.68 and P = 0.44, respectively). CONCLUSION: Net clinical benefit following DOACs was not different between patients with and without DM over a period of 2.2 years.

Simultaneous Diagnosis of Emphysematous Osteomyelitis and Emphysematous Pyelonephritis in a Diabetic Patient.

BACKGROUND Emphysematous osteomyelitis of the spine is characterized by intravertebral or intraosseous air. Emphysematous pyelonephritis (EP) is the infection of the renal parenchyma and perirenal tissues caused by gas forming microorganisms and thus is characterized by gas formation. Prompt diagnosis and initiation of necessary treatment is crucial, as both entities are associated with high mortality rates. CASE REPORT A 57-year-old female with uncontrolled hyperglycemia presented to the emergency department with history of sudden onset of weakness, nausea, vomiting and diarrhea for 3 days and with a fall on the same level the previous day. Laboratory examinations revealed leukocytosis, lymphopenia, thrombocytopenia, deteriorated renal function, and hyperglycemic hyperosmolar non-ketotic state. She was placed on aggressive intravenous hydration and insulin infusion pump. Due to the deterioration of her medical condition, she underwent abdominal and pelvic CT scanning that revealed emphysematous osteomyelitis of the spine and emphysematous pyelonephritis. Despite vigorous fluid resuscitation and systemic broad-spectrum antibiotic therapy, the patient's condition deteriorated further and eventually led to death within 48 h. CONCLUSIONS This case of fatal emphysematous osteomyelitis of the spine and EP serves as a significant reminder of those rare life-threatening entities, which affect patients with comorbidities, such as diabetes mellitus and other etiologies causing immunosuppression. The aim of the present case report is to highlight the importance and contribution of computed tomography in diagnosing these conditions and to emphasize the rare coexistence of these 2 emphysematous entities.