Antihypertensive Research Articles

Antihypertensive treatment during pregnancy and maternal and fetal outcomes

Abstract Introduction Arterial hypertension affects about 5-10% of pregnancies and has detrimental effects on pregnancy outcomes in both the mother and fetus. The study aimed to analyse the outcomes of pregnancy in women treated for arterial hypertension in pregnancy in the Czech Republic. Methodology Nationwide data on all births and abortions in the period 2012-2022 in the Czech Republic were obtained from the National Registry of Reproductive Health (NRRZ) and the National Registry of Reimbursable Health Services (NRHZS). Women who had the diagnosis I10 within one year before pregnancy and were prescribed any antihypertensive drug from selected ATC groups (C02, C03, C07, C08, C09) were classified as pre-existing hypertension. Women diagnosed with O13 or I10 during pregnancy were classified as pregnancy induced hypertension. Hypoxia in the new-born was defined as pH <7.1 or Apgar score <8 present after delivery. For all factors, univariate logistic regression was used to calculate the odds ratios (OR) of adverse outcomes. Results There were total of 1,154,648 deliveries in the 11-year period. 95,215 women had hypertension in pregnancy, out of these 21,094 (22.2%) were treated with antihypertensive drugs. Odds ratios for caesarean section, pre-term delivery, low birth weight, new-born hypoxia and pre-eclampsia in women using different antihypertensive classes and drugs are shown in the Table. Risk of maternal and fetal complications was found to be higher with calcium channel blockers (mainly amlodipine) compared to methyldopa and beta blockers. Among beta blockers, bisoprolol had the most favourable safety profile. Although used in limited numbers, diuretics, verapamil, ACE-inhibitors and angiotensin receptor blockers (ARBs) appeared to be comparably safe to methyldopa. Combination of multiple antihypertensive drugs was associated with higher risk of adverse outcomes. Conclusion Bisoprolol, verapamil and diuretics seem to have the risk of adverse maternal and fetal outcomes comparable to methyldopa. Amlodipine and multiple antihypertensive drug combinations are associated with increased risk.Table

Blood pressure polygenic risk scores associate with resistant hypertension in individuals with type 1 diabetes

Abstract Background Hypertension is a major risk factor of global disease burden, but treatment goals are often not met. A subset of individuals with hypertension is affected by treatment-resistant hypertension (RHTN), and they suffer from increased cardiovascular morbidity and mortality. Early identification of individuals at risk of RHTN could lead to more efficient antihypertensive drug treatment. Purpose The aim of this study was to investigate whether polygenic risk scores (PRS) for systolic (SBP) and diastolic blood pressure (DBP) predict RHTN in individuals with or without type 1 diabetes (T1D). Methods We performed association analyses between PRSs and RHTN in two Finnish cohorts: The Finnish Diabetic Nephropathy Study (FinnDiane) and the Finnish individuals of the LIFE Study (LIFE-Fin). FinnDiane is an ongoing, observational nationwide study aiming to identify genetic and clinical risk factors for complications of T1D. We included data from 778 adults (476 with RHTN and 302 with controlled hypertension). LIFE is a randomized, double-blind study evaluating long-term effects of losartan compared with atenolol in patients with signs of left ventricular hypertrophy. We used SBP and DBP data from 378 Finnish individuals (173 with RHTN and 205 with controlled hypertension) at the four-year visit of the study. In FinnDiane, RHTN was defined as SBP ≥130 or DBP ≥85 mmHg and the use of three or more antihypertensive drugs, or SBP <130 and DBP <85 mmHg and the use of four or more antihypertensive drugs. In LIFE-Fin, RHTN was defined as SBP ≥140 or DBP ≥90 mmHg and the use of three or more antihypertensive drugs. Controlled hypertension was defined as the use of three or fewer antihypertensive drugs and SBP <130 and DBP <85 mmHg in FinnDiane, and as SBP <140 and DBP <90 mmHg in LIFE-Fin. We calculated a PRS for each participant using genome-wide association study data for 1,098,015 genetic variants; the variant-specific data were derived from UK Biobank based PRS-CS-method computed PRSs (1). Results We observed significant associations of SBP and DBP PRSs with RHTN in FinnDiane (OR 1.56 [1.30; 1.87], P = 1.8e-6, and OR 1.25 [1.04; 1.50], P = 0.02, per one-SD increase of the PRS value) when adjusted for age, sex, estimated glomerular filtration rate and body mass index. The association between SBP PRS and RHTN remained significant when T1D individuals with or without albuminuria were analysed separately. Neither SBP nor DBP PRSs were significantly associated with RHTN in LIFE-Fin. Conclusion Higher SBP PRSs associate with higher risk of RHTN in individuals with T1D, with or without albuminuria, but not in nondiabetic individuals with hypertension. It remains to be investigated whether general blood pressure genetics contribute to RHTN in the general population.

Impact of changes in left heart geometry on predicting new-onset atrial fibrillation in patients with hypertension

Abstract Background Hypertension-induced left ventricular hypertrophy (LVH) increases end-diastolic LV pressure and contributes to left atrial enlargement (LAE), which are associated with development of atrial fibrillation (AF). However, the impact of LVH and LAE and their regression following antihypertensive therapy on AF incidence remains unclear. Purpose This study aimed to investigate the impact of changes in the LVH and LAE status on the occurrence of new-onset AF (NOAF). Methods This retrospective analysis included patients with sinus rhythm who underwent echocardiography at hypertension diagnosis and after 6–18 months. LVH was defined as LV mass index >115 g/m2 (men) and >95 g/m2 (women), and LAE was defined as LA volume index >42 ml/m2. LVH and LAE regression was defined as the absence of LVH and LAE on follow-up echocardiography, respectively. The occurrence of NOAF was assessed in relation to changes in LVH and LAE status. Results Among the 1,464 patients included in the study, 163 (11.1%) patients developed NOAF during a median follow-up of 63.8 months (interquartile range, 35.9–128.5 months). On average, 12 electrocardiograms per patient were reviewed for AF detection. New-onset LVH (adjusted HR 1.88, 95% CI 1.20–2.94, P=0.006) and LAE (adjusted HR 1.89, 95% CI 1.05–3.40, P=0.034) were significant predictors of NOAF. Conversely, regression of LVH (adjusted HR 0.51, 95% CI 0.280.91, P=0.022) or LAE (adjusted HR: 0.30, 95% CI 0.15–0.63, P=0.001) after antihypertensive therapy was associated with a reduced risk of NOAF. The risk of NOAF was higher in patients with LVH and LAE together (adjusted HR 4.30, 95% CI 2.81–6.56, P<0.001) than in those with either LVH or LAE, or those with neither, as determined by follow-up echocardiography. Conclusion In patients with hypertension and sinus rhythm, regression of LVH and LAE following antihypertensive therapy is associated with a decreased incidence of NOAF, whereas newly developed LVH or LAE is associated with a higher risk of NOAF. The changes in left heart geometry can serve as a predictive marker for NOAF in patients with hypertension.

Nighttime blood pressure reductions after radiofrequency renal denervation through 24 months in patients with uncontrolled hypertension: pooled analysis from the SPYRAL HTN trials

Abstract Introduction Studies have shown that elevated nighttime and early morning systolic blood pressure (SBP) are associated with the highest risk for cardiovascular (CV) events. Radiofrequency renal denervation (RF RDN) is an interventional therapy to reduce BP in patients with uncontrolled hypertension (HTN). Although sustained, durable reductions in office and 24-h ambulatory systolic BP (SBP) after RDN have been observed, whether the therapy produces similar, durable nighttime and early morning SBP reductions requires further evaluation. Objective To assess whether RF RDN significantly reduces nighttime SBP through long-term follow-up, in addition to other times of the day. Methods We pooled data from patients with uncontrolled HTN undergoing RF RDN using the latest-generation Symplicity SpyralTM multi-electrode catheter from the published SPYRAL HTN-OFF and -ON MED clinical trials. Office and 24-h ambulatory SBP were evaluated from baseline through 24 months. We also assessed BP changes during specific, diurnal time ranges including nighttime (1am-6am), early morning (7am-9am), and daytime (9am-9pm). The number of antihypertensive drugs and drug burden (determined by number of classes and prescribed dosage) from urine and plasma drug testing were tabulated from baseline through 24 months. Results Outcomes from 388 patients undergoing RF RDN were pooled for this analysis. Patients were on average 54±10yrs old, 26.8% female, mean BMI was 31.3±6.0, 45.1% with >10yrs diagnosis of hypertension, 7.7% with type 2 diabetes, 9.8% with obstructive sleep apnea, 47.7% with a history of smoking. The baseline nighttime SBP was 139±11mmHg, morning SBP was 154±15mmHg, and daytime SBP was 156±9mmHg. At baseline, 92.5% of patients had nocturnal hypertension (BP ≥120/70 mmHg) and took 1.0±1.2 antihypertensive drugs. 12 months after RF RDN, 30.6% of patients no longer had nocturnal hypertension (p<0.0001). The mean nighttime SBP change at 12 months was -10.8±15.4mmHg, morning changed was -12.8±20.4mmHg, and daytime changed was -12.2±13.6mmHg (Figure). The mean 24-h ambulatory SBP change at 12 months was -11.9±12.4mmHg, and the office SBP change was -17.7±15.4mmHg . Patients took 1.8±1.1 antihypertensive drugs at 12 months. Results from 24 months, not currently available, will also be presented for the first time. Conclusions In this pooled cohort of RDN patients with uncontrolled hypertension, nocturnal hypertension was highly prevalent. Clinically meaningful reductions at 12 months throughout the 24-hr circadian cycle, including at nighttime and early morning SBP, are consistent with the "always on" effect of RDN. Results from 24 months will also be presented for the first time at ESC. As an adjunctive therapy to pharmacotherapy, RDN may help to reduce CV risk by lowering nighttime and morning SBP.

Control of arterial hypertension in the context of metabolically-associated disease: challenges and opportunities in Ukraine

Abstract Background/Introduction Arterial hypertension is a prevalent, but modifiable cardiovascular (CV) risk factor. Effective control of blood pressure (BP) is associated with decreased rates of CV morbidity and mortality, as was convincingly demonstrated in randomized clinical trials. There is a substantial gap between BP control in clinical trials and real clinical practice due to multiple factors – e.g. lack of awareness, low medication compliance, side effects of medications, and insufficient availability of medical care – to name the few. The association between poor BP control and metabolically associated disease (MAD) like diabetes and obesity is widely acknowledged and considered the key challenge in effective management of arterial hypertension. Purpose To determine patterns of awareness and control of arterial hypertension in the context of MAD in Ukrainian outpatient patient sample. Methods We enrolled 309 subjects (108 with MAD and 201 without MAD). MAD was defined as the presence of type 2 diabetes and/or overweight/obesity. All subjects were consented for the structured interview and triple sitting BP measurement with an automated device. Results MAD-positive and MAD-negative groups were comparable by age (54.4±1.34 vs 51.8±1.2 years, p=0.29), systolic BP (141.3±2.0 vs 137.4±1.6 mm Hg, p=0.082), diastolic BP (85.2±1.2 vs 82.5±0.9 mm Hg, p=0.13). Presence of MAD was associated with increased odds of having BP>139/89 mm Hg (odds ratio [OR] 1.66, 95% confidence interval [CI] 1.04-2.67, p=0.035), better awareness on hypertension (OR 2.65, CI 1.64-4.28, p=0.0001), and less prevalent normotension (OR 0.51, CI 0.31-0.84, p=0.008). Among MAD-positive patients without history of HTN, 50% actually had elevated office BP, although it did not reach statistical significance as compared to MAD-negative subjects (OR 1.32 CI 0.68-2.56, p=0.42, see Picture 1). Less MAD-positive patients did not take any antihypertensive drugs (37.0% vs 56.7%, difference -19.7%, CI -8.03 to -30.51%, p=0.001), and more of them were taking 3 antihypertensive drugs (17.6% vs 7.5%, difference 10.1% CI 2.58-18.85. p=0.007). Only 53.7% of MAD-positive subjects and 39.8% of MAD-negative subjects claimed they were taking BP-lowering medications on a regular basis (p=0.02). There was no difference in achievement of BP control between MAD-positive and MAD-negative groups (39.2 vs 38.7% for subjects who were aware of HTN, 31.9 vs 31.3% of all hypertensive individuals, p=NS for both). More MAD-positive than MAD-negative subjects admitted they consume alcohol several times per week or daily (22.2 vs 12.4%, p=0.025). Conclusions MAD disease is associated with more prevalent HTN and better awareness on elevated BP. MAD requires more intensive BP-lowering therapy to achieve target BP, but the compliance to medications is suboptimal.Patterns of awareness and BP control

Comparison of the predicting value for incident cardiovascular events by vascular age based on brachial-ankle pulse wave velocity or carotid-femoral pulse wave velocity

Abstract Background There is a good correlation between brachial-ankle pulse wave velocity（baPWV）and carotid-femoral pulse wave velocity (cfPWV). Whether baPWV has the same predictability for cardiovascular risk as cfPWV in calculating vascular age remains to be clarified. Purpose This study examines which vascular age calculated by baPWV or cfPWV has a stronger association with the risk of cardiovascular events. Methods This prospective cohort study included 5725 participants from a community atherosclerosis cohort in Beijing, China. Vascular age was the predicted age in a multivariable regression model, including classical cardiovascular risk factors (sex, systolic and diastolic blood pressure, glycemia, triglyceride, low density lipoprotein cholesterol, waist, body mass index, heart rate, smoking) and treatment (anti-hypertensive agents, hypoglycemic agents, lipid-lowering agents) and pulse wave velocity. Residuals between chronological age and vascular age were defined as ∆-age, and the 10th and 90th percentiles of ∆-age were used as cutoffs to define supernormal vascular aging, normal vascular aging, and early vascular aging, respectively. The major adverse cardiovascular event was a composite of myocardial infarction, stroke, and cardiovascular death. The study used Cox proportional hazards regression to examine the association between vascular age and major adverse cardiovascular events. Results During the median 3-year follow-up period, 172 endpoint events were observed. After adjusting for age and sex, ∆-age as a continuous variable calculated by baPWV was significantly and increasingly associated with cardiovascular events (every 1-year increase led to a rise of 1.04% [95% confidence interval [CI]: 1.00%-1.08%; p=0.03] in cardiovascular events risk). After adjusting for age, sex, smoking, body mass index, hypertension, diabetes, dyslipidemia, anti-hypertensive agents, lipid-lowering agents, hypoglycemic agents, family history of atherosclerotic cardiovascular disease, and estimated glomerular filtration rate, early vascular aging group calculated by baPWV had an increased risk of cardiovascular events (hazard ratio: 1.76; 95% CI: 1.19-2.62 p=0.005), compared with the normal vascular aging group. In contrast, no significant results were observed in vascular age calculated by cfPWV. Conclusion(s) Vascular age calculated by baPWV has a stronger predictive ability for cardiovascular events than that calculated by cfPWV in the Chinese population. Considering baPWV is a simple and convenient method, it is recommended for vascular age calculation.

Serum from Hypertensive Patients Induces Cancer-Supporting Phenotype of Vascular Endothelium In Vitro

Background/Objectives: Large-scale epidemiological studies have established a bidirectional association between hypertension and cancer. However, the underlying mechanisms explaining this connection remain unclear. In our study, we investigated whether serum from patients with hypertension (HT) could enhance the aggressiveness of cancer cells in vitro through alterations in endothelial cell phenotype. Methods: Experiments were performed using EAhy926 endothelial cells and ovarian (SKOV-3), colorectal (SW480), pancreatic (PSN-1), breast (MCF-7), and lung (A549) cancer cell lines. Results: This study showed that conditioned medium (CM) produced by EAhy926 cells, when exposed to serum from patients with untreated hypertension (HT-CM), promotes the proliferation, migration, and invasion of every cancer cell line tested. In addition, endothelial cells subjected to HT serum promote the adhesion of all cancer cell types except PSN-1. An intensified transendothelial invasion of cancer cells was accompanied by decreased expression of junctional proteins (connexin 43, E-cadherin, occluding, desmoglein) in HT serum-treated endothelial cells. Quantitative analysis of the secretome of endothelial cells subjected to HT serum showed that they secrete increased amounts of CCL2, CXCL1, CXCL8, bFGF, HGF, IL-6, PAI-1, and TGF-β1. Moreover, cancer cells exposed to HT-CM display increased mRNA expression for several pro-cancerogenic agents, including CXCL8, tPA, and VEGF. Conclusions: Our report shows that hypertension may potentiate cancer cell aggressiveness by modulating endothelial cell phenotype. Further tests with antihypertensive drugs are required to assess whether effective treatment of hypertension can mitigate its cancer-promoting potential.

Blood pressure and renal function changes in patients with severe chronic kidney disease undergoing radiofrequency renal denervation: 12 months outcomes from the Global SYMPLICITY Registry DEFINE

Abstract Background Radiofrequency renal denervation (RF RDN) lowers blood pressure (BP) in patients with uncontrolled hypertension (HTN). The impact of renal function on safety and efficacy of RDN is unknown. Purpose To assess BP and renal function in patients with HTN following RDN. Methods All patients treated with RF RDN (n=3332) from the observational Global SYMPLICITY Registry Denervation Findings in Real World (GSR DEFINE) were included. Patients were categorized into CKD stages by the corresponding estimated glomerular filtration rate (eGFR; mL/min/1.73m2): <45 (CKD stage 3b and higher; n=339), 45-59 (CKD stage 3a; n=467), ≥60 (CKD stage 2 and lower; n=2334). BP (office, 24h ambulatory BP), eGFR changes from baseline through 12 months were compared between groups. Comparisons between groups were made after adjusting for baseline BP and change in number of antihypertensive drug classes from baseline. Results At baseline, office systolic SBP (OSBP) in eGFR groups <45, 45-59, and ≥60 ml/min/1.73 m2 was: 164±25, 163±26 and 165±25 mmHg, respectively (p=0.083). 24-h ambulatory systolic BP (ASBP) was: 156±19, 153±20 and 154±19 mmHg, respectively (p=0.082). Mean eGFR was: 32.5±11.2, 53.6±4.4, and 86.8±18.6 ml/min/1.73 m2, respectively. A total of 1.1% of patients were on dialysis. Patients in eGFR group <45 ml/min/1.73 m2 were significantly older, had higher rates of ischemic heart disease, heart failure, diabetes, on more antihypertensive drug classes compared to higher eGFR groups. Patients were on 5.0±1.3, 4.6±1.3, and 4.5±1.4 antihypertensive drugs in eGFR <45, 45-59 and ≥60 ml/min/1.73 m2 groups, respectively (p<0.001). At 12 months, all had significant OSBP drop from baseline within the different eGFR groups (p<0.001). OSBP changed by -10.8±27.8, -10.5±25.9 and -14.7±26.6 mmHg in eGFR <45, 45-59 and ≥60 ml/min/1.73 m2 groups, respectively (adjusted p=0.095; Figure 1A). Similarly at 12 months, all patients had significant ASBP reductions from baseline across the eGFR groups (p<0.01). ASBP changed by -5.2±18.0, -6.9±18.8, and -8.5±18.8 mmHg in eGFR <45, 45-59 and ≥60 ml/min/1.73 m2 subgroups, respectively (adjusted p=0.16). At 12 months, eGFR did not significantly change from baseline in eGFR <45 and 45-59 ml/min/1.73 m2 groups (Figure 1B): 0.1±14.6 (p=0.92) and -0.6±12.8 ml/min/1.73 m2 (p=0.45), respectively. Estimated GFR changed from baseline by -5.6±15.5 ml/min/1.73 m2 in eGFR ≥60 ml/min/1.73 m2 group (p<0.001). Between group differences in eGFR changes were statistically significant (adjusted p<0.001), but by a numerically small difference. The no. of antihypertensive drug classes changed by -0.2±1.3, -0.1±1.0 and -0.1±1.0 in eGFR <45 and 45-59 ml/min/1.73 m2 groups, respectively. Conclusion Patients with uncontrolled HTN with different CKD severity including those with eGFR <45 ml/min/1.73 m2 had significant SBP reductions from baseline through 12 months, whilst renal function was preserved.Figure 1

Blood pressure lowering efficacy of antihypertensive drugs and their combinations: a systematic review and meta-analysis of 500 randomised, double-blind placebo-controlled trials

Abstract Background Each 1 mmHg reduction in systolic blood pressure (SBP) reduces the risk of major cardiovascular disease events by about 2%. However, there are currently no tools to provide randomised trial-derived estimates of blood pressure (BP)-lowering efficacy of different antihypertensive regimens despite the vast number of possible drug-dose permutations. There has also been no attempt to classify efficacy of treatment regimens into low, moderate, and high intensity. Purpose We aimed to quantify the BP-lowering efficacy of the five major classes of antihypertensive drugs and their combinations. Methods We conducted a systematic review and meta-analysis of randomised double-blind placebo-controlled trials. CENTRAL, MEDLINE and Epistimonikos were searched from inception until December 2022 to identify trials, that compared angiotensin-converting-enzyme inhibitors, angiotensin II receptor blockers, beta-blockers, calcium channel blockers, and diuretics versus placebo, for 4-26 weeks. Primary outcomes were reduction in SBP and diastolic blood pressure (DBP). Doses were classified into standard dose based on the World Health Organisation Defined Daily Dose. BP-lowering efficacy was estimated for each drug and dose using fixed-effects meta-analyses and meta-regressions, standardised to baseline SBP 154 mmHg. Treatment regimens were categorised into low, moderate, and high intensity according to estimated SBP-lowering efficacy of <10, 10-19 and ≥20 mmHg, respectively. Results A total of 500 trials (106,358 participants, 44% female) were included, which included 66 single antihypertensive drugs (monotherapy) and 89 two drug (dual) combinations. The mean baseline BP was 154/100 mmHg and mean follow-up was 8.6 weeks. Monotherapy at one standard dose reduced SBP by 8.5 (95% CI, 8.2-8.9) mmHg, with an additional 1.2 (1.0-1.5) mmHg reduction for each 10 mmHg higher pre-treatment SBP, and an additional 1.5 (1.2-1.8) mmHg reduction with each doubling in dose. There was significant heterogeneity between monotherapies, and 72% were classified as low intensity efficacy. Dual combinations at one standard doses of both the drugs reduced SBP by 15.2 (13.4-17.1) mmHg, and an additional 2.6 (1.4-3.8) mmHg reduction with doubling the doses of both the drugs. There was considerable heterogeneity between dual combinations and 59% were classified as moderate, and 11% as high intensity efficacy. The BP lowering efficacy of adding additional drug classes was confirmed to be additive after accounting for pre-treatment SBP. Triple combinations were classified as high intensity efficacy based on meta-regression analyses. Conclusions There is significant variability in the efficacy of different BP-lowering regimens. The present analyses, available in an online tool, can estimate the BP lowering efficacy for any combination of drug(s) and dose(s), and can classify treatment regimens into low, moderate or high intensity.

Antihypertensive treatment of masked hypertension guided by ambulatory blood pressure monitoring: a double-blind, placebo-controlled trial

Abstract Background Masked hypertension, office normotension combined with out-of-office hypertension, is associated with target organ damage (TOD), but whether antihypertensive treatment guided by out-of-office blood pressure (BP) would reduce TOD is unproven. Purpose To assess TOD change on antihypertensive treatment guided by ambulatory BP monitoring. Methods We conducted a double-blind, placebo-controlled randomized trial at 15 Chinese hospitals. Enrolment started on February 14, 2017 and follow-up ended on October 31, 2021. Patients of either sex, aged 30-70 years, not on antihypertensive drugs were eligible, if at two screening visits 1-week apart office BP was <140/<90 mm Hg and the 24 hour, daytime or nighttime ambulatory BP was ≥130/≥80, ≥135/≥85, or ≥120/≥70 mm Hg, respectively. Patients had ≥1 sign of TOD: ECG left ventricular hypertrophy (LVH), brachial-ankle pulse wave velocity (baPWV) ≥1400 cm/s, or urinary albumin-to-creatinine ratio (ACR) ≥3.5 mg/mmol in women and ≥2.5 mg/mmol in men. Active antihypertensive treatment consisted of allisartan starting at 80 mg/day to be increased to 160 mg/day at month 2 and to be combined with amlodipine 2.5 mg/day at month 4, if the ambulatory BP remained uncontrolled. Matching placebos were used likewise in the control group. The primary endpoint included normalization of baPWV, ACR or LVH or ≥20% reduction in baPWV or ACR. Results Of 320 patients (43.1% women; mean age 54 years), 153 were randomized to active antihypertensive treatment and 167 to placebo. At baseline, office BP averaged 130/81 mm Hg and the 24 hour BP 136/84 mm Hg. The prevalence of elevated baPWV, ACR and LVH was 97.5%, 12.5%, and 7.8%. The 24-hour systolic/diastolic decreased by 9.0/5.6 mm Hg (95% CI: 7.5-10.5/4.8-6.5 mm Hg) on active treatment and by 1.4/1.0 mm Hg (-0.1-2.8/0.2-1.8 mm Hg) on placebo. Regression of TOD, the primary outcome, occurred more frequently in patients randomized to active treatment than in those assigned to placebo with 1 year rate of 45.8% (95% CI: 37.9-53.7%) and 25.8% (19.1-32.4%), respectively (P<.001 for between-group differences in BP and TOD). Per-protocol and subgroup analyses were confirmatory. Conclusions Masked hypertensive patients require antihypertensive treatment guided by out-of-office BP monitoring before subclinical TOD progresses to major cardiovascular complications.

Late pseudo-aneurysms after coarctation repair with extra-anatomic ascending-descending aortic bypass surgery

Abstract Background Extra-anatomic ascending-descending aortic bypass operations are an alternative to difficult aortic arch reconstruction in patients with complex aortic coarctation. Reported short-term results are favorable, however, data on long-term outcomes are sparse. The aim of our study was to report long-term outcomes in affected adult patients. Methods We identified all adults with extra-anatomic ascending-descending aortic bypass surgeries followed at our center. Outcomes were assessed by chart review with a specific focus on formation of late pseudo-aneurysms and requirement for redo surgery. Results We identified a total of 12 adults (67% males) with previous ascending-descending aortic bypass surgery. These patients account for 12/171 (7%) of adults with aortic coarctation followed at our center. 10/12 patients (83%) had undergone coarctation repair by different repair techniques before ascending-descending aortic bypass surgeries. Median age at ascending-descending aortic bypass surgery was 17 years (range: 7-42 years). Prosthetic conduit sizes ranged from 12-22mm. In long-term follow-up, 11/12 patients (92%) required antihypertensive medication (median 2 antihypertensive drugs, 50% ≥ 3 drugs). A total of 5/12 patients (42%) required redo-surgery for formation of pseudo-aneurysms (figure 1) at graft anastomoses (4 proximal anastomosis at ascending aorta, 1 distal anastomosis to descending aorta) at a median age of 47.6 years (28.2-65.0 years) and a median of 22.1 years (range: 14.7-24.6 years) after the initial extra-anatomic ascending-descending aortic bypass operation (figure 2). Two of these patients required redo-operations / interventions for recurrent pseudo-aneurysms at 26 and 33 months after the redo-operations. Conclusions Although reported short- and medium-term outcomes after ascending-descending aortic bypass surgery for complex aortic coarctation are favorable, our data suggest a high rate of pseudo-aneurysm formation late (>10 years) after surgery. Our data highlight the need for careful long-term (life-long!) follow-up of these patients at specialized centers.

Symptomatic patients without coronary artery disease do not have excess cardiovascular risk compared to the general population

Abstract Background Patients with stable angina with no coronary atherosclerosis by coronary computed tomography angiography (CCTA) have a lower cardiovascular risk compared to CCTA patients with greater atherosclerotic burden. However, it remains unknown whether these symptomatic patients have excess cardiovascular risk when compared to the general population and if any excess risk is sex or age dependent. Purpose To examine the 10-year cardiovascular risk and mortality in patients with no coronary atherosclerosis by CCTA compared to a matched general population comparison cohort. Methods We included every symptomatic CCTA patient with no coronary artery disease (CAD), defined as no coronary plaques and Agatston calcium score of 0, in Western Denmark from 2008-2021. Each patient was matched by age and sex with 5 individuals with no previous history of ischemic heart disease from the Western Danish general population. Maximum follow-up was 10 years. Outcomes were myocardial infarction, ischemic stroke, and all-cause death. We estimated 10-year risk difference (RD) and incidence rate ratios (IRR) using a conditional Poisson regression, comparing patients with no CAD to the general population cohort. Additionally, we performed age- (<45 year, 45-65 years, and ≥65 years) and sex stratified analyses. Results We included 39,223 patients with no CAD who were matched with 196,115 individuals from the general population. Median age was 54 and 60% were women. Baseline use of anti-thrombotic agents, statins, and anti-hypertensive drugs was higher in patients with no CAD than the general population. Median follow-up was 6.1 years. CCTA patients with no CAD had lower risk of myocardial infarction [RD -0.2%, IRR 0.75 (95% CI 0.65-0.85)] and death [RD -3.3%, IRR 0.51 (95% CI 0.48-0.55)], but similar risk of ischemic stroke [RD 0.0%, IRR 0.93 (95% CI 0.84-1.02)] compared to the general population (Figure 1). However, patients <45 years had higher 10-year risk of both myocardial infarction and ischemic stroke despite absence of CAD by CCTA compared the general population (Figure 2). Conclusions Symptomatic patients without CAD by CCTA do not have excess cardiovascular risk when compared to a general population cohort without known ischemic heart disease. Future cardiovascular risk management of these patients should therefore follow primary prevention guidelines. However, patients <45 years did exhibit higher risk of ischemic outcomes and may require intensified preventative treatment.Figure 1Figure 2

The trends of arterial hypertension and ischemic heart disease in Lithuanian population (1983-2023)

Abstract Background During the past two decades, in Lithuania, the morbidity and mortality from circulatory system diseases such as ischemic heart disease (IHD) have been increasing. The increasing incidence of IHD can be linked to the IHD prevention program implemented in Lithuania, which was launched in 2005. This study aimed to determine and evaluate the prevalence of IHD, their risk factors, and trends among middle-aged (45-64 years) urban males and females in Lithuania over the last 40 years. Methods During our study, the changes in the prevalence of arterial hypertension (AH) and IHD, among Kaunas city inhabitants aged 45-64 years in six population-based cohorts (1982-1983 (n = 1660), 1986-1987 (n = 1152), 1992-1993 (n = 824), 2001-2002 (n = 978), 2006-2008 (n = 4604) and 2023 (n = 554)) were analyzed. AH was defined when the arterial blood pressure was ≥140/90 mmHg or a person had taken antihypertensive drugs during 2 weeks. IHD was defined when a person had a previous myocardial infarction (MI) and/or ischemic changes on electrocardiogram (ECG) were assessed by Minnesota codes. The prevalence of AH and IHD changes were evaluated using regression analysis. Results During 1983-2023, the prevalence of AH among males aged 45-64 significantly increased from 58.7% (1982-1983) to 72.7% (2023) (p = 0.04), but among females aged 45-64 the prevalence of AH tended to decrease from 63.0% (1982-1983) to 50.9% (2023) (p = 0.18). The prevalence of IHD among males aged 45-64 was without significant changes and was from 14.4% (1982-1983) to 13.6% (2023) (p = 0.7), but among females aged 45-64 the prevalence of IHD significantly decreased from 21.7% (1982-1983) to 16.6% (2023) (p = 0.04). Conclusions From 1983 to 2023, among Lithuanian middle-aged urban males, the prevalence of AH significantly increased, but the prevalence of IHD was stable, meanwhile, among Lithuanian middle-aged urban females the prevalence of AH tended to decrease, but the prevalence of IHD significantly decreased. Key messages • From 1983 to 2023, among Lithuanian middle-aged urban males, the prevalence of AH significantly increased, meanwhile among females - tended to decrease. • Over 40 years, the prevalence of IHD among Lithuanian males was without significant changes, but among females - significant decreased.

Cost-Effectiveness of Salt Substitution and Antihypertensive Drug Treatment in Chinese Prehypertensive Adults.

Recent guidelines recommend antihypertensive drug treatment for prehypertensive individuals with blood pressure between 130/80 and 139/89 mm Hg. This study evaluates the cost-effectiveness of 3 interventions in Chinese prehypertensive adults: salt substitution, antihypertensive drug treatment, and their combination. We developed a Markov cohort model to estimate cardiovascular disease (CVD) events, costs, and quality-adjusted life years (QALYs) over a lifetime. Data from the China Kadoorie Biobank informed the simulation. Costs and utilities were drawn from published sources. We evaluated the cost-effectiveness of salt substitution alone, antihypertensive drug treatment alone, and a combination of the 2, focusing on the overall prehypertensive population, those at high CVD risk, and different starting ages (40, 50, 60, and 70 years). Incremental cost-effectiveness ratios (ICERs) were calculated per QALY gained. Salt substitution at age 40 years is the only cost-effective strategy for prehypertensive individuals, with an ICER of $6413.62/QALY. For those at high CVD risk, the combination intervention starting at age 40 years is most cost-effective, with an ICER of $2913.30/QALY. Interventions initiated at younger ages yielded greater CVD reductions and lower ICERs. For example, a combined intervention at age 40 years reduces CVD events by 5.3% with an ICER of $2913.30/QALY, compared with 4.9% and $32 635.33/QALY at age 70 years. These results were consistent across sensitivity analyses. In China, replacing usual salt with a salt substitute is more cost-effective than treating prehypertensive individuals over the age of 40 years with antihypertensive drugs. Furthermore, starting intervention at a younger age in prehypertensive adults can result in even greater cost savings.

10 years after treatment with renal denervation of the sympathetic nerves for resistant hypertension: what happened to the patients and their office blood pressure? An observational study

Abstract Background Catheter-based renal denervation of the sympathetic nerves (RDN) for resistant hypertension has long been controversial. A renewed clinical and scientific interest in defining the appropriate role of RDN in the treatment of resistant hypertension has become evident in recent years. The efficacy and safety of RDN treatment is mainly based on available data up to three years, whereas data concerning the long-term effect and safety are scarce. Purpose We therefore wanted to investigate the long time change in blood pressure (BP) in patients treated with RDN for resistant hypertension. Methods A review of data from the electronic patient journal concerning all RDN treated patients was initiated and completed in October 2023. Every registration of an office BP listed in the patient file, antihypertensive treatment, cardiovascular events, and renal function between 2012 and 2023 were registered. For each patient the average of all office post RDN blood were averaged for every year and for their complete follow-up. The outcome in blood pressure was the change in BP from baseline pre RDN office to follow-up Results Between January 2012 and October 2013, 19 consecutive patients underwent RDN treatment, 10 men and 9 women with a median age of 63 years (range 35-74 years). At baseline the median systolic office BP was 181 mmHg (range 162–230 mmHg) and the diastolic office BP 97 mmHg (range 82-123 mmHg) on a median of 5 (range 0-7 ) antihypertensive drugs. During follow-up the number of antihypertensive drugs were reduced in 7, unchanged in 10, and increased in 2 patients. Two patients left the outpatient clinic with normal BP after 2 years. Two patients developed heart failure after 7 years and were censored at that time-point. 15 (79%) patients had office BP recorded up to 9 or 10 years. In the 15 (79%) patients with available office BP 9 to 10 years after RDN the median systolic and diastolic office BPs were reduced by 39 mmHg (range -2 to - 66 mmHg) and 18 mmHg (range -11 to - 55 mmHg) respectively, relative reduction 22% (range 5-36%) and 20% (range 6-32), respectively. Conclusion During a follow-up of 9 to 10 years after RDN without a step-up in antihypertensive medication a relative decrease of ~20% in systolic and diastolic BP was observed.

Deficiency of transcription factor E4BP4 suppresses neointimal formation after vascular injury

Abstract Aim In addition to traditional risk factors such as hypertension, diabetes, and dyslipidemia, chronic inflammation is deeply involved in the onset and pathogenesis of atherosclerotic diseases. Furthermore, diurnal fluctuations are observed in the rupture of atherosclerotic plaques and the onset of myocardial infarction. There are still many patients for whom medical treatments such as statins and antihypertensive drugs do not respond adequately, and new treatment methods are expected. E4BP4 (also known as NFIL3) is a basic leucine zipper (bZIP)-type transcription factor associated with circadian rhythms and cell viability, and it has been reported that E4BP4 regulates inflammation. Therefore, to investigate how the circadian transcription factor E4BP4 which is involved in inflammation, we decided to examine the role of E4BP4 in neointimal formation after vascular injury. Methods and Results Using E4BP4-deficient (E4BP4−/−) and wild-type (WT) mice, we investigated neointimal formation 2 weeks after femoral artery injury induced by an external vascular cuff model. Intimal and medial area were measured, and the intima/media ratio was calculated. Systolic blood pressure was similar between groups (WT mice: 92 ± 5 mmHg [n = 5] vs. E4BP4−/− mice: 90 ± 4 mmHg [n = 5]). And there was no significant difference in baseline body weight between groups (WT mice: 22.4 ± 0.8 g [n = 5] vs. E4BP4−/− mice: 22.0 ± 1.1 g [n = 5]). The mean intimal area and the intima/media ratio of E4BP4−/− mice decreased by 86 % (WT mice: 3,683 ± 512 μm2 [n = 10] vs. E4BP4−/− mice: 521 ± 363 μm2 [n = 10]; P < 0.0001) and 97% (WT mice: 0.33 ± 0.05 vs. E4BP4−/− mice: 0.01 ± 0.03; P < 0.0001), compared with WT mice. However, we observed no significant difference in the medial area (WT mice: 11,019 ± 358 μm2 vs. E4BP4−/− mice: 11,281 ± 401 μm2; P = NS) between groups (Figure). Immunohistochemistry for NK cell (NKp46) revealed the percentage of NKp46 positive area in the adventitia of E4BP4−/− mice was significantly lower compared with WT mice at 14 days post-injury (P <0.05). Furthermore, the positive area of IL-6 (P<0.05), TNF-α (P<0.05) and IFN-γ (P<0.05) in the intima of E4BP4−/− mice tended to be much smaller than those of WT mice. Our findings indicate that E4BP4 might induce vascular inflammation following vascular injury. Conclusions Deficiency of E4BP4 reduced the inflammatory cytokines and suppressed neointimal formation after injury. We also observed a decrease in NKp46, suggesting that NK cell development is impaired by E4BP4 deficiency. The present study is the first to demonstrate that E4BP4 plays an important role in the increase of neointimal formation after injury in vivo, thus suggesting that E4BP4 inhibition may represent a useful strategy to inhibit vascular inflammation.Neointimal formation after cuff injury

A survey of availability and affordability of polypills for primary and secondary prevention of cardiovascular diseases in selected countries

Abstract Background/Introduction The recent inclusion of polypills—fixed-dose combinations of two or more antihypertensive drugs and statin with or without aspirin—in the World Health Organization’s Essential Medicines List (EML) reiterates the potential of this approach to improve global treatment coverage for primary or secondary prevention of cardiovascular diseases (CVDs). Although there exists extensive evidence on efficacy, safety, and acceptability of polypills, there is no research to-date assessing the "real world" availability and affordability of polypills globally. Purpose We conducted a cross-sectional survey of public and private sector facilities in 13 countries from around the world to evaluate the availability and affordability of polypills. Methods In the surveyed countries, we first ascertained whether any polypill was authorized for marketing and/or included in the national EMLs and clinical guidelines. The facility survey employed a modified WHO/Health Action International methodology. In each country, we collected retail and price data for polypills from at least one public sector facility and three private pharmacies using convenience sampling. Polypills were considered unaffordable in a given country if the lowest paid worker spends more than a days’ wage to purchase monthly supply. Results Polypills were approved for marketing in four of the 13 surveyed countries: Spain, India, Mauritius, and Argentina. None of these countries included polypills in national guidelines, formularies, or EMLs. Further, none of the surveyed public pharmacies in any of the four countries stocked any polypills. Among the surveyed private sector facilities, availability ranged from 0% in India (out-of-stock on the survey day but listed for sale) to 100% in Argentina and Spain. In the private sector, we identified seven unique polypill combinations, marketed by eight different companies. Although not in stock, India had a wider range of various combinations (n=5). Many combinations (63%) found in this survey were affordable in the local context, but these were limited to India and Spain. A lowest paid government worker would spend between 0.2 (India)–2.8 (Mauritius) days’ wages to pay the price for one month’s supply of the polypills. Polypills were likely to be affordable in countries that locally manufactured them. Further, two-pill combinations (one antihypertensive and a statin) were stocked by private pharmacies in Argentina, Bangladesh, Cameroon, India, Nepal, and Spain, with affordability ranging from 0.2 (India)–7.1 (Cameroon) days’ wages. Conclusion Low availability and affordability of polypills in both public and private sectors suggest that the implementation and overall uptake of polypills remains poor globally. Context-specific multi-disciplinary health system research is required to understand factors affecting polypill implementation and to design and evaluate appropriate implementation strategies.

The Relationship between Compliance with Medication and Blood Pressure in Hypertension Sufferers

Hypertension is a chronic medical condition that requires long-term management through medication and lifestyle changes. Adherence to the treatment regimen is a key factor in controlling blood pressure and preventing potentially fatal complications. This study aims to evaluate the relationship between adherence to medication consumption and blood pressure in hypertension sufferers. This study used a cross-sectional design involving 40 respondents who were diagnosed with hypertension at several health centers in Nganjuk City. Data was collected through a questionnaire that measured the patient's level of compliance with taking antihypertensive drugs and blood pressure checks carried out by medical personnel. The results of the analysis showed that there was a significant relationship between the level of adherence to taking medication and the level of blood pressure control (p < 0.05). Patients who have a high level of compliance tend to have better controlled blood pressure compared to patients who are not compliant. These findings emphasize the importance of improving adherence to treatment in hypertension management to achieve optimal health outcomes.

Could piano music therapy alleviate high sinus rhythm in subjects with controlled hypertension?

Abstract Background/Introduction With a millenary tradition, music is rediscovered nowadays, as adjuvant therapy. The number of beats per minute (bpm) is the common factor of cardiology – representing heart rate (HR), and music – reprezentative for tempo. Purpose Our goal was the HR modulation in patients (pts) with moderate tachycardia using three piano kits: K1 – Adagio by Albinoni, K2 – Piano Concerto nr. 21 by Mozart, second part; and K3 – Liebestraum by Liszt. Methods During 1st January – 31st December 2023, we identified by ambulatory screening 288 pts adequate for our goal. As exclusion criterion, we considered any type of rhythm or conduction dysturbances. All selected pts were controlled with antihypertensive agents not altering HR, usually thiazide/thiazide-like diuretics and/or ACEis/ARBs. The study group consisted in 144 hypertensive pts controlled at least six months, without any other cardiac diseases. The control group consisted in 144 pts with normal cardiologic examination. Both groups were demographically balanced. The HR at admission was between 84 and 120 bpm, the pts being stratified in three bpm subcategories. All pts have done three visits consisting in: physical examination, ECG, lab markers, TTE for V1 at initiation and EoS at six months, and respectively, physical exam and ECG for V2 at 3 months. Results (in bpm): Inside the group with HR 84-96 treated with K1, the Controlled HTN group (CHG) and the Normal Cardiac group (NCG) alleviated HR from 85,8 +/- 12,6 to 82,6 +/- 12,2; and from 85,7 +/- 12,6 to 80,8 +/- 11,9, respectively. For pts inside the interval 97-108 treated with K1, the CHG group and the NCG alleviated HR from 94,3 +/- 14,1 to 90,9 +/- 13,7 and, respectively, from 94,4 +/- 14,1 to 89,7 +/- 13,6. In pts from HR spectrum 97-108 treated with K2, the CHG and the NCG alleviated HR from 98,4 +/- 14,6 to 95,7 +/- 14,1; and from 98,5 +/- 14,6 to 94,1 +/- 13,8; respectively. Inside the group with HR spectrum 109-120 treated with K1, the CHG and the NCG alleviated HR from 97,1 +/- 14,3 to 94,8 +/- 13,9; and, respectively, from 97,0 +/- 14,3 to 93,9 +/- 13,7. For pts inside the interval 109-120 treated with K2, the CHG and the NCG alleviated HR from 101,7 +/- 14,6 to 99,3 +/- 14,2; and from 101,8 +/- 14,6 to 97,3 +/- 14,1; respectively. In pts from HR spectrum 109-120 treated with K3, the CHG and the NCG alleviated HR from 106,1 +/- 14,7 to 103,8 +/- 14,6; and from 106,5 +/- 14,4 to 103,6 +/- 14,4; respectively. Conclusions The effect of piano music on HR seems favorable in controlled hypertensive pts without major comorbidities, probably by interfering the sympathetic vegetative nervous system. In this regard, it could be used as adjuvant in optimizing this cardiac parameter. However, a multicentered randomized clinical study will be needed.

A higher adherence to perindopril-based anti-hypertensive therapy is associated with a reduced risk of cardiovascular outcomes and all-cause mortality in real clinical practice in Italy

Abstract Background Therapeutic management of hypertension is a landmark of cardiovascular (CV) risk prevention. Combined therapies with at least 2 anti-hypertensive agents are required in many patients in whom monotherapy and lifestyle interventions failed in blood pressure control. It is well-known that poor medication adherence remains a major barrier to achieving the therapeutic targets for all CV drugs, including anti-hypertensives. Purpose We evaluated the relationship between adherence to perindopril (PER)-based therapeutic regimen prescribed as single-pill combination (SPC) or free-pill and CV outcomes and all-cause mortality in a large Italian population. Methods A retrospective analysis was performed using administrative databases corresponding to around 6.7 million health-assisted residents. Hypertensive adults were first identified through hospitalization discharge diagnosis or exemption codes for hypertension between 2010 and 2021. Patients prescribed PER-based therapies were screened for all combinations of PER with amlodipine (AML) and/or indapamide (IND) (all formulations, single-pill or free-pill). Time of the first prescription of a PER-based regimen during the inclusion period was considered the index-date. The analysis included all hypertensive subjects prescribed a PER-based therapy, having available data at least 12 months before and 24 months after the index-date, respectively. Since the analysis was focused on the possible associations between adherence level and CV outcomes and all-cause mortality, adherence was assessed during the first year of follow-up on alive patients and outcomes were assessed during the second year. Adherence was assessed using the proportion of days covered (PDC) approach on 1-year follow-up, and considering a PDC<80% as poor-to-moderate adherence, and PDC ≥80% as good adherence. The Cox’s proportional hazard model was applied to estimate Hazard Ratio (HR) adjusting for baseline covariates, including comorbidity profile and pill burden. Results The included cohort (N=24,476) was divided into sub-groups according to adherence in poor-to-moderate (N=6,781) and good adherent patients (N=17,695) with a mean age of 64.8±13.3 and 64.6±11.9 years old, respectively. The Cox’s proportional hazard model showed that good adherence was associated with a relative risk reduction of 23% in all-cause mortality (Table 1A), 21% in all CV events (Table 1B), 17% in ischemic heart disease (Table 1C), 33% in cerebrovascular events (Table 1E), and 22% in the composite outcome of CV events/all-cause mortality (Table 1G). Conclusions The present analysis provided evidence from the Italian real clinical practice that good adherence to PER-based anti-hypertensive therapy results in significantly lower cardiovascular risk and all-cause mortality. These data further emphasize the importance of promoting cost-effective measures to increase medication adherence in patients on anti-hypertensive treatment.