Aims

A hallmark of advanced atherosclerosis is inadequate immunosuppression by regulatory T (Treg) cells inside atherosclerotic lesions. Dyslipidemia has been suggested to alter Treg cell migration by affecting the expression of specific membrane proteins, thereby decreasing Treg cell migration towards atherosclerotic lesions. Besides membrane proteins, cellular metabolism has been shown to be a crucial factor in Treg cell migration. We aimed to determine whether dyslipidemia contributes to altered migration of Treg cells, in part, by affecting cellular metabolism.

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Nighttime aircraft noise exposure has been associated with increased risk of hypertension and myocardial infarction, mechanistically linked to sleep disturbance, stress, and endothelial dysfunction. It is unclear, whether the most widely used metric to determine noise exposure, equivalent continuous sound level (L_eq), is an adequate indicator of the cardiovascular impact induced by different noise patterns.

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Oxidized phospholipids and microRNAs (miRNAs) are increasingly recognized to play a role in endothelial dysfunction driving atherosclerosis. NRF2 transcription factor is one of the key mediators of the effects of oxidized phospholipids, but the gene regulatory mechanisms underlying the process remain obscure. Here, we investigated the genome-wide effects of oxidized phospholipids on transcriptional gene regulation in human umbilical vein endothelial cells and aortic endothelial cells with a special focus on miRNAs.

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Prior studies have focused on the role of the kidney and vasculature in salt-induced modulation of blood pressure; however, recent data indicate that sodium accumulates in tissues and can activate immune cells. We sought to examine mechanisms by which salt causes activation of human monocytes both in vivo and in vitro.

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Atherosclerotic vascular disease has an inflammatory pathogenesis. Heme from intraplaque haemorrhage may drive a protective and pro-resolving macrophage M2-like phenotype, Mhem, via AMPK and activating transcription factor 1 (ATF1). The antidiabetic drug metformin may also activate AMPK-dependent signalling. Hypothesis: Metformin systematically induces atheroprotective genes in macrophages via AMPK and ATF1, thereby suppresses atherogenesis.

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A blood pressure (BP)-independent metabolic shift towards a catabolic state upon high sodium (Na⁺) diet, ultimately favouring body fluid preservation, has recently been described in pre-clinical controlled settings. We sought to investigate the real-life impact of high Na⁺ intake on measures of renal Na⁺/water handling and metabolic signatures, as surrogates for cardiovascular risk, in hypertensive patients.

The United Kingdom was among the first countries to introduce a salt reduction program in 2003 to reduce cardiovascular disease (CVD) incidence risk. Despite its initial success, the program has stalled recently and is yet to achieve national and international targets. We used age- and sex-stratified salt intake of 19 to 64 years old participants in the National Diet and Nutrition Surveys 2000 to 2018 and a multistate life table model to assess the effects of the voluntary dietary salt reduction program on premature CVD, quality-adjusted survival, and health care and social care costs in England. The program reduced population-level salt intake from 9.38 grams/day per adult (SE, 0.16) in 2000 to 8.38 grams/day per adult (SE, 0.17) in 2018. Compared with a scenario of persistent 2000 levels, assuming that the population-level salt intake is maintained at 2018 values, by 2050, the program is projected to avoid 83 140 (95% CI, 73 710–84 520) premature ischemic heart disease (IHD) cases and 110 730 (95% CI, 98 390–112 260) premature strokes, generating 542 850 (95% CI, 529 020–556 850) extra quality-adjusted life-years and £1640 million (95% CI, £1570–£1660) health care cost savings for the adult population of England. We also projected the gains of achieving the World Health Organization target of 5 grams/day per adult by 2030, which by 2050 would avert further 87 870 (95% CI, 82 050–88 470) premature IHD cases, 126 010 (95% CI, 118 600–126 460) premature strokes and achieve £1260 million (95% CI, £1180–£1260) extra health care savings compared with maintaining 2018 levels. Strengthening the salt reduction program to achieve further reductions in population salt intake and CVD burden should be a high priority.

The 2017 American College of Cardiology/American Heart Association high blood pressure (BP) guidelines recommend risk assessment of atherosclerotic cardiovascular disease to inform hypertension treatment in adults with elevated BP or low-risk stage I hypertension. The use of coronary artery calcium (CAC) score to guide hypertension therapy has not been adequately evaluated. Participants free of cardiovascular disease were pooled from Multi-Ethnic Study of Atherosclerosis, Coronary Artery Risk Development in Young Adults, and Jackson Heart Study. The risk for incident cardiovascular events (heart failure, stroke, coronary heart disease), by CAC status (CAC-0 or CAC>0) and BP treatment group was assessed using multivariable-adjusted Cox regression. The 10-year number needed to treat to prevent a single cardiovascular event was also estimated. This study included 6461 participants (median age 53 years; 53.3% women; 32.3% Black participants). Over a median follow-up of 8.5 years, 347 incident cardiovascular events occurred. Compared with those with normal BP, the risk of incident cardiovascular event was higher among those with elevated BP/low-risk stage I hypertension and CAC>0 (hazard ratio, 2.4 [95% CI, 1.7–3.4]) and high-risk stage I/stage II hypertension (BP, 140–160/80–100 mm Hg) with CAC>0 (hazard ratio, 2.9 [95% CI, 2.1–4.0]). A similar pattern was evident across racial subgroups and for individual study outcomes. Among those with CAC-0, the 10-year number needed to treat was 160 for elevated BP/low-risk stage I hypertension and 44 for high-risk stage I or stage II hypertension (BP, 140–160/80–100 mm Hg). Among those with CAC>0, the 10-year number needed to treat was 36 and 22, respectively. Utilization of the CAC score may guide the initiation of hypertension therapy and preventive approaches to personalize cardiovascular risk reduction among individuals where the current guidelines do not recommend treatment.

Upright postural tachycardia syndrome (POTS) resembles hemorrhage with reduced central blood volume, parasympathetic withdrawal, and sympathetic activation. Baroreflex dysfunction causes low heart rate variability, enhanced blood pressure variability, and decreased maximum baroreflex gain (G_max) putatively measured by spontaneous fluctuation of blood pressure and heart rate. We investigated whether/how cardiovagal baroreflex in POTS differ from control, supine, and upright by comparing indices of spontaneous baroreflex function to that measured using the reference standard modified Oxford method. This uses sodium nitroprusside and phenylephrine to generate the sigmoidal cardiovagal baroreflex curve. Baroreflex in POTS was evaluated supine and upright untreated and then treated to determine whether pyridostigmine or digoxin (a vagotonic agent) corrects baroreflex deficits. Supine, G_max was reduced by 25% in POTS compared with controls, and descriptors of this sigmoidal relationship showed a reduction, downward shift, and left shift of the response to the pharmacological decrease and increase in blood pressure. Digoxin normalized supine cardiovagal baroreflex while pyridostigmine resulted in partial normalization as G_max, and other descriptors of these relationships were similar to control. Upright, cardiovagal curves were distorted and displaced in untreated POTS, while digoxin and pyridostigmine left shifted the cardiovagal curves due to sympathetic activity. Cardiovagal baroreflex deficits in POTS relate to parasympathetic withdrawal while supine, remediated completely by digoxin, and sympathetic activation upright through alteration of baroreflex responsivity. Since these baroreflex effects resemble those measured following microgravity/chronic bedrest, vagotonic/sympatholytic treatment combined with aerobic exercise might normalize the cardiovagal baroreflex and provide therapeutic benefit in patients with POTS.

Kidney donation reduces renal function by ≈30% allowing study of the cardiovascular effects of a reduced estimated glomerular filtration rate without comorbidities. We report 5-year results of a longitudinal, parallel-group, blinded end-point study of living kidney donors (n=50) and healthy controls (n=45). The primary end point, left ventricular mass, was measured using cardiac magnetic resonance. Secondary end points, 24-hour ambulatory blood pressure, and pulse wave velocity were measured using validated blood pressure monitors and the SphygmoCor device. Effect sizes were calculated as differences between change from baseline in the donor and control groups. In donors, estimated glomerular filtration rate was 95±15 mL/min per 1.73 m2 at baseline (predonation) and 67±14 mL/min per 1.73 m2 at 5 years. In controls, there was a −1±2 mL/min per 1.73 m2 decline per annum. Change in left ventricular mass at 5 years was not significantly different between donors and controls (mean difference, +0.40 g [95% CI, −4.68 to 5.49] P=0.876), despite an initial increase in mass in donors compared with controls at 12 months. Pulse wave velocity, which increased in donors at 12 months, returned to levels not different from controls at 5 years (mean difference, −0.24 m/s [95% CI, −0.69 to 0.21]). Change in ambulatory systolic blood pressure was not different in donors compared with controls (mean difference, +1.91 mm Hg [95% CI, −2.72 to 6.54]). We found no evidence that the reduction in estimated glomerular filtration rate after kidney donation was associated with a change in left ventricular mass detectable by magnetic resonance imaging at 5 years.

Previous studies have reported associations between ambient fine particle concentrations and preeclampsia; however, the impact of particulate pollution on early- and late-onset preeclampsia is understudied. Furthermore, few studies have examined the association between source-specific particles such as markers of traffic pollution or wood combustion on adverse pregnancy outcomes. Electronic medical records and birth certificate data were linked with land-use regression models in Monroe County, New York for 2009 to 2013 to predict monthly pollutant concentrations for each pregnancy until the date of clinical diagnosis during winter (November–April) for 16 116 births. Up to 30% of ambient wintertime fine particle concentrations in Monroe County, New York is from wood combustion. Multivariable logistic regression was used to separately estimate the odds of preeclampsia (all, early-, and late-onset) associated with each interquartile range increase in fine particles, traffic pollution, and woodsmoke concentrations during each gestational month, adjusting for maternal characteristics, birth hospital, temperature, and relative humidity. Each 3.64 µg/m³ increase in fine particle concentration was associated with an increased odds of early-onset preeclampsia during the first (odds ratio, 1.35 [95% CI, 1.08–1.68]), second (odds ratio, 1.51 [95% CI, 1.23–1.86]), and third (odds ratio, 1.25 [95% CI, 1.06–1.46]) gestational months. Increases in traffic pollution and woodsmoke during the first gestational month were also associated with increased odds of early-onset preeclampsia. Increased odds of late-onset preeclampsia were not observed. Our findings suggest that exposure to wintertime particulate pollution may have the greatest effect on maternal cardiovascular health during early pregnancy.

Aims

B cell functions in the process of atherogenesis have been investigated but several aspects remain to be clarified.

Aims 

The cardiac ryanodine receptor (RyR2), which mediates intracellular Ca²⁺ release to trigger cardiomyocyte contraction, participates in development of acquired and inherited arrhythmogenic cardiac disease. This study was undertaken to characterize the network of inter- and intra-subunit interactions regulating the activity of the RyR2 homotetramer.

Aims

Human influenza A virus (hIAV) infection is associated with important cardiovascular complications, although cardiac infection pathophysiology is poorly understood. We aimed to study the ability of hIAV of different pathogenicity to infect the mouse heart, and establish the relationship between the infective capacity and the associated in vivo, cellular and molecular alterations.

Aims

Vascular calcification is a recognized predictor of cardiovascular risk in the diabetic patient, with DNA damage and accelerated senescence linked to oxidative stress-associated pathological calcification. Having previously shown that systemic SIRT1 is reduced in diabetes, the aim was to establish whether SIRT1 is protective against a DNA damage-induced senescent and calcified phenotype in diabetic vascular smooth muscle cells (vSMCs).

Aims

In long QT syndrome (LQTS) patients, modifier genes modulate the arrhythmic risk associated with a disease-causing mutation. Their recognition can improve risk stratification and clinical management, but their discovery represents a challenge. We tested whether a cellular-driven approach could help to identify new modifier genes and especially their mechanism of action.

After initially hypothesizing a positive relationship between use of renin-angiotensin-aldosterone system inhibitors and risk of coronavirus disease 2019 (COVID-19), more recent evidence suggests negative associations. We examined whether COVID-19 risk differs according to antihypertensive drug class in patients treated by ACE (angiotensin-converting enzyme) inhibitors and angiotensin receptor blockers (ARBs) compared with calcium channel blockers (CCBs). Three exclusive cohorts of prevalent ACE inhibitors, ARB and CCB users, aged 18 to 80 years, from the French National Health Insurance databases were followed from February 15, 2020 to June 7, 2020. We excluded patients with a history of diabetes, known cardiovascular disease, chronic renal failure, or chronic respiratory disease during the previous 5 years, to only consider patients treated for uncomplicated hypertension and to limit indication bias. The primary end point was time to hospitalization for COVID-19. The secondary end point was time to intubation/death during a hospital stay for COVID-19. In a population of almost 2 million hypertensive patients (ACE inhibitors: 566 023; ARB: 958 227; CCB: 358 306) followed for 16 weeks, 2338 were hospitalized and 526 died or were intubated for COVID-19. ACE inhibitors and ARBs were associated with a lower risk of COVID-19 hospitalization compared with CCBs (hazard ratio, 0.74 [95% CI, 0.65–0.83] and 0.84 [0.76–0.93], respectively) and a lower risk of intubation/death. Risks were slightly lower for ACE inhibitor users than for ARB users. This large observational study may suggest a lower COVID-19 risk in hypertensive patients treated over a long period with ACE inhibitors or ARBs compared with CCBs. These results, if confirmed, tend to contradict previous hypotheses and raise new hypotheses.

Hypertension has been identified as a risk factor for coronavirus disease 2019 (COVID-19) and associated adverse outcomes. This study examined the association between preinfection blood pressure (BP) control and COVID-19 outcomes using data from 460 general practices in England. Eligible patients were adults with hypertension who were tested or diagnosed with COVID-19. BP control was defined by the most recent BP reading within 24 months of the index date (January 1, 2020). BP was defined as controlled (<130/80 mm Hg), raised (130/80–139/89 mm Hg), stage 1 uncontrolled (140/90–159/99 mm Hg), or stage 2 uncontrolled (≥160/100 mm Hg). The primary outcome was death within 28 days of COVID-19 diagnosis. Secondary outcomes were COVID-19 diagnosis and COVID-19–related hospital admission. Multivariable logistic regression was used to examine the association between BP control and outcomes. Of the 45 418 patients (mean age, 67 years; 44.7% male) included, 11 950 (26.3%) had controlled BP. These patients were older, had more comorbidities, and had been diagnosed with hypertension for longer. A total of 4277 patients (9.4%) were diagnosed with COVID-19 and 877 died within 28 days. Individuals with stage 1 uncontrolled BP had lower odds of COVID-19 death (odds ratio, 0.76 [95% CI, 0.62–0.92]) compared with patients with well-controlled BP. There was no association between BP control and COVID-19 diagnosis or hospitalization. These findings suggest BP control may be associated with worse COVID-19 outcomes, possibly due to these patients having more advanced atherosclerosis and target organ damage. Such patients may need to consider adhering to stricter social distancing, to limit the impact of COVID-19 as future waves of the pandemic occur.

Exposure to traffic-related air pollution (TRAP) may contribute to increased prevalence of hypertension and elevated blood pressure (BP) for residents of near-highway neighborhoods. Relatively few studies have investigated the effects of reducing TRAP exposure on short-term changes in BP. We assessed whether reducing indoor TRAP concentrations by using stand-alone high-efficiency particulate arrestance (HEPA) filters and limiting infiltration through doors and windows effectively prevented acute (ie, over a span of hours) increases in BP. Using a 3-period crossover design, 77 participants were randomized to attend three 2-hour-long exposure sessions separated by 1-week washout periods. Each participant was exposed to high, medium, and low TRAP concentrations in a room near an interstate highway. Particle number concentrations, black carbon concentrations, and temperature were monitored continuously. Systolic BP (SBP), diastolic BP, and heart rate were measured every 10 minutes. Outcomes were analyzed with a linear mixed model. The primary outcome was the change in SBP from 20 minutes from the start of exposure. SBP increased with exposure duration, and the amount of increase was related to the magnitude of exposure. The mean change in SBP was 0.6 mm Hg for low exposure (mean particle number and black carbon concentrations, 2500 particles/cm³ and 149 ng/m³), 1.3 mm Hg for medium exposure (mean particle number and black carbon concentrations, 11 000 particles/cm³ and 409 ng/m³), and 2.8 mm Hg for high exposure (mean particle number and black carbon concentrations, 30 000 particles/cm³ and 826 ng/m³; linear trend P=0.019). There were no statistically significant differences in the secondary outcomes, diastolic BP, or heart rate. In conclusion, reducing indoor concentrations of TRAP was effective in preventing acute increases in SBP.

Activation of AT₁ (type 1 Ang) receptors stimulates cardiomyocyte hypertrophy in vitro. Accordingly, it has been suggested that regression of cardiac hypertrophy associated with renin-Ang system blockade is due to inhibition of cellular actions of Ang II in the heart, above and beyond their effects to reduce pressure overload. We generated 2 distinct mouse lines with cell-specific deletion of AT_1A receptors, from cardiomyocytes. In the first line (C-SMKO), elimination of AT_1A receptors was achieved using a heterologous Cre recombinase transgene under control of the Sm22 promoter, which expresses in cells of smooth muscle lineage including cardiomyocytes and vascular smooth muscle cells of conduit but not resistance vessels. The second line (R-SMKO) utilized a Cre transgene knocked-in to the Sm22 locus, which drives expression in cardiac myocytes and vascular smooth muscle cells in both conduit and resistance arteries. Thus, although both groups lack AT₁ receptors in the cardiomyocytes, they are distinguished by presence (C-SMKO) or absence (R-SMKO) of peripheral vascular responses to Ang II. Similar to wild-types, chronic Ang II infusion caused hypertension and cardiac hypertrophy in C-SMKO mice, whereas both hypertension and cardiac hypertrophy were reduced in R-SMKOs. Thus, despite the absence of AT_1A receptors in cardiomyocytes, C-SMKOs develop robust cardiac hypertrophy. By contrast, R-SMKOs developed identical levels of hypertrophy in response to pressure overload–induced by transverse aortic banding. Our findings suggest that direct activation of AT₁ receptors in cardiac myocytes has minimal influence on cardiac hypertrophy induced by renin-Ang system activation or pressure overload.

The association of blood pressure (BP) and hypertension with the presence of different types of brain lesions in patients with atrial fibrillation is unclear. BP values were obtained in a multicenter cohort of patients with atrial fibrillation. Systolic and diastolic BP was categorized in predefined groups. All patients underwent brain magnetic resonance imaging and neurocognitive testing. Brain lesions were classified as large noncortical or cortical infarcts, small noncortical infarcts, microbleeds, or white matter lesions. White matter lesions were graded according to the Fazekas scale. Overall, 1738 patients with atrial fibrillation were enrolled in this cross-sectional analysis (mean age, 73 years, 73% males). Mean BP was 135/79 mm Hg, and 67% of participants were taking BP-lowering treatment. White matter lesions Fazekas ≥2 were found in 54%, large noncortical or cortical infarcts in 22%, small noncortical infarcts in 21%, and microbleeds in 22% of patients, respectively. Compared with patients with systolic BP <120 mm Hg, the adjusted odds ratios (95% CI) for Fazekas≥2 was 1.25 (0.94–1.66), 1.41 (1.03–1.93), and 2.54 (1.65–3.95) among patients with systolic BP of 120 to 140, 140 to 160, and ≥160 mm Hg (P for linear trend<0.001). Per 5 mm Hg increase in systolic and diastolic BP, the adjusted β-coefficient (95% CI) for log-transformed white matter lesions was 0.04 (0.02–0.05), P<0.001 and 0.04 (0.01–0.06), P=0.004. Systolic BP was associated with small noncortical infarcts (odds ratios [95% CI] per 5 mm Hg 1.05 [1.01–1.08], P=0.006), microbleeds were associated with hypertension, but large noncortical or cortical infarcts were not associated with BP or hypertension. After multivariable adjustment, BP and hypertension were not associated with neurocognitive function. Among patients with atrial fibrillation, BP is strongly associated with the presence and extent of white matter lesions, but there is no association with large noncortical or cortical infarcts.

Observational studies have shown an association between hypertension and atrial fibrillation (AF). Aggressive blood pressure management in patients with known AF reduces overall arrhythmia burden, but it remains unclear whether hypertension is causative for AF. To address this question, this study explored the relationship between genetic predictors of blood pressure and risk of AF. We secondarily explored the relationship between genetically proxied use of antihypertensive drugs and risk of AF. Two-sample Mendelian randomization was performed using an inverse-variance weighted meta-analysis with weighted median Mendelian randomization and Egger intercept tests performed as sensitivity analyses. Summary statistics for systolic blood pressure, diastolic blood pressure, and pulse pressure were obtained from the International Consortium of Blood Pressure and the UK Biobank discovery analysis and AF from the 2018 Atrial Fibrillation Genetics Consortium multiethnic genome-wide association studies. Increases in genetically proxied systolic blood pressure, diastolic blood pressure, or pulse pressure by 10 mm Hg were associated with increased odds of AF (systolic blood pressure: odds ratio [OR], 1.17 [95% CI, 1.11–1.22]; P=1×10⁻¹¹; diastolic blood pressure: OR, 1.25 [95% CI, 1.16–1.35]; P=3×10⁻⁸; pulse pressure: OR, 1.1 [95% CI, 1.0–1.2]; P=0.05). Decreases in systolic blood pressure by 10 mm Hg estimated by genetic proxies of antihypertensive medications showed calcium channel blockers (OR, 0.66 [95% CI, 0.57–0.76]; P=8×10⁻⁹) and β-blockers (OR, 0.61 [95% CI, 0.46–0.81]; P=6×10⁻⁴) decreased the risk of AF. Blood pressure–increasing genetic variants were associated with increased risk of AF, consistent with a causal relationship between blood pressure and AF. These data support the concept that blood pressure reduction with calcium channel blockade or β-blockade could reduce the risk of AF.

Compared with brachial blood pressure (BP), central systolic BP (SBP) can provide a better indication of the hemodynamic strain inflicted on target organs, but it is unclear whether this translates into improved cardiovascular risk stratification. We aimed to assess which of central or brachial BP best predicts cardiovascular risk and to identify the central SBP threshold associated with increased risk of future cardiovascular events. This study included 13 461 participants of CARTaGENE with available central BP and follow-up data from administrative databases but without cardiovascular disease or antihypertensive medication. Central BP was estimated by radial artery tonometry, calibrated for brachial SBP and diastolic BP (type I), and a generalized transfer function (SphygmoCor). The outcome was major adverse cardiovascular events. Cox proportional-hazards models, differences in areas under the curves, net reclassification indices, and integrated discrimination indices were calculated. Youden index was used to identify SBP thresholds. Over a median follow-up of 8.75 years, 1327 major adverse cardiovascular events occurred. The differences in areas under the curves, net reclassification indices, and integrated discrimination indices were of 0.2% ([95% CI, 0.1–0.3] P<0.01), 0.11 ([95% CI, 0.03–0.20] P=0.01), and 0.0004 ([95% CI, −0.0001 to 0.0014] P=0.3), all likely not clinically significant. Central and brachial SBPs of 112 mm Hg (95% CI, 111.2–114.1) and 121 mm Hg (95% CI, 120.2–121.9) were identified as optimal BP thresholds. In conclusion, central BP measured with a type I device is statistically but likely not clinically superior to brachial BP in a general population without prior cardiovascular disease. Based on the risk of major adverse cardiovascular events, the optimal type I central SBP appears to be 112 mm Hg.

Aims

Hepatocyte growth factor-regulated tyrosine kinase substrate (Hgs), a key component of the endosomal sorting complex required for transport (ESCRT), has been implicated in many essential biological processes. However, the physiological role of endogenous Hgs in the vascular system has not previously been explored. Here, we have generated brain endothelial cell (EC) specific Hgs knockout mice to uncover the function of Hgs in EC polarity and cerebrovascular stability.

Serum urate has been implicated in hypertension and cardiovascular disease, but it is not known whether it is exerting a causal effect. To investigate this, we performed Mendelian randomization analysis using data from UK Biobank, Million Veterans Program and genome-wide association study consortia, and meta-analysis of randomized controlled trials. The main Mendelian randomization analyses showed that every 1-SD increase in genetically predicted serum urate was associated with an increased risk of coronary heart disease (odds ratio, 1.19 [95% CI, 1.10–1.30]; P=4×10⁻⁵), peripheral artery disease (1.12 [95% CI, 1.03–1.21]; P=9×10⁻³), and stroke (1.11 [95% CI, 1.05–1.18]; P=2×10⁻⁴). In Mendelian randomization mediation analyses, elevated blood pressure was estimated to mediate approximately one-third of the effect of urate on cardiovascular disease risk. Systematic review and meta-analysis of randomized controlled trials showed a favorable effect of urate-lowering treatment on systolic blood pressure (mean difference, −2.55 mm Hg [95% CI, −4.06 to −1.05]; P=1×10⁻³) and major adverse cardiovascular events in those with previous cardiovascular disease (odds ratio, 0.40 [95% CI, 0.22–0.73]; P=3×10⁻³) but no significant effect on major adverse cardiovascular events in all individuals (odds ratio, 0.67 [95% CI, 0.44–1.03]; P=0.07). In summary, these Mendelian randomization and clinical trial data support an effect of higher serum urate on increasing blood pressure, which may mediate a consequent effect on cardiovascular disease risk. High-quality trials are necessary to provide definitive evidence on the specific clinical contexts where urate lowering may be of cardiovascular benefit.

Antihypertensive drug treatment is cost-effective for adults at high risk of developing cardiovascular disease (CVD). However, the cost-effectiveness in people with stage 1 hypertension (140–159 mm Hg systolic blood pressure) at lower CVD risk remains unclear. The objective was to establish the 10-year CVD risk threshold where initiating antihypertensive drug treatment for primary prevention in adults, with stage 1 hypertension, becomes cost-effective. A lifetime horizon Markov model compared antihypertensive drug versus no treatment, using a UK National Health Service perspective. Analyses were conducted for groups ranging between 5% and 20% 10-year CVD risk. Health states included no CVD event, CVD and non-CVD death, and 6 nonfatal CVD morbidities. Interventions were compared using cost-per-quality-adjusted life-years. The base-case age was 60, with analyses repeated between ages 40 and 75. The model was run separately for men and women, and threshold CVD risk assessed against the minimum plausible risk for each group. Treatment was cost-effective at 10% CVD risk for both sexes (incremental cost-effectiveness ratio £10 017/quality-adjusted life-year [$14 542] men, £8635/QALY [$12 536] women) in the base-case. The result was robust in probabilistic and deterministic sensitivity analyses but was sensitive to treatment effects. Treatment was cost-effective for men regardless of age and women aged >60. Initiating treatment in stage 1 hypertension for people aged 60 is cost-effective regardless of 10-year CVD risk. For other age groups, it is also cost-effective to treat regardless of risk, except in younger women.

Systolic interarm differences in blood pressure have been associated with all-cause mortality and cardiovascular disease. We undertook individual participant data meta-analyses to (1) quantify independent associations of systolic interarm difference with mortality and cardiovascular events; (2) develop and validate prognostic models incorporating interarm difference, and (3) determine whether interarm difference remains associated with risk after adjustment for common cardiovascular risk scores. We searched for studies recording bilateral blood pressure and outcomes, established agreements with collaborating authors, and created a single international dataset: the Inter-arm Blood Pressure Difference - Individual Participant Data (INTERPRESS-IPD) Collaboration. Data were merged from 24 studies (53 827 participants). Systolic interarm difference was associated with all-cause and cardiovascular mortality: continuous hazard ratios 1.05 (95% CI, 1.02–1.08) and 1.06 (95% CI, 1.02–1.11), respectively, per 5 mm Hg systolic interarm difference. Hazard ratios for all-cause mortality increased with interarm difference magnitude from a ≥5 mm Hg threshold (hazard ratio, 1.07 [95% CI, 1.01–1.14]). Systolic interarm differences per 5 mm Hg were associated with cardiovascular events in people without preexisting disease, after adjustment for Atherosclerotic Cardiovascular Disease (hazard ratio, 1.04 [95% CI, 1.00–1.08]), Framingham (hazard ratio, 1.04 [95% CI, 1.01–1.08]), or QRISK cardiovascular disease risk algorithm version 2 (QRISK2) (hazard ratio, 1.12 [95% CI, 1.06–1.18]) cardiovascular risk scores. Our findings confirm that systolic interarm difference is associated with increased all-cause mortality, cardiovascular mortality, and cardiovascular events. Blood pressure should be measured in both arms during cardiovascular assessment. A systolic interarm difference of 10 mm Hg is proposed as the upper limit of normal.

Renal denervation (RDNX) lowers mean arterial pressure (MAP) in patients with resistant hypertension. Less well studied is the effect of celiac ganglionectomy (CGX), a procedure which involves the removal of the nerves innervating the splanchnic vascular bed. We hypothesized that RDNX and CGX would both lower MAP in genetically hypertensive Schlager (BPH/2J) mice through a reduction in sympathetic tone. Telemeters were implanted into the femoral artery in mice to monitor MAP before and after RDNX (n=5), CGX (n=6), or SHAM (n=6). MAP, systolic blood pressure, diastolic blood pressure, and heart rate were recorded for 14 days postoperatively. The MAP response to hexamethonium (10 mg/kg, IP) was measured on control day 3 and postoperative day 10 as a measure of global neurogenic pressor activity. The efficacy of denervation was assessed by measurement of tissue norepinephrine. Control MAP was similar among the 3 groups before surgical treatments (≈130 mm Hg). On postoperative day 14, MAP was significantly lower in RDNX (−11±2 mm Hg) and CGX (−11±1 mm Hg) groups compared with their predenervation values. This was not the case in SHAM mice (−5±3 mm Hg). The depressor response to hexamethonium in the RDNX group was significantly smaller on postoperative day 10 (−10±5 mm Hg) compared with baseline control (−25±10 mm Hg). This was not the case in mice in the SHAM (day 10; −28±5 mm Hg) or CGX (day 10; −34±7 mm Hg) group. In conclusion, both renal and splanchnic nerves contribute to hypertension in BPH/2J mice, but likely through different mechanisms.

Activation of PRR ([pro]renin receptor) contributes to enhancement of intrarenal RAS and renal medullary α-ENaC and thus elevated blood pressure during Ang II (angiotensin II) infusion. The goal of the present study was to test whether such action of PRR was mediated by sPRR (soluble PRR), generated by S1P (site-1 protease), a newly identified PRR cleavage protease. F1 B6129SF1/J mice were infused for 6 days with control or Ang II at 300 ng/kg per day alone or in combination with S1P inhibitor PF-429242 (PF), and blood pressure was monitored by radiotelemetry. S1P inhibition significantly attenuated Ang II–induced hypertension accompanied with suppressed urinary and renal medullary renin levels and expression of renal medullary but not renal cortical α-ENaC expression. The effects of S1P inhibition were all reversed by supplement with histidine-tagged sPRR termed as sPRR-His. Ussing chamber technique was performed to determine amiloride-sensitive short-circuit current, an index of ENaC activity in confluent mouse cortical collecting duct cell line cells exposed for 24 hours to Ang II, Ang II + PF, or Ang II + PF + sPRR-His. Ang II–induced ENaC activity was blocked by PF, which was reversed by sPRR-His. Together, these results support that S1P-derived sPRR mediates Ang II–induced hypertension through enhancement of intrarenal renin level and activation of ENaC.

Intrinsic frequencies (IFs) derived from arterial waveforms are associated with cardiovascular performance, aging, and prevalent cardiovascular disease (CVD). However, prognostic value of these novel measures is unknown. We hypothesized that IFs are associated with incident CVD risk. Our sample was drawn from the Framingham Heart Study Original, Offspring, and Third Generation Cohorts and included participants free of CVD at baseline (N=4700; mean age 52 years, 55% women). We extracted 2 dominant frequencies directly from a series of carotid pressure waves: the IF of the coupled heart and vascular system during systole (ω₁) and the IF of the decoupled vasculature during diastole (ω₂). Total frequency variation (Δω) was defined as the difference between ω₁ and ω₂. We used Cox proportional hazards regression models to relate IFs to incident CVD events during a mean follow-up of 10.6 years. In multivariable models adjusted for CVD risk factors, higher ω₁ (hazard ratio [HR], 1.14 [95% CI], 1.03–1.26]; P=0.01) and Δω (HR, 1.16 [95% CI, 1.03–1.30]; P=0.02) but lower ω₂ (HR, 0.87 [95% CI, 0.77–0.99]; P=0.03) were associated with higher risk for incident composite CVD events. In similarly adjusted models, higher ω₁ (HR, 1.23 [95% CI, 1.07–1.42]; P=0.004) and Δω (HR, 1.26 [95% CI, 1.05–1.50]; P=0.01) but lower ω₂ (HR, 0.81 [95% CI, 0.66–0.99]; P=0.04) were associated with higher risk for incident heart failure. IFs were not significantly associated with incident myocardial infarction or stroke. Novel IFs may represent valuable markers of heart failure risk in the community.

Aims

Chronic pressure or volume overload induce concentric vs. eccentric left ventricular (LV) remodelling, respectively. Previous studies suggest that distinct signalling pathways are involved in these responses. NADPH oxidase-4 (Nox4) is a reactive oxygen species-generating enzyme that can limit detrimental cardiac remodelling in response to pressure overload. This study aimed to assess its role in volume overload-induced remodelling.

Aim

In cardiomyocytes, transverse tubules (T-tubules) associate with the sarcoplasmic reticulum (SR), forming junctional membrane complexes (JMCs) where L-type calcium channels (LTCCs) are juxtaposed to Ryanodine receptors (RyR). Junctophilin-2 (JPH2) supports the assembly of JMCs by tethering T-tubules to the SR membrane. T-tubule remodelling in cardiac diseases is associated with downregulation of JPH2 expression suggesting that JPH2 plays a crucial role in T-tubule stability. Furthermore, increasing evidence indicate that JPH2 might additionally act as a modulator of calcium signalling by directly regulating RyR and LTCCs. This study aimed at determining whether JPH2 overexpression restores normal T-tubule structure and LTCC function in cultured cardiomyocytes.

Aims

The effects of serelaxin, a recombinant form of human relaxin-2 peptide, on vascular function in the coronary microvascular and systemic macrovascular circulation remain largely unknown. This mechanistic, clinical study assessed the effects of serelaxin on myocardial perfusion, aortic stiffness, and safety in patients with stable coronary artery disease (CAD).

Aims

Cardiac ischaemia does not elicit an efficient angiogenic response. Indeed, lack of surgical revascularization upon myocardial infarction results in cardiomyocyte death, scarring, and loss of contractile function. Clinical trials aimed at inducing therapeutic revascularization through the delivery of pro-angiogenic molecules after cardiac ischaemia have invariably failed, suggesting that endothelial cells in the heart cannot mount an efficient angiogenic response. To understand why the heart is a poorly angiogenic environment, here we compare the angiogenic response of the cardiac and skeletal muscle using a lineage tracing approach to genetically label sprouting endothelial cells.

Aims

The risk of mortality from the coronavirus disease that emerged in 2019 (COVID-19) is increased by comorbidity from cardiovascular and pulmonary diseases. Air pollution also causes excess mortality from these conditions. Analysis of the first severe acute respiratory syndrome coronavirus (SARS-CoV-1) outcomes in 2003, and preliminary investigations of those for SARS-CoV-2 since 2019, provide evidence that the incidence and severity are related to ambient air pollution. We estimated the fraction of COVID-19 mortality that is attributable to the long-term exposure to ambient fine particulate air pollution.