Focus on blood pressure: sex-specific association with atrial fibrillation, role of gliflozins in hypertension, and new therapeutic targets in hypertension and orthostatic hypotension

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on hypertension, diabetes, and metabolic disorders contains the Clinical Research article entitled ‘Long-term pulse pressure trajectories and risk of incident atrial fibrillation: the Tromsø Study’ by Ekaterina Sharashova from the UiT The Arctic University of Norway, and colleagues.1 The causes of atrial fibrillation (AF) are complex, as are the mechanisms of sex-based differences.2–8 The authors explored sex-based differences in the association of long-term trends in pulse pressure with future risk of AF using data from the population-based Tromsø Study 1986–2016. Women (n = 8331) and men (n = 7638) aged ≥20 years who attended at least two of the three Tromsø Study surveys conducted between 1986 and 2001 (the exposure period) were followed up for incident AF throughout 2016. Pulse pressure ≥60 mmHg was considered elevated. Group-based trajectory modelling and Cox regression were used for statistical analyses. Three long-term trajectory groups for pulse pressure were identified: group 1 had normal pulse pressure throughout the exposure period, group 2 had normal pulse pressure at the beginning and elevated pulse pressure at the end of the exposure period, and group 3 had elevated pulse pressure throughout. Over the follow-up period, 6.8% of women and 10.5% of men developed AF. After adjustment for potential confounders at baseline, the long-term trajectory groups for elevated pulse pressure were associated with increased risk of AF in women, but not in men. In women, the adjusted hazard ratios of AF were 1.60 for group 2 and 2.78 for group 3, compared with group 1 (Figure 1). Sex-specific associations between long-term elevated pulse pressure trajectories and the risk of incident atrial fibrillation in the Tromsø Study. Women, but not men, with sustained elevated pulse pressure (≥60 mmHg) showed an increased risk of atrial fibrillation, emphasizing the need for sex-specific strategies to monitor and manage arterial stiffness to prevent atrial fibrillation1 The authors conclude that long-term elevated pulse pressure trajectories are independently associated with increased risk of AF in women, but not in men, and that the mechanisms behind these sex-based differences remain largely unexplained. The contribution is accompanied by an Editorial by Rosa Maria Bruno and Emmanuelle Vidal Petiot from the Université Paris Cité in France.9 The authors conclude that the study by Sharashova and colleagues not only paves the way for improved risk stratification for AF, it also adds new knowledge on consequences of accelerated vascular ageing in women, with relevant clinical implications, as the causal pathway leading from elevated pulse pressure to AF may be potentially reversible with both non-pharmacological and pharmacological interventions. Hypertension has a high prevalence in heart failure with preserved ejection fraction (HFpEF), which can be controlled, uncontrolled, or even resistant. In a Clinical Research article entitled ‘Empagliflozin in resistant hypertension and heart failure with preserved ejection fraction: the EMPEROR-Preserved trial’, Michael Böhm from the Saarland University in Homburg, Germany, and colleagues explored the effects of empagliflozin on systolic blood pressure (SBP), time in target range, and incidence of hypertensive urgencies, and studied cardiovascular and renal outcomes in different hypertension categories and after treatment with empagliflozin in the EMPEROR-Preserved trial.10 A total of 5533 patients were studied, and the population was separated into resistant (resHTN), uncontrolled (uctrHTN) and controlled (ctrHTN) hypertension. The effect of SBP on outcomes and treatment effects of empagliflozin were explored. Analyses were done with Cox regression analyses adjusted for demographic and clinical confounders and with a mixed model for repeated measures. Empagliflozin reduced SBP in resHTN slightly more than in the other categories in the first weeks, while thereafter there were no significant differences. The modest reduction in SBP resulted in a moderate increase in time at target and reduced hypertensive urgencies The primary endpoint was more prevalent in resHTN (P = .03) but the treatment effect of empagliflozin on the primary endpoint was similar in resHTN, uctrHTN, and ctrHTN (P for interaction = .92), as were the improvement of the estimated glomerular filtration rate slope (P for interaction = .95) and change in quality of life by empagliflozin. The authors conclude that in HFpEF, the prevalence of resHTN is high and is associated with higher outcome rates compared with ctrHTN and uctrHTN. The treatment effect is not modified by hypertension categories. The contribution is accompanied by an Editorial by Franz Messerli, Renate Schoenenberger-Berzins, and Michel Burnier from the Luzerner Kantonsspital in Switzerland.11 The authors conclude that the take-home lesson from the BP analysis of Böhm et al. is simple and straightforward: sodium–glucose co-transporter 2 (SGLT2) inhibitors such as empagliflozin are of little use ‘for’ hypertension but may be exceedingly helpful ‘in’ hypertension. When added in hypertensive patients, SGLT2 inhibitors are prone to be particularly efficacious in mitigating hypertensive target organ disease. Individuals with HF, other forms of cardiovascular disease, or kidney disease are at increased risk for the development and adverse health effects of diabetes. Gliflozins have been shown to be beneficial in HF, chronic kidney disease, and diabetes.12–16 In a Clinical Research article entitled ‘Sodium–glucose co-transporter 2 inhibitors and new-onset diabetes in cardiovascular or kidney disease’, John Ostrominski from the Harvard Medical School in Boston, MA, USA, and colleagues note that the aim of this meta-analysis was to determine the effect of SGLT2 inhibitors on incident diabetes in HF across the spectrum of left ventricular ejection fraction (LVEF) and across the broader spectrum of cardiovascular or kidney disease.12 First, the effects of dapagliflozin vs placebo on new-onset diabetes were assessed in a pooled, participant-level analysis of the DAPA-HF and DELIVER trials. New-onset diabetes was defined as the new initiation of glucose-lowering therapy during follow-up, and time from randomization to new-onset diabetes was evaluated using Cox proportional hazards models. Second, PubMed and Embase were searched to identify large-scale randomized clinical outcomes trials (RCTs) comparing SGLT2 inhibitors with placebo among adults with cardiovascular or kidney disease. A trial-level meta-analysis was then conducted to summarize the treatment effects of SGLT2 inhibitors on the incidence of new-onset diabetes. In the pooled analysis of DAPA-HF and DELIVER including >5500 participants with HF but without diabetes at baseline, dapagliflozin reduced the incidence of new-onset diabetes by 33% (hazard ratio [HR], 0.67; P = .012) when compared with placebo. There was no evidence of heterogeneity across the spectrum of continuous LVEF or key subgroups. Among seven complementary RCTs including ∼18 000 participants with cardiovascular or kidney disease, SGLT2 inhibitors reduced the incidence of new-onset diabetes by 26% (HR, 0.74; P < .001), with consistent effects across trials (Figure 2). Findings of a participant-level pooled analysis of the DAPA-HF and DELIVER trials evaluating treatment effects of dapagliflozin vs placebo on new-onset diabetes requiring initiation of glucose-lowering therapy (left). Findings of a fixed-effects meta-analysis of seven complementary cardiovascular and kidney trials evaluating the effect of SGLT2i on new-onset diabetes (right). DAPA-CKD, Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease; DAPA-HF, Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; DAPA-MI, Dapagliflozin in Patients with Myocardial Infarction; DELIVER, Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure; EMPA-KIDNEY, Study of Heart and Kidney Protection with Empagliflozin; EMPEROR-Preserved, Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction; EMPEROR-Reduced, Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction; HR, hazard ratio; LVEF, left ventricular ejection fraction; SGLT2i, sodium–glucose co-transporter 2 inhibitor12 The authors conclude that SGLT2 inhibitors reduce the incidence of new-onset diabetes among individuals with cardiovascular or kidney disease. These findings suggest that SGLT2 inhibitor implementation may have an important ancillary benefit on prevention or delay of diabetes in these high-risk populations. The contribution is accompanied by an Editorial by Anna Norhammar and Viveca Ritsinger from the Karolinska Institutet in Stockholm, Sweden.17 The authors conclude that the study by Ostrominski et al. is timely and important as it highlights that we should not miss the opportunity to detect unknown diabetes and pre-diabetes among our cardiology patients. This is especially true in this era where we have several strategies to prevent, delay, and regress diabetes, and at the same time prevent future cardiovascular events. Dendritic cells (DCs) are closely related to BP regulation. Mineralocorticoid receptors (MRs) are an important drug target for antihypertensive treatment.18 However, the role of DC MR in the pathogenesis of hypertension has not been fully elucidated. In a Translational Science article entitled ‘Dendritic cell mineralocorticoid receptor controls blood pressure by regulating T helper 17 differentiation: role of the Plcβ1/4–Stat5–NF-κB pathway’, Yong-Li Wang from the Shanghai Jiao Tong University School of Medicine in China, and colleagues aimed to determine the role of DC MR in BP regulation and to explore the mechanism.19 Renal biopsy and peripheral blood samples were collected from hypertensive patients for immunostaining and flow cytometry. Dendritic cell MR knockout (DCMRKO) mice, DC MR-overexpressing (DCMROV) mice, DCMROV/IL-17A knockout (DCMROV/IL-17AKO) mice, and finerenone-treated C57BL/6 mice were infused with angiotensin II (Ang II) to establish hypertensive models. Western blotting, chromatin immunoprecipitation, co-immunoprecipitation, and in vivo DC depletion or adoptive transfer were used to delineate the functional importance of DC MRs in hypertension development. Finerenon suppressed DC aggregation and activation, as well as hypertension in HTN and mice. Compared with littermate control mice, DCMRKO mice had strikingly decreased BPs and attenuated target organ damage after Ang II infusion. Flow cytometry showed that DC MR deficiency mitigated Ang II-induced DC activation and T helper 17 (Th17) cell differentiation. RNA sequencing revealed that MR-deficient DCs had elevated expression of Plcβ1 and Plcβ4, knockdown of which reversed the inhibitory effect of MR deficiency on DC activation and Th17 differentiation. Adoptive transfer of MR-deficient DCs protected Ang II-induced hypertension, whereas knockdown of Plcβ1/4 eliminated the protective effects. At the molecular level, MRs negatively regulated Plcβ1/4, which recruited SHP-1 to inactivate Stat5, resulting in enhanced NF-κB activation and Th17 polarization. Furthermore, DCMROV mice manifested more elevated BPs and target organ damage than control mice after Ang II infusion, and these differences were abolished in DCMROV/IL-17AKO mice. Finally, MR antagonists decreased the aggregation of Th17 in HTN and mice. The authors conclude that DC MRs play important roles in the pathogenesis of hypertension by regulating Th17 through Plcβ1/4–Stat5–NF-κB signalling, and blockade of DC MRs is beneficial for treating hypertension. This manuscript is accompanied by an Editorial by Tomasz Mikolajczyk, Tomasz Śliwa, and Tomasz Guzik from the Jagiellonian University Medical College from Krakow, Poland.20 The authors note that the study by Wang et al. provides crucial mechanistic insights into the regulation of BP by DC MRs, particularly through the MR–Plcβ1/4–Stat5–NF–κB axis, which controls both DC activation and subsequent Th17 polarization. This research exemplifies the effective use of both clinical–translational and experimental models to understand high BP mechanisms. It highlights the significant role of immunometabolism in the pathogenesis of hypertension. These findings underscore the need for new therapies to target vascular and cardiovascular inflammation in a more precise and specific manner by addressing focused mechanisms of immune activation. In a Rapid Communications contribution entitled ‘Carbon dioxide for neurogenic orthostatic hypotension in adults: a novel therapy’, Jacquie Baker from the University of Calgary in Canada, and colleagues tested the hypothesis that increased inspired CO2 increases standing BP in patients with neurogenic orthostatic hypotension (nOH).21 Neurogenic orthostatic hypotension is a hallmark feature of autonomic nervous system failure.22 On standing, people with nOH experience large reductions in BP (≥20/10 mmHg) and debilitating symptoms (e.g. light-headedness, blurred vision, and syncope). Current BP therapies have limited efficacy and potentially serious side effects, including supine hypertension, creating a strong clinical need for new therapeutic approaches. Whether exogenous CO2 can prevent OH in these patients is unknown. In this proof-of-concept trial, the authors performed a randomized, unblinded study in 17 nOH patients. Participants completed three sit-to-stand tests breathing: (i) 0 mmHg CO2 relative to baseline; (ii) + 5 mmHg CO2 relative to baseline (+5CO2), and (iii) + 10 mmHg CO2 relative to baseline (+10CO2). At 0CO2, 71% of patients met the SBP criteria for OH. During +5CO2, 47% of patients met OH criteria, while only 25% met OH criteria during +10CO2. Further, + 10CO2 reduced the proportion of patients meeting OH criteria compared with 0CO2 (P = .02). Importantly, increased inspired CO2 reduced the duration of OH while patients were standing. The authors conclude that increased inspired CO2 powerfully elevates standing BP in patients with nOH and reduces the duration of OH. Rather than through changes in heart rate or systematic vascular resistance, this response is primarily driven by an increase in stroke volume and cardiac output. This haemodynamic profile strongly suggests that inspired CO2 increases BP via enhanced cardiac venous return. The editors hope that this issue of the European Heart Journal will be of interest to its readers. Dr. Crea reports speaker fees from Abbott, Amgen, Astra Zeneca, BMS, Chiesi, Daiichi Sankyo, enarini outside the submitted work. With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.