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Cardiovascular disease remains the leading cause of death worldwide. Cardiovascular research has therefore never been more crucial. Cardiovascular researchers must be provided with a research environment that enables them to perform at their highest level, maximizing their opportunities to work effectively with key stakeholders to address this global issue. At present, cardiovascular researchers face a range of challenges and barriers, including a decline in funding, job insecurity and a lack of diversity at senior leadership levels. Indeed, many cardiovascular researchers, particularly women, have considered leaving the sector, highlighting a crucial need to develop strategies to support and retain researchers working in the cardiovascular field. In this Roadmap article, we present solutions to problems relevant to cardiovascular researchers worldwide that are broadly classified across three key areas: capacity building, research funding and fostering diversity and equity. This Roadmap provides opportunities for research institutions, as well as governments and funding bodies, to implement changes from policy to practice, to address the most important factors restricting the career progression of cardiovascular researchers.

Cardiovascular disease remains the leading cause of death worldwide. Cardiovascular research has therefore never been more crucial. Cardiovascular researchers must be provided with a research environment that enables them to perform at their highest level, maximizing their opportunities to work effectively with key stakeholders to address this global issue. At present, cardiovascular researchers face a range of challenges and barriers, including a decline in funding, job insecurity and a lack of diversity at senior leadership levels. Indeed, many cardiovascular researchers, particularly women, have considered leaving the sector, highlighting a crucial need to develop strategies to support and retain researchers working in the cardiovascular field. In this Roadmap article, we present solutions to problems relevant to cardiovascular researchers worldwide that are broadly classified across three key areas: capacity building, research funding and fostering diversity and equity. This Roadmap provides opportunities for research institutions, as well as governments and funding bodies, to implement changes from policy to practice, to address the most important factors restricting the career progression of cardiovascular researchers.

——The concept of local formation of angiotensin II in the kidney has changed over the last 10–15 years. Local synthesis of angiotensinogen in the proximal tubule has been proposed, combined with prorenin synthesis in the collecting duct. Binding of prorenin via the so-called (pro)renin receptor has been introduced, as well as mega-lin-mediated uptake of filtered plasma-derived renin-angiotensin system (RAS) components. Moreover, angiotensin metabolites other than angiotensin II [notably angiotensin-(1-7)] exist, and angiotensins exert their effects via three different receptors, of which angiotensin II type 2 and Mas receptors are considered renoprotective, possibly in a sex-specific manner, whereas angiotensin II type 1 (AT1) receptors are believed to be deleterious. Additionally, internalized angiotensin II may stimulate intracellular receptors. Angiotensin-converting enzyme 2 (ACE2) not only generates angiotensin-(1-7) but also acts as coronavirus receptor. Multiple, if not all, cardiovascular diseases involve the kidney RAS, with renal AT1 receptors often being claimed to exert a crucial role. Urinary RAS component levels, depending on filtration, reabsorption, and local release, are believed to reflect renal RAS activity. Finally, both existing drugs (RAS inhibitors, cyclooxygenase inhibitors) and novel drugs (angiotensin receptor/nepri-lysin inhibitors, sodium-glucose cotransporter-2 inhibitors, soluble ACE2) affect renal angiotensin formation, thereby displaying cardiovascular efficacy. Particular in the case of the latter three, an important question is to what degree they induce renoprotection (e.g., in a renal RAS-dependent manner). This review provides a unifying view, explaining not only how kidney angiotensin formation occurs and how it is affected by drugs but also why drugs are renoprotective when altering the renal RAS. Significance Statement——Angiotensin formation in the kidney is widely accepted but little understood, and m

Multiple types of renin-angiotensin system (RAS) blockers exist, allowing interference with the system at the level of renin, angiotensin-converting enzyme, or the angiotensin II receptor. Yet, in particular, for the treatment of hypertension, the number of patients with uncontrolled hypertension continues to rise, either due to patient noncompliance or because of the significant renin rises that may, at least partially, overcome the effect of RAS blockade (RAS escape). New approaches to target the RAS are either direct antisense oligonucleotides that inhibit angiotensinogen RNA translation, or small interfering RNA (siRNA) that function via the RNA interference pathway. Since all angiotensins stem from angiotensinogen, lowering angiotensinogen has the potential to circumvent the RAS escape phenomenon. Moreover, antisense oligonucleotides and small interfering RNA require injections only every few weeks to months, which might reduce noncompliance. Of course, angiotensinogen suppression also poses a threat in situations where the RAS is acutely needed, for instance in women becoming pregnant during treatment, or in cases of emergency, when severe hypotension occurs. This review discusses all preclinical data on angiotensinogen suppression, as well as the limited clinical data that are currently available. It concludes that it is an exciting new tool to target the RAS with high specificity and a low side effect profile. Its long-term action might revolutionize pharmacotherapy, as it could overcome compliance problems. Preclinical and clinical programs are now carefully investigating its efficacy and safety profile, allowing an optimal introduction as a novel drug to treat cardiovascular and renal diseases in due time.

OBJECTIVE: Angiogenesis inhibitors are effective anti-cancer agents, but also cause hypertension and renal injury. Earlier, we observed in rats that high-dose aspirin (capable of blocking cyclooxygenase (COX)-1 and -2) prevented these side effects better than low-dose aspirin (blocking COX-1 only). Therefore, we hypothesized that selective COX-2 inhibition would prevent toxicity during angiogenesis inhibition, and that this toxicity involves a reduced ratio of vasodilator/constrictor COX-derived prostanoids, i.e., prostacyclin (PGI2) and thromboxane (TXA2). DESIGN AND METHOD: Male WKY rats received vehicle, angiogenesis inhibition (sunitinib (SU), 14 mg/kg/day) alone or combined with COX-2 inhibition (celecoxib, 10 mg/kg/day), a PGI2 analogue (iloprost 100 mcg/kg/day), or a dual TXA2 synthase/receptor antagonist (picotamide, 2.5 mg/kg/day) for 8 days (n = 7-8/group). Mean arterial pressure (MAP) was measured via radiotelemetry, vascular function was assessed via wire myography, and biochemical measurements were performed by ELISA. RESULTS: SU induced a rapid increase in MAP (16 ± 2 vs. 3 ± 1 mmHg after vehicle on day 6, P < 0.001), which was blunted by celecoxib (10 ± 2 mmHg on day 6, P = 0.06 versus SU), temporarily attenuated by iloprost (on treatment days 1-2) and unaffected by picotamide. Wire myography demonstrated a trend towards increased vasoconstrictor response to endothelin-1 in iliac arteries after SU, which was prevented by celecoxib (P < 0.001). SU increased albuminuria (0.6 ± 0.1 vs. 0.3 ± 0.1 mg/24 h after vehicle; P < 0.001), and this was prevented by celecoxib only (0.4 ± 0.1 mg/24 h, P = 0.01 vs. SU). SU increased the PGI2/TXA2 ratio in both plasma (3.0 ± 1.1 vs. 0.6 ± 0.2 after vehicle, P = 0.02) and urine (23 ± 2.1 vs. 0.9 ± 0.2 after vehicle, P < 0.0001). CONCLUSIONS: In conclusion, selective COX-2 inhibition combats angiogenesis inhibitor-induced hypertension and renal toxicity. SU paradoxically increases the PGI2/TXA2 ratio, par

Previous studies showed that postmenopausal women are more likely to have poorly controlled hypertension than men of the same age. Whether this is caused by inadequate treatment or poor response to antihypertensive agents remains unknown. The aim of this study is to analyze treatment response to the most potent renin angiotensin aldosterone system (RAAS) inhibitor perindopril in different age categories in women and men. Individual patient data were used from the combined European Trial on Reduction of Cardiac Events With Perindopril (EUROPA), Perindopril Protection Against Recurrent Stroke Study (PROGRESS), and Action in Diabetes and Vascular disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) trials, which include patients with vascular disease (n = 29,463). We studied the relative and absolute changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) during a 4-week run-in phase in which all patients were treated with the perindopril-based treatment in different age categories. In total, 8366 women and 21,097 men were included in the analysis. Women greater than 65 years of age showed a significantly smaller blood pressure reduction after perindopril treatment (2.8 mmHg [95% confidence interval {CI} = 0.1–5.5] less reduction compared to women ≤45 years, p = 0.039). In men, the SBP reduction after perindopril in patients greater than 55–65 and greater than 65 years was lower compared to the age category less than or equal to 45 years (adjusted mean difference >55–65: 2.8 mmHg [95% CI = 1.8–3.7], p < 0.001, >65: 3.7 mmHg [95% CI = 2.7–4.7], p < 0.001). A trend of less blood pressure reduction was seen with ageing in both men and women (p < 0.001). To conclude, we observed that in both women and men the perindopril leads to less SBP reduction with increasing age, whereas the DBP reduction increases with age. More research is needed to determine whether it would be beneficial to use age-adjusted perindopril dosages.

The New Investigators Committee (NIC) of the International Society of Hypertension (ISH) is a dynamic group of junior doctors and scientists, actively involved in various society activities. This report highlights the events (scientific meetings and summer schools) and activities (social media, mentorship and networking) during 2019 including May Measurement Month and collaborative efforts with the ISH Women in Hypertension Research Committee (WiHRC). The ISH NIC is proud to sponsor awards for outstanding work by junior and emerging researchers at hypertension conferences and also provides opportunities to showcase their work on our social media features such as 'Our Fellows Work' and the New Investigator Spotlight of the month. In 2020, the ISH NIC aims to promote women in leadership roles and to foster strong collaborations with and between society committees and other scientific organizations.