From strokes and heart attacks to organ damage and premature death, high blood pressure takes a huge toll on human health. In an op-ed published in The Washington Post, Dr. Tom Frieden, former director of the U.S. Centers for Disease Control and Prevention (CDC), described hypertension as "the deadliest yet most overlooked and pervasive epidemic of our time."
Key points
➤ Dysregulated aldosterone secretion (sometimes caused by obesity) can lead to high blood pressure. ➤ Targeted therapies that directly reduce aldosterone synthesis may be helpful in treating cases of refractory hypertension.
Epidemiological data on hypertension
Hypertension is a major modifiable risk factor for premature death from cardiovascular disease worldwide. In 2021, hypertension was responsible for 10.8 million cardiovascular deaths and 11.3 million deaths worldwide. This and other alarming statistics highlight that hypertension is a huge ongoing public health challenge:
➤ The national hypertension sample survey conducted by the mainland in 1958~1959, 1979~1980, 1991 and 2002 found that the crude prevalence of hypertension among ≥ 15-year-old residents was 5.1%, 7.7%, 13.6% and 17.6%, respectively, showing an overall upward trend.
➤ According to the China Hypertension Survey (CHS), the crude prevalence of hypertension among Chinese ≥ 18-year-old residents in 2012~2015 was 27.9%, and the weighted rate was 23.2%, and the estimated number of adults with hypertension in China was 245 million, and the crude rate of high normal blood pressure was 39.1%, and the weighted rate was 41.3%, and it was estimated that there were 435 million people with high normal blood pressure in China.
➤ In 2015, the hypertension control rate of ≥ 18-year-old adults in China was 16.8%, which is a significant improvement compared with previous surveys, but still at a low level.
Currently, a variety of antihypertensive drugs and their combination therapies are approved for the treatment of hypertension. While we have made great strides in controlling blood pressure, there is an urgent need for more effective and targeted treatment strategies for the large number of patients whose blood pressure remains uncontrolled.
The role of aldosterone in hypertension
A variety of factors can contribute to hypertension, but emerging research is focusing on a culprit that is not yet fully understood: aldosterone.
Aldosterone is a steroid hormone secreted by the globular band of the adrenal cortex and plays an important role in maintaining sodium and water homeostasis. These classical effects are mediated by mineralocorticoid receptors (MRs).
However, dysregulated or overactive aldosterone reactions can have cascading harmful effects on the cardiovascular system, kidneys, and metabolism. The new data suggest that the MR-independent pathway is important in a number of deleterious effects, such as G protein-coupled estrogen receptor 1 (GPER1) and its role in aldosterone-induced endothelial cell dysfunction.
Hidden hormones in high blood pressure
Not all cases of hypertension involve aldosterone dysregulation, but studies have shown that aldosterone plays a significant role in up to 30% of cases. Aldosterone works through MR-dependent and MR-independent pathways, ultimately leading to sodium, water retention, and increased blood pressure.
Patients with aldosterone-driven hypertension are at higher risk of complications than those with classical hypertension for the following reasons:
➤ Increased risk of coronary heart disease, stroke, and heart failure;
➤ Metabolic syndrome and diabetes;
➤ Progression of chronic kidney disease.
In addition, obesity rates have risen alarmingly over the past few decades, presenting a complex picture intertwined with high blood pressure. Obesity is the main risk factor for hypertension, accounting for 65%~78% of hypertension cases, and studies have also revealed a strong association between obesity and aldosterone dysregulation.
For example, aldosterone dysregulation in obese patients includes both renin-dependent and renin-independent disorders, but the individual driving mechanisms of the latter are complex. The investigators hypothesize that the hormone leptin secreted by adipocytes represents a renin-independent pathway and is a direct regulator of aldosterone synthase expression, which in turn promotes increased blood pressure and cardiovascular dysfunction and other related diseases.
Old and new treatment options
1. Previous treatment regimens
Current standard of care such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin receptor antagonists (ARBs) target the renin-angiotensin-aldosterone system (RAAS), but their focus is primarily on the renin-dependent pathway. Patients treated with ACE inhibitors/ARBs initially have decreased aldosterone levels, but up to 30%~40% of patients have increased aldosterone levels after long-term treatment (known as aldosterone "escape breakthrough"). Therefore, further suppression of aldosterone levels is critical for a significant number of patients treated with ACE inhibitors/ARBs with persistent and poorly controlled blood pressure.
Mineralocorticoid receptor antagonists (MRAs) are the only aldosterone-specific therapies available, but they have certain limitations:
➤ Antialdosterone effect is only mediated by an MR-dependent mechanism, allowing continuous transmission of aldosterone signaling through an MR-independent mechanism;
➤ elevated plasma aldosterone concentrations as a compensatory response, which may lead to greater aldosterone signaling via an MR-independent mechanism;
➤ Patients with resistant hypertension have a worse prognosis compared with adrenalectomy;
➤ By binding to progesterone and androgen receptors, it causes menstrual irregularities, sexual dysfunction and gynecomastia;
➤ Potential adverse effects, such as hyperkalemia, hyponatremia, and fatigue, limit its use in specific patient populations.
2. Emerging treatment options
Given the limitations of MRA, other targeted therapy regimens that reduce aldosterone synthesis may be beneficial in patients with aldosterone-dependent hypertension, including investigational agents such as lorundrostat (Mineralys Therapeutics) and baxdrostat (AstraZeneca). Lorundrostat and baxdrostat are two of the latest investigational drugs in aldosterone synthase inhibitors (ASIs) that selectively target aldosterone by inhibiting aldosterone synthase (CYP11B2). Selective inhibitors of aldosterone synthase have the following potential:
➤ Provide more targeted hypertension management programs for patients with aldosterone-dependent (or promoting) hypertension;
➤ Significantly reduces aldosterone levels without affecting cortisol and reduces signaling (MR and non-MR effects) in all aldosterone pathways;
➤ Improve blood pressure control rate, especially for patients with high blood pressure where aldosterone is the underlying cause.
The Target-HTN trial, published in September, showed that lorundrostat was efficacious in patients with a body mass index (BMI) of ≥30 kg/m² (placebo-adjusted systolic blood pressure reduction of 16.7 mmHg and 12.3 mmHg, respectively) in the 50 mg and 100 mg once-daily treatment groups, and improved blood pressure control in the general patient population. These findings suggest that obesity may be an important type of ASI treatment.
In addition, a post-hoc analysis of the trial showed that increased BMI was associated with an increase in the leptin cycle, which is consistent with emerging evidence for the existence of a leptin-driven positive feedback loop between obesity, aldosterone, and hypertension.
prospect
As Dr. Frieden points out in his op-ed, getting 50% of people with high blood pressure to reach their target blood pressure would prevent 200 deaths and 200 million strokes and heart attacks each year over the next 25 years.
ASI represents a new innovation that may provide new treatment options for lowering blood pressure, especially in cases of uncontrolled hypertension caused by obesity-driven dysregulation of aldosterone secretion, without the adverse hormonal effects of MRA. Future acceptance and adoption of well-tolerated regimens may improve patient outcomes and gradually reduce the burden of hypertension.
Bibliography:
[1] Florian Rader, MD. Aldosterone: The hidden hormone linking hypertension and obesity, and a potential target. Healio. March 18, 2024.
[2] Summary of China Cardiovascular Health and Disease Report 2022[J].Chinese Journal of Circulation,2023,38(06):583-612.
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