By América Torres
Resistant or refractory arterial hypertension is defined as blood pressure that remains above the target despite the use of three or more antihypertensive medications, including diuretics.
This complex condition affects a significant proportion of the hypertensive population and is associated with increased cardiovascular morbidity and mortality. Despite the availability of a wide range of pharmacological therapies, achieving optimal blood pressure control in patients with resistant hypertension remains a significant challenge.
Fortunately, recent advances in the field have made several promising pharmacological options available to physicians and patients, including spironolactone, mineralocorticoid receptor antagonists, and renal denervation. Additionally, adopting a personalized management approach based on genetic and other biomarkers may offer new opportunities to tailor therapy and improve outcomes.
This article focuses on the pathophysiology and management strategies of resistant arterial hypertension.
Definition of Resistant Arterial Hypertension
Definition of Resistant Arterial Hypertension
Resistant arterial hypertension is defined as blood pressure above target levels despite the use of at least three antihypertensive medications of different substance classes, including a diuretic, at appropriate doses and combination.
The following table outlines how different authorities classify resistant arterial hypertension:
Prevalence of Resistant Arterial Hypertension
Prevalence of Resistant Arterial Hypertension
Resistant arterial hypertension is a significant public health concern due to its high prevalence. In a meta-analysis including data from 91 cohort or cross-sectional studies comprising more than 3.2 million patients, the prevalence of apparent and true resistant hypertension was 15% and 10% in patients treated for hypertension, respectively. The prevalence in the included studies ranged from 5% to 35%, highlighting three challenges in determining the true prevalence of resistant hypertension.
The prevalence of resistant hypertension varies depending on several factors, including age, sex, race, ethnicity, and comorbid medical conditions. It is more prevalent in older adults, men, and individuals with obesity, diabetes, or kidney disease.
Types of Resistant Arterial Hypertension
Types of Resistant Arterial Hypertension
Pseudo-Resistant Hypertension: Before concluding that the patient is truly resistant to treatment, it is necessary to exclude pseudo-resistant hypertension. This occurs when blood pressure is elevated due to factors other than hypertension, such as:
- Poor adherence to prescribed medications.
- White-coat hypertension, in which blood pressure is elevated in a medical setting compared to normal ambulatory blood pressure.
- Incorrect blood pressure measurements due to errors such as using a cuff that is too small or not allowing the patient to rest before measuring their blood pressure.
- Irrational therapy regimens and/or inadequate dosing.
The diagnosis of pseudo-resistant hypertension can be confirmed by performing ambulatory blood pressure monitoring (ABPM) over a 24-hour period. Additionally, improving measurement techniques, addressing medication adherence issues, or using alternative medication options are recommended.
Refractory Arterial Hypertension: Occurs when blood pressure remains elevated despite optimal treatment with multiple antihypertensive medications and lifestyle modifications. Refractory hypertension is a rare condition that may require more invasive interventions, such as renal denervation or baroreceptor activation therapy. These interventions are typically reserved for patients with severe hypertension who have failed multiple treatment options.
True Resistant Arterial Hypertension
True Resistant Arterial Hypertension
True resistant hypertension occurs when elevated blood pressure is due to various factors. The most common ones include:
Genetic predisposition: One of the most associated genes with resistant hypertension is the angiotensinogen (AGT) gene. The AGT gene encodes a protein that is a precursor to angiotensin II, a potent vasoconstrictor critical in blood pressure regulation.
Lifestyle factors: Various lifestyle factors can significantly and chronically affect blood pressure. Among these are stress (both mental and physical), environmental pollution, and lack of quality sleep. Sleep deprivation is crucial as it induces stress on the body, which can increase salt appetite and reduce renal salt-fluid excretion.
Medication nonadherence: A study investigated the relationship between medication regimen complexity and medication adherence in hypertensive patients. The results showed that patients prescribed more than three antihypertensive medications had lower adherence rates compared to those prescribed fewer medications.
Underlying medical conditions: Two notable conditions are obesity and sleep apnea. Obesity can modify the structure and function of blood vessels, promote insulin resistance and inflammation, and result in increased sodium retention, making it challenging to control blood pressure effectively. It's essential to note that adipose tissue is an active endocrine organ that produces various pro-inflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), contributing to endothelial dysfunction and vascular remodeling.
Several studies have demonstrated that sleep apnea is associated with resistant hypertension. One of them found that 83% of patients with resistant hypertension had moderate to severe sleep apnea. Another clinical trial found that 53% of patients with resistant hypertension had sleep apnea, compared to 31% of patients with controlled hypertension.
Sympathetic nervous system: The effect of the sympathetic nervous system on the vascular system, heart, and kidneys plays a crucial role in blood pressure regulation. Sympathetic nervous system activation can lead to heightened vasoconstriction, increased heart rate and contractility, reduced venous capacitance, and increased sodium and water retention, promoting hypertension development. Additionally, sympathetic activation can contribute to oxidative stress and inflammation, leading to endothelial dysfunction and vascular remodeling, key features of hypertension.
The diagnosis of resistant hypertension requires careful evaluation to exclude secondary causes of hypertension and optimize medication therapy. Recent research indicates that applying principles of chaos theory can provide new perspectives on this issue, using an approach based on the fact that biological systems are inherently non-linear and chaotic. Thus, minor changes in systemic blood pressure can cause significant effects on the overall response to treatment.
Management and treatment of resistant hypertension
Management and treatment of resistant hypertension
True resistant hypertension requires a comprehensive evaluation and varied treatment strategies to achieve control. Treatment approaches may include using different classes of antihypertensive medications, improving patient adherence to medication therapy, lifestyle modifications, and addressing underlying medical conditions. Let's delve a bit deeper into these options.
Lifestyle modification. The TRIUMPH clinical trial found that changes including weight loss, physical activity, and a balanced diet are associated with a significant reduction in blood pressure among patients with resistant hypertension. In fact, the study “Combined Aerobic and Resistance Exercises Evokes Longer Reductions on Ambulatory Blood Pressure in Resistant Hypertension: A Randomized Crossover Trial “ found that combining aerobic and resistance exercise three times per week for 12 weeks resulted in significant reductions in systolic and diastolic blood pressure.
Pharmacological intervention. Among the available drugs, one that has received considerable attention in recent years is mineralocorticoid receptor antagonists (MRAs). MRAs, such as spironolactone and eplerenone, have been shown to reduce blood pressure in patients with resistant hypertension. MRAs have even been shown to reduce mortality in patients with heart failure with reduced ejection fraction (HFrEF), hence they are recommended for patients with resistant hypertension and secondary hyperaldosteronism.
On the other hand, combining drugs from diverse classes to lower blood pressure has been shown to be approximately five times more effective compared to doubling the dose of a single drug (monotherapy). However, the study “Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials” showed that combining two drugs from different classes led to a more substantial reduction in blood pressure of approximately 9 mmHg, resulting in an additional reduction of 15% in coronary heart disease events and 19% in stroke incidence.
Furthermore, the effect of renin-angiotensin-aldosterone system (RAAS) blockers is enhanced by thiazide-induced increase in sodium excretion, as it stimulates renin release. Concurrently, RAAS blockers attenuate thiazide-induced potassium depletion, thereby minimizing the likelihood of hypokalemia.
Advantages of ABPM in the diagnosis and treatment of resistant hypertension
Advantages of ABPM in the diagnosis and treatment of resistant hypertension
As mentioned earlier, before diagnosing a patient with resistant hypertension, a thorough evaluation is necessary. One of the most widespread therapies to achieve an accurate diagnosis is the use of a 24-hour ABPM. All ABPMs work the same way; what makes the difference is the technology of the recorders and the functionalities of their software to generates the 24-hour monitoring report.
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REFERENCES
Meeti Keyur Champaneria et al. When blood pressure refuses to budge: exploring the complexity of resistant hypertension. Front Cardiovasc Med. 2023; 10: 1211199. Published online 2023 Jun 21. doi: 10.3389/fcvm.2023.1211199
Lucas Lauder, Felix Mahfoud and Michael Böhm. Management of Resistant Hypertension. Vol. 75:443-457 (Volume publication date January 2024) https://doi.org/10.1146/annurev-med-050922-052605
