Cardiovascular Outcomes and Potential Long-term Benefits of Renal Denervation in Patients with Resistant Hypertension

    Authors

    Abstract

    Resistant hypertension is the failure to achieve target blood pressure in spite of using a minimum of 3 antihypertensive drugs of different classes, one of which must be a diuretic, at maximal tolerated doses. The prevalence of true resistant hypertension ranges between 7.9-10.0% and is associated with higher risk of kidney and cardiovascular system damage. Treatment of resistant hypertension focuses on lifestyle modifications and pharmacological therapy. Device-based therapies are indicated in patients in whom pharmacological agents failed to control the blood pressure. Evidence suggests beneficial effects of renal sympathectomy on life expectancy and prevention of cardiovascular complications in patients with resistant hypertension with chronic activation of the sympathetic nervous system, such as chronic kidney disease and type 2 diabetes mellitus. In terms of costs, there is no question pharmacoeconomically that effective blood pressure control in resistant hypertension with drugs and new innovative devices therapies is cheaper than treating the consequences of hypertensive target organ damage.

    Keywords

    resistant hypertension, cardiovascular risk, renal denervation

    DOI

    https://doi.org/10.15836/ccar2018.277

    Full Text

    Arterial hypertension is the most common chronic disease in modern society, affecting 30 – 45% of the general population, with the ratio increasing with age. The existing guidelines of the European Society of Hypertension/European Society of Cardiology define arterial hypertension as systolic pressure values above 140 mmHg and diastolic pressure above 90 mmHg (1). A linear association has been demonstrated between blood pressure (BP) and cardiovascular (CV) events such as stroke, myocardial infarction, chronic heart failure, and chronic kidney disease (CKD). The risk of CV mortality doubles with every increase of 20/10 mmHg in systolic and diastolic BP (2). Arterial hypertension is generally comorbid with other CV risk factors such as diabetes, hyperlipidemia, and obesity, the latter of which is reaching pandemic proportions (1). Resistant hypertension (RH) is hypertension in which the recommended BP values (2 and renal arteries with appropriate anatomy, i.e. a diameter greater than 4 mm (12). After the early studies demonstrated the safety and effectiveness of the method (postprocedural reduction of BP by 27/17 mmHg after 12 months and 32/12 mmHg after 6 months), demonstration of effectiveness in a randomized study was attempted, but the SYMPLICITY HNT-3 study from 2014, due to a number of procedural issues, did not demonstrate the target reduction in BP of more than 10 mmHg in comparison with the control group (15). Today, uncontrolled RH must be confirmed before every renal denervation procedure using the 24-hour ambulatory blood pressure monitor. Pseudoresistant and secondary hypertension must be eliminated and anatomical suitability for the procedure must be confirmed, as must patient compliance not only by measuring the number of pills the patient consumes but also by determining medication levels in blood and/or urine (19). The greatest problem of the early studies on renal denervation was not only the heterogeneity of responses after renal denervation in the reduction BP, but also a large ratio of patients who had a partial response to treatment or were nonresponders, i.e. the treatment did not have any effect, which is understandable if we consider the pathogenic process of BP regulation (20). Increased activity of the sympathetic nervous system is the most common but not the only underlying cause of hypertension. A similar response regarding heterogeneity can also be observed in prescribing antihypertensive medication (6, 20). There are several potential ways of reducing the variability of responses in reduction of BP values after renal denervation: the quality of the procedure itself (new catheters allow more distal denervation where most of the sympathetic plexus is located, and the experience of the interventional radiologist/cardiologist also plays a role) as well as choosing patients who will benefit from additional treatment with renal denervation (21). In choosing patients for renal denervation, the current recommendation is to determine arterial stiffness using pulse wave velocity (PWV) measurement, which is a predictor of total and CV mortality, associating elevated PWV with poorer response to renal denervation procedures: increased PWV was found in older patients, patients with isolated systolic hypertension, and diabetics (22). ## Long-term outcomes for renal denervation – individual studies Increased sympathetic activity is the most common underlying factor for hypertension, heart failure, CKD, and glucose metabolism disorder (23). Individual studies have shown that renal denervation could be an additional effective method for reducing BP values (the goal of renal denervation is to reduce BP values by 10 mmHg, not to normalize BP) in persons with RH and that renal denervation had a positive effect on controlling blood glucose levels, heart function, obstructive sleep apnea, and signs of target organ damage (23-29). Increased sympathetic activity also plays an important role in the pathogenesis of left ventricular hypertrophy (LVH) and heart failure. The presence of LVH is associated with increased incidence of CV events and death, irrespective of other CV risk factors and BP values. On the other hand, LVH regression improves CV outcomes (23). Reducing sympathetic pre-activity by renal denervation also reduces peripheral vasoconstriction and peripheral vascular resistance, which are factors that have a significant role in the development of heart failure. Left ventricular mass regression correlates with the level of myocardial hypertrophy and is more significant in patients with a larger reduction in systolic pressure values. Individual studies after renal denervation in patients with congestive heart failure found a significant reduction in the incidence of ventricular tachyarrhythmia, and in addition to BP reduction in patients who were previously treated for atrial fibrillation with pulmonary vein isolation, renal denervation also resulted in an additional reduction in the number of atrial fibrillation episodes (26). A reduction of BP variability after renal denervation was also demonstrated (27). Chronic activation of the sympathetic nervous system is the main factor contributing to insulin resistance and metabolic syndrome, which are associated with the central obesity and risk of developing diabetes. A positive effect was found after renal denervation on the glucose metabolism in patients suffering from RH, consisting of a reduction in levels of insulin, C-peptides, HOMA-index, and glucose. It is therefore believed that renal denervation could slow or even stop the progression of insulin resistance in this high-risk patient group (28). Increased sympathetic activity is also evident in the early stages of CKD and is associated with deterioration of kidney function and target organ damage in addition to being a factor for CV and total mortality in patients with end stage CKD (29). Albuminuria is a significant independent predictor for CV and kidney diseases as well as death in conditions such as hypertension, kidney disease, diabetes, vascular disease, and the general population. Albuminuria is linearly associated with CV mortality, and there is an association between increased urine secretion of albumin (>30 mg/d) and elevated values of norepinephrine and epinephrine (30). A study in which 59 patients with RH and increased urine albumin-to-creatinine ratio (UACR) were subjected to renal denervation found that it significantly reduced UACR values in patients with micro- and macroalbuminuria (31). The prevalence of microalbuminuria and macroalbuminuria was significantly reduced 6 months after renal denervation (31). Three months after renal denervation in patients with CKD, there was no deterioration in kidney disease but rather an improvement in the form of improved glomerular filtration (32). Obstructive sleep apnea (OSA) affects 3-7% of the adult population and is associated with increased risk of CV events, including stroke, heart failure, ischemic heart disease, and death (33). Analysis of the effects of renal denervation on systolic pressure in patients with and without OSA and comparison with patients from the control group in the SYMPLICITY HTN-3 study found that patients with OSA treated with renal denervation had a greater reduction in systolic pressure than patients in the OSA control group. Additionally, the change in systolic BP during the night was more pronounced in patients subjected to renal denervation. In the control group, the ratio of patients with nondipping had increased 6 months after the start of the study, but this trend was not observed in patients with OSA in the group treated with renal denervation. The reduction in the activity of the sympathetic nervous system through renal denervation leads to a reduction in BP pressure values and OSA levels, and a reduction of the apnea-hypopnea index, oxygen desaturation index, Epworth Sleepiness Scale score, and plasma glucose concentration was also observed (34). Given that positive effects have been observed after renal denervation even regarding associated diseases such as diabetes, CKD, metabolic syndrome, and OSA syndrome, which are often comorbid with RH, which is more common in women, the clinical benefits of this treatment procedure are significantly higher and require more long-term outcome monitoring in a now defined population of patients who should undergo previous arterial stiffness measurement using PWV (35), an outcome predictor for additional treatment for renal denervation (36). Pharmacoeconomic analyses show that hypertension control though medication and methods such as renal denervation is cheaper than treating complications of hypertensive target organ remodeling such as chronic heart failure and dialysis treatment (37). Renal denervation reduces 10-year relative risk (0.70/0.03 for stroke; 0.68/0.85 for myocardial infarction; 0.78/0.90 for coronary artery disease; 0.79/0.92 for heart failure; 0.72/0.81 for end-stage renal disease) and improves survival (37). ## Conclusion Individual studies on renal denervation have found improvements in multiple risk factors for CV diseases and CKD. Renal denervation has been demonstrated to reduce proteinuria and reestablish circadian rhythm. The contribution of renal denervation to total CV varies between different groups of patients, so it is extremely important to perform patient selection depending on the associated risk factors in order to choose patients who will benefit most from renal denervation.

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    Cardiovascular Outcomes and Potential Long-term Benefits of Renal Denervation in Patients with Resistant Hypertension

    Professional Article
    Issue9-10
    Published
    Pages277-282
    PDF via DOIhttps://doi.org/10.15836/ccar2018.277
    resistant hypertension
    cardiovascular risk
    renal denervation

    Authors

    Marija Magdalena JakopovićORCIDMedicinski fakultet Sveučilišta u Zagrebu, Zagreb, Hrvatska
    Anja IvoševićORCIDMedicinski fakultet Sveučilišta u Zagrebu, Zagreb, Hrvatska
    Marija StankovićORCIDMedicinski fakultet Sveučilišta u Zagrebu, Zagreb, Hrvatska
    Ingrid Prkačin*ORCIDMedicinski fakultet Sveučilišta u Zagrebu, Zagreb, Hrvatska

    *Correspondence email: ingrid.prkacin@gmail.com

    Abstract

    Resistant hypertension is the failure to achieve target blood pressure in spite of using a minimum of 3 antihypertensive drugs of different classes, one of which must be a diuretic, at maximal tolerated doses. The prevalence of true resistant hypertension ranges between 7.9-10.0% and is associated with higher risk of kidney and cardiovascular system damage. Treatment of resistant hypertension focuses on lifestyle modifications and pharmacological therapy. Device-based therapies are indicated in patients in whom pharmacological agents failed to control the blood pressure. Evidence suggests beneficial effects of renal sympathectomy on life expectancy and prevention of cardiovascular complications in patients with resistant hypertension with chronic activation of the sympathetic nervous system, such as chronic kidney disease and type 2 diabetes mellitus. In terms of costs, there is no question pharmacoeconomically that effective blood pressure control in resistant hypertension with drugs and new innovative devices therapies is cheaper than treating the consequences of hypertensive target organ damage.

    Full Text

    Arterial hypertension is the most common chronic disease in modern society, affecting 30 – 45% of the general population, with the ratio increasing with age. The existing guidelines of the European Society of Hypertension/European Society of Cardiology define arterial hypertension as systolic pressure values above 140 mmHg and diastolic pressure above 90 mmHg (1). A linear association has been demonstrated between blood pressure (BP) and cardiovascular (CV) events such as stroke, myocardial infarction, chronic heart failure, and chronic kidney disease (CKD). The risk of CV mortality doubles with every increase of 20/10 mmHg in systolic and diastolic BP (2). Arterial hypertension is generally comorbid with other CV risk factors such as diabetes, hyperlipidemia, and obesity, the latter of which is reaching pandemic proportions (1).

    Resistant hypertension (RH) is hypertension in which the recommended BP values (<140/90 mmHg for the general population and <130/80 mmHg for diabetics and patients with CKD) cannot be achieved despite the application of at least three types of hypertensives in optimal doses, one of which is a diuretic, and the application of lifestyle changes. BP control with optimal doses of 4 or more antihypertensive medications from different groups is hard to achieve and maintain (3, 4). The prevalence of true RH is today estimated at 7.9-10% of all patients with hypertension (5, 6). Patients with diagnosed RH have at least double the risk of target organ damage, including higher CV morbidity and mortality, reduced kidney function, and the presence of endothelial dysfunction or albuminuria (7). Treatment of hypertension is primarily focused on identifying and changing risk-related habits and lifestyles, which contribute to resistance to therapy. Before establishing the diagnosis of RH, the potential secondary causes of hypertension must be excluded. The appropriate (based on individual characteristics and laboratory results) combined antihypertensive medication treatment must be chosen. The basic principle in the treatment of RH is blocking the mechanisms that lead to BP increase, including volume expansion reduction, peripheral vascular resistance, and blocking the activation of the renin-angiotensin-aldosterone system. The basic treatment for patients with RH includes blocking the renin-angiotensin-aldosterone system, a calcium antagonist, and a diuretic. Medication should be prescribed at adequate doses and in proper intervals (7). Today, the introduction of an aldosterone antagonist as the fourth medication for the treatment of RH is recommended. Aldosterone has an important role in the pathogenesis of RH due to its vasoconstrictive effect and by changing vascular permeability (8). Medication such as beta blockers are recommended as the fifth line of medication, unless they are indicated earlier due to the presence of congestive heart failure or myocardial infarction.

    Sex differences and cardiovascular risk in patients with resistant hypertension

    Resistant hypertension is often comorbid with target organ damage: the development of diseases of the brain, heart, and kidneys, and results in tripled risk of developing hypertensive organ damage and CV complications. The risk of developing RH is higher in women than in men. These are women that more frequently suffer from obesity, dyslipidemia, and diabetes and are of advanced age. Women with RH have a 1.4 times higher risk of total mortality in comparison with women with hypertension regulated by treatment as well as a 2.3 times higher risk in comparison with women without hypertension. Women with newly-diagnosed hypertension have a higher risk of developing CKD, a higher incidence of CKD, and consequently higher total CV risk (9). Lowering systolic BP values by only 10 mmHg leads to a risk reduction for CV diseases of 20%, 17% for coronary diseases, 27% for stroke, 28% for heart failure, and total mortality reduction of 13% (10). If we compare patients with hypertension who do not have RH to those with RH, the RH population has a higher prevalence of comorbidities, specifically diabetes (48% vs. 30% in non-resistant hypertension), CKD (45% vs. 24%), ischemic heart disease (41% vs. 22%), cerebrovascular disease (16% vs. 9%, p<0.001) (11). Within the RH population, it is important to distinguish two groups: the group with controlled RH and the group with uncontrolled RH, which is larger (61.7%) and has a higher risk of developing target organ damage (cerebrovascular risk is higher by 23%, while the risk for end stage CKD is 25% higher in comparison with the controlled RH group) (11).

    Preparation for renal denervation and a brief overview of renal denervation

    Catheter renal denervation is a minimally invasive method for treating RH that modulates the tonus of the sympathetic nervous system by selective ablation of afferent and efferent sympathetic nerves of both renal arteries. The procedure has been practiced for less than a decade or so, and there have been more than 1900 publications on the topic of renal denervation since 2009 (12–18).

    There are several systems by different manufacturers around the world that are applied in performing renal denervation, among which the most widespread is the Symplicity Renal Denervation System. Delivery of radiofrequency energy to the endoluminal part of the renal artery is performed via an electrode at the tip of a catheter. In early studies it was delivered at several points (4–8) from the distal towards the proximal part of the renal artery. Today, the procedure is performed using a more modern catheter which delivers energy to 4 points with a single touch, reducing the duration of the procedure, and the smaller diameter of the catheter makes the new method appropriate for renal arteries with a diameter of less than 4 mm (which was an obstacle before) (7, 12–14). Early studies included patients for renal denervation procedures if they had RH with systolic BP values ≥160 mmHg (≥150 mmHg in diabetics) despite treatment with 3 antihypertensive medications of different classes in adequate doses, including a diuretic and lifestyle modification. The first studies (SYMPLICITY HNT-1 and HNT-2) did not include ambulatory blood pressure monitoring (12–14). Patients had renal function eGFR≥45 mL/min/1.73 m2 and renal arteries with appropriate anatomy, i.e. a diameter greater than 4 mm (12). After the early studies demonstrated the safety and effectiveness of the method (postprocedural reduction of BP by 27/17 mmHg after 12 months and 32/12 mmHg after 6 months), demonstration of effectiveness in a randomized study was attempted, but the SYMPLICITY HNT-3 study from 2014, due to a number of procedural issues, did not demonstrate the target reduction in BP of more than 10 mmHg in comparison with the control group (15). Today, uncontrolled RH must be confirmed before every renal denervation procedure using the 24-hour ambulatory blood pressure monitor. Pseudoresistant and secondary hypertension must be eliminated and anatomical suitability for the procedure must be confirmed, as must patient compliance not only by measuring the number of pills the patient consumes but also by determining medication levels in blood and/or urine (19).

    The greatest problem of the early studies on renal denervation was not only the heterogeneity of responses after renal denervation in the reduction BP, but also a large ratio of patients who had a partial response to treatment or were nonresponders, i.e. the treatment did not have any effect, which is understandable if we consider the pathogenic process of BP regulation (20). Increased activity of the sympathetic nervous system is the most common but not the only underlying cause of hypertension. A similar response regarding heterogeneity can also be observed in prescribing antihypertensive medication (6, 20). There are several potential ways of reducing the variability of responses in reduction of BP values after renal denervation: the quality of the procedure itself (new catheters allow more distal denervation where most of the sympathetic plexus is located, and the experience of the interventional radiologist/cardiologist also plays a role) as well as choosing patients who will benefit from additional treatment with renal denervation (21). In choosing patients for renal denervation, the current recommendation is to determine arterial stiffness using pulse wave velocity (PWV) measurement, which is a predictor of total and CV mortality, associating elevated PWV with poorer response to renal denervation procedures: increased PWV was found in older patients, patients with isolated systolic hypertension, and diabetics (22).

    Long-term outcomes for renal denervation – individual studies

    Increased sympathetic activity is the most common underlying factor for hypertension, heart failure, CKD, and glucose metabolism disorder (23). Individual studies have shown that renal denervation could be an additional effective method for reducing BP values (the goal of renal denervation is to reduce BP values by 10 mmHg, not to normalize BP) in persons with RH and that renal denervation had a positive effect on controlling blood glucose levels, heart function, obstructive sleep apnea, and signs of target organ damage (23–29). Increased sympathetic activity also plays an important role in the pathogenesis of left ventricular hypertrophy (LVH) and heart failure. The presence of LVH is associated with increased incidence of CV events and death, irrespective of other CV risk factors and BP values. On the other hand, LVH regression improves CV outcomes (23). Reducing sympathetic pre-activity by renal denervation also reduces peripheral vasoconstriction and peripheral vascular resistance, which are factors that have a significant role in the development of heart failure. Left ventricular mass regression correlates with the level of myocardial hypertrophy and is more significant in patients with a larger reduction in systolic pressure values.

    Individual studies after renal denervation in patients with congestive heart failure found a significant reduction in the incidence of ventricular tachyarrhythmia, and in addition to BP reduction in patients who were previously treated for atrial fibrillation with pulmonary vein isolation, renal denervation also resulted in an additional reduction in the number of atrial fibrillation episodes (26). A reduction of BP variability after renal denervation was also demonstrated (27).

    Chronic activation of the sympathetic nervous system is the main factor contributing to insulin resistance and metabolic syndrome, which are associated with the central obesity and risk of developing diabetes. A positive effect was found after renal denervation on the glucose metabolism in patients suffering from RH, consisting of a reduction in levels of insulin, C-peptides, HOMA-index, and glucose. It is therefore believed that renal denervation could slow or even stop the progression of insulin resistance in this high-risk patient group (28).

    Increased sympathetic activity is also evident in the early stages of CKD and is associated with deterioration of kidney function and target organ damage in addition to being a factor for CV and total mortality in patients with end stage CKD (29). Albuminuria is a significant independent predictor for CV and kidney diseases as well as death in conditions such as hypertension, kidney disease, diabetes, vascular disease, and the general population. Albuminuria is linearly associated with CV mortality, and there is an association between increased urine secretion of albumin (>30 mg/d) and elevated values of norepinephrine and epinephrine (30). A study in which 59 patients with RH and increased urine albumin-to-creatinine ratio (UACR) were subjected to renal denervation found that it significantly reduced UACR values in patients with micro- and macroalbuminuria (31). The prevalence of microalbuminuria and macroalbuminuria was significantly reduced 6 months after renal denervation (31). Three months after renal denervation in patients with CKD, there was no deterioration in kidney disease but rather an improvement in the form of improved glomerular filtration (32).

    Obstructive sleep apnea (OSA) affects 3-7% of the adult population and is associated with increased risk of CV events, including stroke, heart failure, ischemic heart disease, and death (33). Analysis of the effects of renal denervation on systolic pressure in patients with and without OSA and comparison with patients from the control group in the SYMPLICITY HTN-3 study found that patients with OSA treated with renal denervation had a greater reduction in systolic pressure than patients in the OSA control group. Additionally, the change in systolic BP during the night was more pronounced in patients subjected to renal denervation. In the control group, the ratio of patients with nondipping had increased 6 months after the start of the study, but this trend was not observed in patients with OSA in the group treated with renal denervation. The reduction in the activity of the sympathetic nervous system through renal denervation leads to a reduction in BP pressure values and OSA levels, and a reduction of the apnea-hypopnea index, oxygen desaturation index, Epworth Sleepiness Scale score, and plasma glucose concentration was also observed (34). Given that positive effects have been observed after renal denervation even regarding associated diseases such as diabetes, CKD, metabolic syndrome, and OSA syndrome, which are often comorbid with RH, which is more common in women, the clinical benefits of this treatment procedure are significantly higher and require more long-term outcome monitoring in a now defined population of patients who should undergo previous arterial stiffness measurement using PWV (35), an outcome predictor for additional treatment for renal denervation (36). Pharmacoeconomic analyses show that hypertension control though medication and methods such as renal denervation is cheaper than treating complications of hypertensive target organ remodeling such as chronic heart failure and dialysis treatment (37). Renal denervation reduces 10-year relative risk (0.70/0.03 for stroke; 0.68/0.85 for myocardial infarction; 0.78/0.90 for coronary artery disease; 0.79/0.92 for heart failure; 0.72/0.81 for end-stage renal disease) and improves survival (37).

    Conclusion

    Individual studies on renal denervation have found improvements in multiple risk factors for CV diseases and CKD. Renal denervation has been demonstrated to reduce proteinuria and reestablish circadian rhythm. The contribution of renal denervation to total CV varies between different groups of patients, so it is extremely important to perform patient selection depending on the associated risk factors in order to choose patients who will benefit most from renal denervation.

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