Renal Denervation, LV Mass and Resistant Hypertension
Renal Denervation, LV Mass and Resistant Hypertension
Renal denervation offers a novel approach to effectively reduce BP and sympathetic activity by selectively interrupting renal sympathetic fibres. It has been demonstrated to reduce LVM and improve diastolic function measured by echocardiography. Cardiac magnetic resonance is more sensitive and highly reproducible in assessing cardiac function and morphology and allows a considerable reduction in the patient numbers to prove changes in remodelling parameters after RDN when compared with echocardiography. The results of the present prospective, multi-centre, blinded study demonstrated that RDN in patients with resistant hypertension significantly decreases BP and LVMI, improves EF and circumferential strain in patients with impairments at baseline and reduces the number of patients with LAE. Interestingly, the structural and functional cardiac changes occurred partly BP independent, pointing towards a direct role of modulating sympathetic nervous system activity.
Left ventricular hypertrophy represents a strong, independent predictor of increased cardiovascular morbidity and mortality and reflects the long-term effects of hemodynamic and non-hemodynamic factors. Hypertensive LVH has been associated with increased sympathetic activity to the heart as measured by NE spillover and plasma NE concentrations. Regression of LVH by different pharmacological regimens is an accepted treatment target in patients with hypertension that drives beneficial effects on LV function and prognosis independent of other risk factors. Renal denervation decreases both BP and central sympathetic activity in patients with resistant hypertension. Pilot clinical data indicated that RDN could reduce echocardiography-derived LVMI by 17% (53.9 ± 15.6 g/m vs. 44.7 ± 14.9 g/m, n = 46, P < 0.001) 6 months after treatment. Herein, the effect of RDN on LVMI was less pronounced (−7.1%), which might be related to the more precise assessment of cardiac mass using CMR and the blinded investigation. Indeed, repeated measures of the CMR-derived parameters revealed good or excellent reproducibility on intra- and interobserver levels. Recently, a meta-analysis with 6000 patients investigated the effect of different antihypertensive drugs on LVH. The LVMI regression ranged between 7.6 and 12.6%, however, only patients with monotherapy and not treatment resistant patients were included. Interestingly, LVMI was reduced in 15 of the 18 patients with a change in SBP of <10 mm Hg 6 months after RDN, supporting the notion of BP-independent effects of RDN on LVH. This finding is interesting because experimental data indicate that sympathetic nerve fibres directly mediate hypertension-induced LVH by stimulation of cardiomyocyte alpha-adrenergic receptors. In line, clinical and experimental data using the combined alpha- and beta-receptor blocker carvedilol indicate an alpha receptor-mediated effect of anti-sympathetic treatment on LVH, which might also underlie the herein observed effects of RDN. Furthermore, a BP independent effect of sympathectomy on LVH has been described in an animal model of abdominal aortic banding, when BP was unaffected by sympathectomy but LVH decreased significantly.
Besides the reductions in BP and LVMI also LVEF and circumferential strain improved after RDN. Left ventricular wall stress defined as a function of chamber size and configuration, thickness of the ventricular wall, and intraventricular pressure significantly decreased after RDN, which might represent one factor for the improvement in LVEF. There is evidence indicating that LV strains by CMR tagging are impaired in patients with hypertensive heart disease, suggesting cardiomyocyte dysfunction despite normal ejection fraction. In healthy individuals, LV deformation assessed by myocardial strains directly correlates with LVEF, whereas in patients with hypertension and preserved LVEF, there appears to be discordance between regional myocardial strains and global EF. Herein, in patients with reduced contractility at baseline, circumferential strain measurements as a surrogate of diastolic function significantly improved after RDN, whereas no changes occurred in controls. This is supported by the finding that RDN improves myocardial relaxation and end-diastolic pressures as indicated by LV mitral valve E/E′ measured by echocardiography.
Left-atrial enlargement is an independent predictor of common cardiovascular outcomes such as atrial fibrillation, stroke, heart failure, and death. Increased LA volume usually reflects ventricular filling pressure, as it is exposed to LV pressure during ventricular diastole. Left-atrial enlargement may therefore represent the chronicity exposure of the LA to abnormal LV filling pressure, mainly by high arterial BP. The left atrium possesses structural features that contribute to the pathogenesis of atrial fibrillation. Reverse remodelling of the LA by controlling BP represents a treatment target in patients at risk. Treatment with RDN reduced the number of patients with LAE.
Late gadolinium enhancement has demonstrated to be a strong predictor of cardiovascular events at long-term follow-up, suggesting its incremental value for the assessment of long-term prognosis. In our subgroup analysis, LGE-score remained unchanged after RDN. Although LGE reliably detects localized fibrosis, this technique is limited in the assessment of diffuse myocardial fibrosis.
Multiple trials have proven that RDN lowers office and 24-h BP in patients with resistant hypertension. The average BP reduction in the present study was less pronounced compared with the Symplicity trials (−22/−8 vs. −32/−12 mm Hg). Baseline SBP has been identified as a predictor of response to treatment. The fact that baseline BP herein was lower compared with the Symplicity HTN-2 trial (170/90 vs. 178/97 mm Hg) might in part account for the smaller BP lowering effect. In line, non-responders had lower SBP at baseline compared with responders. Additionally, non-responders had larger ventricles indicated by higher LVEDVI and LVESVI, dilated left atria and significantly increased LVMI, which potentially indicate longstanding resistant hypertension with severe structural hypertensive end organ damage. Blood pressure was also reduced in the control group (−11/−7 mm Hg; P = 0.044 for SBP and P = 0.034 for DBP), interestingly, this did not correspond to an improvement in LVMI or EF. Although, some reports suggest that diffuse renal artery constriction and local tissue damage at the ablation site with oedema and thrombus formation may occur after RDN, none of the patients included in the study developed a significant renal artery stenosis or clinical apparent renal embolism during follow-up of 6 months.
The non-randomized study design and the small sample size are limitations of this study that might also limit the evaluation and interpretation of subgroups among the cohort, although it represents the largest cohort of patients undergoing RDN and followed by CMR. Furthermore, CMR is a highly reproducible method, resulting in a considerable reduction in sample sizes of 80–90% when compared with echocardiography. The control group consisted of 17 patients with resistant hypertension on stable antihypertensive medication, which were not anatomical eligible for the procedure or denied an invasive treatment. We carefully checked whether these patients were principally different from those treated with RDN. Except for SBP all other visible potential confounders have not reached statistical significance between both groups. Due to the relative small number of patients minor differences between the treatment group and the control group might not have reached statistical significance probably due to power. In consideration of the relatively small number of patients propensity score matching with respect to these characteristics was not done. However, general linear modelling was performed to assess the regression to the mean and the confounding by indication issue. The results are given in the statistical supplement. Future studies need to address the issue of imbalance between the groups in larger cohorts of patients. Patients with an SBP reduction of ≥10 mm Hg were subsequently defined as responders to RDN. Although this threshold was not provided by guidelines, it represents a clinical relevant BP reduction and was used in the trials. Patients and physicians were instructed not to change antihypertensive medication during the study period. However, antihypertensive drug regimen was reduced in one patient (1%), due to confirmed BP levels below respective target BP and the development of symptomatic hypotension. Antihypertensive treatment was increased in two patients (3%) who remained above target BP during follow-up. Censoring for these post-procedural medication changes did not affect the improvements in LVMI or function, making a relevant influence of treatment intensification unlikely. Furthermore, it is possible that patients changed their medication themselves, as non-adherence is a major problem in patients with resistant hypertension. Adherence to prescribed drug regimen was checked before study entrance and at each visit, making a self-reduction of drug treatment unlikely, although not impossible. However, urine or plasma toxicological analysis of antihypertensive drugs or corresponding metabolites was not part of the study protocol.
Renal denervation reduced BP and significantly improved LVH and myocardial function, as diagnosed by CMR, in patients with resistant hypertension. The beneficial effects of RDN on cardiac remodelling documented herein occurred partly BP independent, suggesting a prognostic benefit of RDN in patients at high cardiovascular risk. Randomized controlled studies are needed to investigate whether these changes correlate to improved outcomes.
Discussion
Renal denervation offers a novel approach to effectively reduce BP and sympathetic activity by selectively interrupting renal sympathetic fibres. It has been demonstrated to reduce LVM and improve diastolic function measured by echocardiography. Cardiac magnetic resonance is more sensitive and highly reproducible in assessing cardiac function and morphology and allows a considerable reduction in the patient numbers to prove changes in remodelling parameters after RDN when compared with echocardiography. The results of the present prospective, multi-centre, blinded study demonstrated that RDN in patients with resistant hypertension significantly decreases BP and LVMI, improves EF and circumferential strain in patients with impairments at baseline and reduces the number of patients with LAE. Interestingly, the structural and functional cardiac changes occurred partly BP independent, pointing towards a direct role of modulating sympathetic nervous system activity.
Left ventricular hypertrophy represents a strong, independent predictor of increased cardiovascular morbidity and mortality and reflects the long-term effects of hemodynamic and non-hemodynamic factors. Hypertensive LVH has been associated with increased sympathetic activity to the heart as measured by NE spillover and plasma NE concentrations. Regression of LVH by different pharmacological regimens is an accepted treatment target in patients with hypertension that drives beneficial effects on LV function and prognosis independent of other risk factors. Renal denervation decreases both BP and central sympathetic activity in patients with resistant hypertension. Pilot clinical data indicated that RDN could reduce echocardiography-derived LVMI by 17% (53.9 ± 15.6 g/m vs. 44.7 ± 14.9 g/m, n = 46, P < 0.001) 6 months after treatment. Herein, the effect of RDN on LVMI was less pronounced (−7.1%), which might be related to the more precise assessment of cardiac mass using CMR and the blinded investigation. Indeed, repeated measures of the CMR-derived parameters revealed good or excellent reproducibility on intra- and interobserver levels. Recently, a meta-analysis with 6000 patients investigated the effect of different antihypertensive drugs on LVH. The LVMI regression ranged between 7.6 and 12.6%, however, only patients with monotherapy and not treatment resistant patients were included. Interestingly, LVMI was reduced in 15 of the 18 patients with a change in SBP of <10 mm Hg 6 months after RDN, supporting the notion of BP-independent effects of RDN on LVH. This finding is interesting because experimental data indicate that sympathetic nerve fibres directly mediate hypertension-induced LVH by stimulation of cardiomyocyte alpha-adrenergic receptors. In line, clinical and experimental data using the combined alpha- and beta-receptor blocker carvedilol indicate an alpha receptor-mediated effect of anti-sympathetic treatment on LVH, which might also underlie the herein observed effects of RDN. Furthermore, a BP independent effect of sympathectomy on LVH has been described in an animal model of abdominal aortic banding, when BP was unaffected by sympathectomy but LVH decreased significantly.
Besides the reductions in BP and LVMI also LVEF and circumferential strain improved after RDN. Left ventricular wall stress defined as a function of chamber size and configuration, thickness of the ventricular wall, and intraventricular pressure significantly decreased after RDN, which might represent one factor for the improvement in LVEF. There is evidence indicating that LV strains by CMR tagging are impaired in patients with hypertensive heart disease, suggesting cardiomyocyte dysfunction despite normal ejection fraction. In healthy individuals, LV deformation assessed by myocardial strains directly correlates with LVEF, whereas in patients with hypertension and preserved LVEF, there appears to be discordance between regional myocardial strains and global EF. Herein, in patients with reduced contractility at baseline, circumferential strain measurements as a surrogate of diastolic function significantly improved after RDN, whereas no changes occurred in controls. This is supported by the finding that RDN improves myocardial relaxation and end-diastolic pressures as indicated by LV mitral valve E/E′ measured by echocardiography.
Left-atrial enlargement is an independent predictor of common cardiovascular outcomes such as atrial fibrillation, stroke, heart failure, and death. Increased LA volume usually reflects ventricular filling pressure, as it is exposed to LV pressure during ventricular diastole. Left-atrial enlargement may therefore represent the chronicity exposure of the LA to abnormal LV filling pressure, mainly by high arterial BP. The left atrium possesses structural features that contribute to the pathogenesis of atrial fibrillation. Reverse remodelling of the LA by controlling BP represents a treatment target in patients at risk. Treatment with RDN reduced the number of patients with LAE.
Late gadolinium enhancement has demonstrated to be a strong predictor of cardiovascular events at long-term follow-up, suggesting its incremental value for the assessment of long-term prognosis. In our subgroup analysis, LGE-score remained unchanged after RDN. Although LGE reliably detects localized fibrosis, this technique is limited in the assessment of diffuse myocardial fibrosis.
Multiple trials have proven that RDN lowers office and 24-h BP in patients with resistant hypertension. The average BP reduction in the present study was less pronounced compared with the Symplicity trials (−22/−8 vs. −32/−12 mm Hg). Baseline SBP has been identified as a predictor of response to treatment. The fact that baseline BP herein was lower compared with the Symplicity HTN-2 trial (170/90 vs. 178/97 mm Hg) might in part account for the smaller BP lowering effect. In line, non-responders had lower SBP at baseline compared with responders. Additionally, non-responders had larger ventricles indicated by higher LVEDVI and LVESVI, dilated left atria and significantly increased LVMI, which potentially indicate longstanding resistant hypertension with severe structural hypertensive end organ damage. Blood pressure was also reduced in the control group (−11/−7 mm Hg; P = 0.044 for SBP and P = 0.034 for DBP), interestingly, this did not correspond to an improvement in LVMI or EF. Although, some reports suggest that diffuse renal artery constriction and local tissue damage at the ablation site with oedema and thrombus formation may occur after RDN, none of the patients included in the study developed a significant renal artery stenosis or clinical apparent renal embolism during follow-up of 6 months.
Limitations
The non-randomized study design and the small sample size are limitations of this study that might also limit the evaluation and interpretation of subgroups among the cohort, although it represents the largest cohort of patients undergoing RDN and followed by CMR. Furthermore, CMR is a highly reproducible method, resulting in a considerable reduction in sample sizes of 80–90% when compared with echocardiography. The control group consisted of 17 patients with resistant hypertension on stable antihypertensive medication, which were not anatomical eligible for the procedure or denied an invasive treatment. We carefully checked whether these patients were principally different from those treated with RDN. Except for SBP all other visible potential confounders have not reached statistical significance between both groups. Due to the relative small number of patients minor differences between the treatment group and the control group might not have reached statistical significance probably due to power. In consideration of the relatively small number of patients propensity score matching with respect to these characteristics was not done. However, general linear modelling was performed to assess the regression to the mean and the confounding by indication issue. The results are given in the statistical supplement. Future studies need to address the issue of imbalance between the groups in larger cohorts of patients. Patients with an SBP reduction of ≥10 mm Hg were subsequently defined as responders to RDN. Although this threshold was not provided by guidelines, it represents a clinical relevant BP reduction and was used in the trials. Patients and physicians were instructed not to change antihypertensive medication during the study period. However, antihypertensive drug regimen was reduced in one patient (1%), due to confirmed BP levels below respective target BP and the development of symptomatic hypotension. Antihypertensive treatment was increased in two patients (3%) who remained above target BP during follow-up. Censoring for these post-procedural medication changes did not affect the improvements in LVMI or function, making a relevant influence of treatment intensification unlikely. Furthermore, it is possible that patients changed their medication themselves, as non-adherence is a major problem in patients with resistant hypertension. Adherence to prescribed drug regimen was checked before study entrance and at each visit, making a self-reduction of drug treatment unlikely, although not impossible. However, urine or plasma toxicological analysis of antihypertensive drugs or corresponding metabolites was not part of the study protocol.
Conclusion
Renal denervation reduced BP and significantly improved LVH and myocardial function, as diagnosed by CMR, in patients with resistant hypertension. The beneficial effects of RDN on cardiac remodelling documented herein occurred partly BP independent, suggesting a prognostic benefit of RDN in patients at high cardiovascular risk. Randomized controlled studies are needed to investigate whether these changes correlate to improved outcomes.