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This editorial refers to ‘Effect of renal denervation on left ventricular mass and function in patients with resistant hypertension: data from a multicentre cardiovascular magnetic resonance imaging trial’, by F. Mahfoud et al. , on page doi:10.1093/eurheartj/ehu093.
Effective blood pressure (BP) control in hypertensive patients is still a missed...
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Context 1
... blood pressure (BP) control in hypertensive patients is still a missed objective, leading to an unacceptably high rate of cardiovascu- lar events. This is particularly true in the case of resistant hyper- tension. Among the 53 530 stable hypertensive patients with subclinical or established atherothrombotic disease enrolled in the international Reduction of Atherothrombosis for Continued Health (REACH) registry, the presence of resistant hypertension is related to an increased incidence of a composite outcome of cardio- vascular death, myocardial infarction, or stroke at 4 years. 1 Left ven- tricular (LV) mass determined at echocardiography is a potent independent predictor of cardiovascular morbidity and mortality in essential hypertension, and its reduction during treatment has a favourable prognostic impact. 2 In resistant hypertensive patients the prevalence of LV hypertrophy (LVH) is exceptionally high, ranging from 55% to 81%. 3 This is not surprising, given that the primum movens of LVH is haemodynamic. When BP increases, the resulting increment in wall stress can be offset by an increase in wall thickness; thus, normalization of systolic stress through LVH contributes to maintain a normal ejection fraction despite the high BP levels. However, many factors contribute to cardiac hypertrophy beyond pressure/volume overload ( Figure 1). Local angiotensin II can promote LVH acting on both myocardiocytes and cardiac fibroblasts, either directly or activating endothelin-1 and aldosterone pathways. A significant role is played by metabolic factors, such as insulin, insulin growth factors, and lipids, even in non-diabetic hypertensive individuals. 4 Sympathetic activation is a key player in LVH development. LV mass is significantly related to central sympathetic nerve hyperactivity even in the absence of clinical LVH, indicating that sympathetic acti- vation may be an important determinant of the growth of human LV myocardium. 5 In experimental studies, both functional and chem- ical (alpha-blockade) sympathectomy have been demonstrated to slow down the process of myocardial interstitial fibrosis occurring in cardiac hypertrophy. 6 However, to date, the role of sympathoinhi- bition as a mechanism of LV regression has never been clearly demon- strated in humans; in particular, beta-blockade failed to induce LVH regression. 7 In the past years, device-based therapies for resistant hyperten- sion, specifically targeting the sympathetic nervous system, have been developed. 8 Both renal denervation and baroceptor-activating therapy demonstrated a rapid and significant reduction of echocar- diographic LV mass in small case series. 9,10 Mahfoud and colleagues have now confirmed those preliminary data by means of cardiac mag- netic resonance in 55 patients with resistant hypertension undergo- ing renal denervation in the Symplicity protocols. 11 It is noteworthy that the LV mass reduction found in this study, of 7%, is lower than that found by echocardiographic studies, which ranges from 13% to 16%. 9,10 A direct comparison between echocardiographic and mag- netic resonance imaging (MRI) values of LVH would have been inter- esting, and the authors did not report whether the already published articles about ultrasound LV mass assessment refer to the same patients. This result resembles the discrepancy found between office and 24 h BP reduction achieved by renal denervation 12 and strongly supports the use of objective measurements for assessment of surrogate endpoints in clinical trials. Furthermore, some methodo- logical flaws do not allow us to draw clear conclusions about the impact of renal denervation on LVH regression. The non-randomized design is a major limitation, since the control group is constituted of only 17 patients who did not meet the inclusion criteria of the Sym- plicity trials. Most importantly, the groups were not matched for BP values, introducing an element of inhomogeneity that can hardly be corrected by statistical analysis. The study shares two important lim- itations with the Symplicity trials: the lack of objective assessment of compliance with drug treatment does not allow LV mass reduction to be attributed to renal denervation with a sufficient degree of certainty. Furthermore, although the authors stated ...
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Background
Renal denervation (RDN), a novel therapy for resistant hypertension, has been shown to have an effect on cardiac remodeling in several small studies. We aimed to pool currently available data to assess the effects of RDN on left ventricular hypertrophy (LVH) and left atrial (LA) enlargement.
Methods and results
Two investigators independ...
Not available DOI: http://dx.doi.org/10.3329/cardio.v5i1.12282 Cardiovasc. j. 2012; 5(1): 112-119
Despite the increased evidence of the important role of matrix metalloproteinases (MMP-9 and MMP‑2) in the pathophysiology of hypertension, the profile of these molecules in resistant hypertension (RHTN) remains unknown.
To compare the plasma levels of MMP-9 and MMP-2 and of their tissue inhibitors (TIMP-1 and TIMP-2, respectively), as well as thei...
Resistant hypertension (RH) was defined many years ago as a clinical situation in which blood pressure remains uncontrolled despite concomitant intake of at least three antihypertensive drugs (one of them preferably being a diuretic) at full doses. This operative definition was aimed at identifying a subset of hypertensive patients requiring a more...
The objectives of the present study were to evaluate the prevalence of resistant hypertension (RH) in
primary care setting and to analyse its biochemical and clinical characteristics. After 3 months of treatment
and evaluation, 721 (14.01%) of 5,146 patients with hypertension did not reach target office blood pressure
of < 140/90 mmHg. After exclus...
Citations
... In particular, both aortic stenosis and hypertension lead to an increase in afterload and subsequent left ventricular concentric hypertrophy, a thickening of the walls that increases the contractile ability of the heart and reduces wall stress (Lorell and Carabello 2000;Grossman et al. 1975). However, development of left ventricular hypertrophy is also associated with increased risk of further cardiovascular disease, heart failure, and mortality (Benjamin et al. 2018;Bruno and Taddei 2014;Cuspidi et al. 2010;Kawel-Boehm et al. 2019). Current treatment options for aortic stenosis and hypertension involve management of afterload and ideally a reduction in hypertrophy. ...
Growth and remodeling in the heart is driven by a combination of mechanical and hormonal signals that produce different patterns of growth in response to exercise, pregnancy, and various pathologies. In particular, increases in afterload lead to concentric hypertrophy, a thickening of the walls that increases the contractile ability of the heart while reducing wall stress. In the current study, we constructed a multiscale model of cardiac hypertrophy that connects a finite-element model representing the mechanics of the growing left ventricle to a cell-level network model of hypertrophic signaling pathways that accounts for changes in both mechanics and hormones. We first tuned our model to capture published in vivo growth trends for isoproterenol infusion, which stimulates β-adrenergic signaling pathways without altering mechanics, and for transverse aortic constriction (TAC), which involves both elevated mechanics and altered hormone levels. We then predicted the attenuation of TAC-induced hypertrophy by two distinct genetic interventions (transgenic Gq-coupled receptor inhibitor overexpression and norepinephrine knock-out) and by two pharmacologic interventions (angiotensin receptor blocker losartan and β-blocker propranolol) and compared our predictions to published in vivo data for each intervention. Our multiscale model captured the experimental data trends reasonably well for all conditions simulated. We also found that when prescribing realistic changes in mechanics and hormones associated with TAC, the hormonal inputs were responsible for the majority of the growth predicted by the multiscale model and were necessary in order to capture the effect of the interventions for TAC.
... As such, sympathoinhibition might be a mechanism of LVH regression independent of BP reduction. 21,55 Though outside the scope of this paper and speculative in those with ESKD, the delayed progressive and evolving pattern observed, may be seen as a result of the time taken to reset central SNA, to assess baroreceptor sensitivity, and for cardiovascular remodeling to manifest. [56][57][58] While technically adequate RDN appeared to have occurred, the level of afferent and efferent nerve damage induced by the procedure is unknown. ...
Sympathetic neural activation is markedly increased in end-stage kidney disease (ESKD). Catheter-based renal denervation (RDN) reduces sympathetic overactivity and blood pressure in resistant hypertension. We investigated the effect of RDN on sympathetic neural activation and left ventricular mass in patients with ESKD.
Methods: Nine ESKD (6 hemodialysis and 3 peritoneal dialysis) patients with dialysis vintage of ≥11 months were treated with RDN (EnligHTN system). Data were obtained on a nondialysis day; at baseline, 1, 3, and 12 months post-RDN.
Results: At baseline sympathetic neural activation measured by muscle sympathetic nervous activity (MSNA) and plasma norepinephrine concentrations were markedly elevated. Left ventricular hypertrophy (LVH) was evident in 8 of the 9 patients. At 12 months post-RDN, blind analysis revealed that MSNAfrequency (–12.2 bursts/min1, 95% CI [–13.6, –10.7]) and LV mass (–27 g/m2, 95% CI [–47, –8]) were reduced. Mean ambulatory BP (systolic: –24 mm Hg, 95% CI [–42, –5] and diastolic: –13 mm Hg, 95% CI [–22, –4]) was also reduced at 12 months. Office BP was reduced as early as 1 month (systolic: –25 mm Hg, 95% CI [–45, –5] and diastolic: –13 mm Hg, 95% CI [–24, –1]). Both ambulatory and office BP had clinically significant reductions in at least 50% of patients out to 12 months.
Discussion: Catheter-based RDN significantly reduced MSNA and LV mass as well as systemic BP in this group of patients with ESKD.
... These results are consistent with recent experimental data in which the renal denervation was performed 4 wk post-MI or after 5 wk of isoproterenol injections; cardiac fibrosis was attenuated in both disease models (36,62). Clinically, renal denervation has been shown to reduce cardiac remodeling in patients with hypertension-induced heart failure (10,19,40). Potentially, the beneficial effects of renal denervation on cardiac fibrosis may be mediated, at least in part, by a decrease in circulating ANG II (58). ...
... Cardiac dysfunction can be caused by conditions that reduce cardiac output through ischemic damage, increased afterload, or restrictive disease such as myocardial infarction (MI), hypertension, and amyloidosis (Jackson et al. 2000, McMurray andPfeffer 2005). Of note, neurohumoral abnormalities and disturbance of autonomic nervous system contribute to the process of cardiac remodeling and the transition to cardiac dysfunction (Bristow 1984, Lymperopoulos et al. 2013, Mann and Bristow 2005, Schrier and Abraham 1999. Renal sympathetic nerve activity plays a pivotal role in the regulation of neurohumoral mechanisms (DiBona and Sawin 2003, Sobotka et al. 2012. ...
... The Symplicity-HTN3 trial failed to show a significant reduction in blood pressure (BP) in patients with resistant hypertension 6 months after renal sympathetic denervation (RSD) as compared with a sham control (Bhatt et al. 2014), but the effects of RSD on left Vol. 64 ventricular hypertrophy and diastolic function might be beyond the improvement in BP (Brandt et al. 2012, Bruno and Taddei 2014, Schirmer et al. 2014. showed that RSD can significantly delay the progression of left ventricular hypertrophy in spontaneously hypertensive rats (SHR). ...
Varied causative and risk factors can lead to cardiac dysfunction. Cardiac dysfunction often evolves into heart failure by cardiac remodeling due to autonomic nervous system disturbance and neurohumoral abnormalities, even if the detriment factors are removed. Renal sympathetic nerve activity plays a pivotal regulatory role in neurohumoral mechanisms. The present study was designed to determine the therapeutic effects of renal sympathetic denervation (RSD) on cardiac dysfunction, fibrosis, and neurohumoral response in transverse aortic constriction (TAC) rats with chronic pressure overload. The present study demonstrated that RSD attenuated myocardial fibrosis and hypertrophy, and structural remodeling of the left atrium and ventricle, up-regulated cardiac ß adrenoceptor (ß-AR, including ß1AR and ß2AR) and sarco-endoplasmic reticulum Ca²⁺⁻ATPase (SERCA) while down-regulated angiotensin II type 1 receptor (AT1R), and decreased plasma B-type natriuretic peptide (BNP), norepinephrine (NE), angiotensin II (Ang II), and arginine vasopressin (AVP) levels in TAC rats with chronic pressure overload. We conclude that RSD attenuates myocardial fibrosis, the left atrial enlargement, and the left ventricular wall hypertrophy; inhibits the overdrive of the sympathetic nervous system (SNS), renin-angiotensin-aldosterone system (RAAS), and AVP system in TAC rats with chronic pressure overload. RSD could be a promising non-pharmacological approach to control the progression of cardiac dysfunction. © 2015 Institute of Physiology v.v.i., Academy of Sciences of the Czech Republic, Prague, Czech Republic.
... Cardiac dysfunction can be caused by conditions that reduce cardiac output through ischemic damage, increased afterload, or restrictive disease such as myocardial infarction (MI), hypertension, and amyloidosis (Jackson et al. 2000, McMurray andPfeffer 2005). Of note, neurohumoral abnormalities and disturbance of autonomic nervous system contribute to the process of cardiac remodeling and the transition to cardiac dysfunction (Bristow 1984, Lymperopoulos et al. 2013, Mann and Bristow 2005, Schrier and Abraham 1999. Renal sympathetic nerve activity plays a pivotal role in the regulation of neurohumoral mechanisms (DiBona and Sawin 2003, Sobotka et al. 2012. ...
... The Symplicity-HTN3 trial failed to show a significant reduction in blood pressure (BP) in patients with resistant hypertension 6 months after renal sympathetic denervation (RSD) as compared with a sham control (Bhatt et al. 2014), but the effects of RSD on left Vol. 64 ventricular hypertrophy and diastolic function might be beyond the improvement in BP (Brandt et al. 2012, Bruno and Taddei 2014, Schirmer et al. 2014. showed that RSD can significantly delay the progression of left ventricular hypertrophy in spontaneously hypertensive rats (SHR). ...
Varied causative and risk factors can lead to cardiac dysfunction. Cardiac dysfunction often evolves into heart failure by cardiac remodeling due to autonomic nervous system disturbance and neurohumoral abnormalities, even if the detriment factors are removed. Renal sympathetic nerve activity plays a pivotal regulatory role in neurohumoral mechanisms. The present study was designed to determine the therapeutic effects of renal sympathetic denervation (RSD) on cardiac dysfunction, fibrosis, and neurohumoral response in transverse aortic constriction (TAC) rats with chronic pressure overload. The present study demonstrated that RSD attenuated myocardial fibrosis and hypertrophy, and structural remodeling of the left atrium and ventricle, up-regulated cardiac beta adrenoceptor (beta-AR, including beta(1)AR and beta(2)AR) and sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA) while down-regulated angiotensin II type l receptor (AT(1)R), and decreased plasma B-type natriuretic peptide (BNP), norepinephrine (NE), angiotensin II (Ang II), and arginine vasopressin (AVP) levels in TAC rats with chronic pressure overload. We conclude that RSD attenuates myocardial fibrosis, the left atrial enlargement, and the left ventricular wall hypertrophy; inhibits the overdrive of the sympathetic nervous system (SNS), renin-angiotensin-aldosterone system (RAAS), and AVP system in TAC rats with chronic pressure overload. RSD could be a promising non-pharmacological approach to control the progression of cardiac dysfunction.
... This represents a similar but smaller degree of LV mass reduction than in the aforementioned echocardiographic study, underscoring potentially increased specificity of imaging and bias in the these smaller, preliminary studies. 27 Systolic function, specifically in patients with baseline reduction in ejection fraction, also increased following RDN (ejection fraction 43% versus 50%, P<0.001). RDN also improved diastolic dysfunction, with a 21% increase in proportion of patients with reduced LV circumferential strain. ...
... 26 These results are susceptible to difficulties similar to those in studies examining hypertension, including difficulty maintaining control groups, medication compliance, and matching for baseline variables such as BP. 27 In light of these preliminary results, 2 large RCTs will compare the effects of RDN and optimal medical therapy on imaging end points, hemodynamics, exercise capacity, and quality of life in heart failure with a preserved ejection fraction (Table). 23 ...
Renal artery denervation (RDN) is a catheter‐based technique designed to decrease renal sympathetic nervous system (SNS) signaling and return the body to more physiological homeostasis. Preliminary investigations suggested an excellent therapeutic profile in resistant hypertension,[1][1]–[2][2]
