Luis M. Ruilope

ESH position paper: renal denervation - an interventional therapy of resistant hypertension

Experts from the European Society of Hypertension prepared this position paper in order to summarize current evidence, unmet needs and practical recommendations on the application of percutaneous transluminal ablation of renal nerves [renal denervation (RDN)] as a novel therapeutic strategy for the treatment of resistant hypertension. The sympathetic nervous activation to the kidney and the sensory afferent signals to the central nervous system represent the targets of RND. Clinical studies have documented that catheter-based RDN decreases both efferent sympathetic and afferent sensory nerve traffic leading to clinically meaningful systolic and diastolic blood pressure (BP) reductions in patients with resistant hypertension. This position statement intends to facilitate a better understanding of the effectiveness, safety, limitations and issues still to be addressed with RDN.

Proceedings from the European clinical consensus conference for renal denervation: considerations on future clinical trial design

Approximately 8–18% of all patients with high blood pressure (BP) are apparently resistant to drug treatment.1,2 In this situation, new strategies to help reduce BP are urgently needed but the complex pathophysiology of resistant hypertension makes this search difficult. Not surprisingly in this context, the latest non-drug treatment which triggered controversy is catheter-based renal denervation (RDN).3,4 The method uses radiofrequency energy, or alternatively ultrasound or chemical denervation, to disrupt renal nerves within the renal artery wall, thereby reducing sympathetic efferent and sensory afferent signalling to and from the kidneys.5,6 Various experimental models of hypertension strongly support this concept7,8 and available evidence also suggests that sympathetic nervous system activation contributes to the development and progression of hypertension and subsequently to target organ damage.7–11 Historical observations have shown that surgical sympathectomy can reduce BP as well as morbidity and mortality in patients with uncontrolled hypertension.12,13 However, the clinical evidence in support of RDN as an effective interventional technique in patients with resistant hypertension is conflicting. A number of observational studies and three randomized, controlled trials (Symplicity HTN-2, Prague-15, and DENERHTN) support both safety and efficacy of this new therapy14–22 but some smaller studies and the large, single-blind, randomized, sham-controlled symplicity HTN-3 trial failed to show superiority of RDN when compared with medical therapy alone.23–25nnWhatever the shortcomings of individual trials may be, the possibility remains that the observed BP responses were due to placebo response, the Hawthorne effect, regression to the mean, unknown co-interventions or other bias.26 The design, conduct, and interpretation …

High prevalence of masked uncontrolled hypertension in people with treated hypertension.

AIMnThere are limited data on the quality of treated blood pressure (BP) control during normal daily life, and in particular, the prevalence of masked uncontrolled hypertension (MUCH) in people with treated and seemingly well-controlled BP is unknown. This is important because masked hypertension in treatment naïve patients is associated with a high risk of cardiovascular events. We therefore conducted the first study to define the prevalence and characteristics of MUCH among a large sample of hypertensive patients in routine clinical practice in whom BP was treated and controlled to recommended clinic BP goals.nnnMETHODS AND RESULTSnWe analysed data from the Spanish Society of Hypertension ambulatory blood pressure monitoring (ABPM) Registry and identified patients with treated and controlled BP according to current international guidelines (clinic BP <140/90 mmHg). Masked uncontrolled hypertension was diagnosed in these patients if despite controlled clinic BP, the mean 24-h ABPM average remained elevated (24-h systolic BP ≥130 mmHg and/or 24-h diastolic BP ≥80 mmHg). From 62 788 patients with treated BP in the Spanish registry, we identified 14 840 with treated and controlled clinic BP, of whom 4608 patients (31.1%) had MUCH according to 24-h ABPM criteria (mean age 59.4 years, 59.7% men). The prevalence of MUCH was significantly higher in males, patients with borderline clinic BP (130-9/80-9 mmHg), and patients at high cardiovascular risk (smokers, diabetes, obesity). Masked uncontrolled hypertension was most often because of poor control of nocturnal BP, with the proportion of patients in whom MUCH was solely attributable to an elevated nocturnal BP almost double that solely attributable to daytime BP elevation (24.3 vs. 12.9%, P < 0.001).nnnCONCLUSIONnThe prevalence of masked suboptimal BP control in patients with treated and well-controlled clinic BP is high. Clinic BP monitoring alone is thus inadequate to optimize BP control because many patients have an elevated nocturnal BP. These findings suggest that ABPM should become more routine to confirm BP control, especially in higher risk groups and/or those with borderline control of clinic BP.

Relationship between Clinic and Ambulatory Blood-Pressure Measurements and Mortality

Background Evidence for the influence of ambulatory blood pressure on prognosis derives mainly from population‐based studies and a few relatively small clinical investigations. This study examined the associations of blood pressure measured in the clinic (clinic blood pressure) and 24‐hour ambulatory blood pressure with all‐cause and cardiovascular mortality in a large cohort of patients in primary care. Methods We analyzed data from a registry‐based, multicenter, national cohort that included 63,910 adults recruited from 2004 through 2014 in Spain. Clinic and 24‐hour ambulatory blood‐pressure data were examined in the following categories: sustained hypertension (elevated clinic and elevated 24‐hour ambulatory blood pressure), “white‐coat” hypertension (elevated clinic and normal 24‐hour ambulatory blood pressure), masked hypertension (normal clinic and elevated 24‐hour ambulatory blood pressure), and normotension (normal clinic and normal 24‐hour ambulatory blood pressure). Analyses were conducted with Cox regression models, adjusted for clinic and 24‐hour ambulatory blood pressures and for confounders. Results During a median follow‐up of 4.7 years, 3808 patients died from any cause, and 1295 of these patients died from cardiovascular causes. In a model that included both 24‐hour and clinic measurements, 24‐hour systolic pressure was more strongly associated with all‐cause mortality (hazard ratio, 1.58 per 1‐SD increase in pressure; 95% confidence interval [CI], 1.56 to 1.60, after adjustment for clinic blood pressure) than the clinic systolic pressure (hazard ratio, 1.02; 95% CI, 1.00 to 1.04, after adjustment for 24‐hour blood pressure). Corresponding hazard ratios per 1‐SD increase in pressure were 1.55 (95% CI, 1.53 to 1.57, after adjustment for clinic and daytime blood pressures) for nighttime ambulatory systolic pressure and 1.54 (95% CI, 1.52 to 1.56, after adjustment for clinic and nighttime blood pressures) for daytime ambulatory systolic pressure. These relationships were consistent across subgroups of age, sex, and status with respect to obesity, diabetes, cardiovascular disease, and antihypertensive treatment. Masked hypertension was more strongly associated with all‐cause mortality (hazard ratio, 2.83; 95% CI, 2.12 to 3.79) than sustained hypertension (hazard ratio, 1.80; 95% CI, 1.41 to 2.31) or white‐coat hypertension (hazard ratio, 1.79; 95% CI, 1.38 to 2.32). Results for cardiovascular mortality were similar to those for all‐cause mortality. Conclusions Ambulatory blood‐pressure measurements were a stronger predictor of all‐cause and cardiovascular mortality than clinic blood‐pressure measurements. White‐coat hypertension was not benign, and masked hypertension was associated with a greater risk of death than sustained hypertension. (Funded by the Spanish Society of Hypertension and others.)

Impact of Ambulatory Blood Pressure Monitoring on Reclassification of Hypertension Prevalence and Control in Older People in Spain.

Ambulatory blood pressure monitoring (ABPM) accurately classifies blood pressure (BP) status but its impact on the prevalence and control of hypertension is little known. The authors conducted a cross‐sectional study in 2012 among 1047 individuals 60 years and older from the follow‐up of a population cohort in Spain. Three casual BP measurements and 24‐hour ABPM were performed under standardized conditions. Approximately 68.8% patients were hypertensive based on casual BP (≥140/90 mm Hg or current BP medication use) and 62.1% based on 24‐hour ABPM (≥130/80 mm Hg or current BP medication use) (P=.009). The proportion of patients with treatment‐eligible hypertension who met BP goals increased from 37.4% based on the casual BP target to 54.1% based on the 24‐hour BP target (absolute difference, 16.7%; P<.01). These results were consistent across alternative BP thresholds. Therefore, compared with casual BP, 24‐hour ABPM led to a reduction in the proportion of older patients recommended for hypertension treatment and a substantial increase in the proportion of those with hypertension control.

Renal denervation reduces office and ambulatory heart rate in patients with uncontrolled hypertension: 12-month outcomes fromthe global SYMPLICITY registry

Objectives: Renal denervation (RDN) can reduce sympathetic activity and blood pressure (BP) in patients with hypertension. The effects on resting and ambulatory heart rate (HR), also regulated by the sympathetic nervous system, are not established. Methods: Herein, we report 12-month outcomes from the Global SYMPLICITY Registry on office and ambulatory HR and BP in patients with uncontrolled hypertension (nu200a=u200a846). Results: HR declined in correlation with the HR at baseline and at 12 months, in particular, in patients in the upper tertile of HR (>74u200abpm). BP reduction was similar in the tertiles of HR at baseline. Similar effects were observed when 24-h ambulatory HR and SBP were determined. Office HR was similarly decreased when patients were on a &bgr;-blocker or not. Antihypertensive treatment remained unchanged during the 12-month period of the Global SYMPLICITY Registry. Conclusion: RDN reduces BP independent from HR. A HR reduction is dependent on baseline HR and unchanged by &bgr;-blocker treatment. The effects of RDN on SBP and HR are durable up to 1 year. HR reduction might be a target for RDN in patients with high HR at baseline, which needs to be scrutinized in prospective trials.

Usefulness of ambulatory blood pressure monitoring (ABPM) in daily clinical practice: Data from the Spanish ABPM registry

u2002Hypertension is one of the most important challenges for public health systems because of its high prevalence and its association with the risk of cardiovascular and renal diseases. u2002Adequate control of hypertension is low in population and medical settings, with physicians frequently misclassifying patients’ blood pressure status based on readings taken in the clinic rather than ambulatory blood pressure measurements (ABPM). u2002Data from the Spanish Society of Hypertension ABPM registry support ABPM as a feasible option in the primary care setting, providing valuable information for the diagnosis and management of hypertension. By using ABPM rather than office BP monitoring, BP control can be doubled. This is an encouraging message to clinicians, although there is still a relatively large degree of undetected controlled and uncontrolled hypertension. u2002This short review describes the design, development and main results of the Spanish Society of Hypertension ABPM registry, a project based on a large‐scale network of Spanish physicians trained in ABPM.

Association Between High and Very High Albuminuria and Nighttime Blood Pressure: Influence of Diabetes and Chronic Kidney Disease.

OBJECTIVE Nighttime blood pressure (BP) and albuminuria are two important and independent predictors of cardiovascular morbidity and mortality. Here, we examined the quantitative differences in nighttime systolic BP (SBP) across albuminuria levels in patients with and without diabetes and chronic kidney disease. RESEARCH DESIGN AND METHODS A total of 16,546 patients from the Spanish Ambulatory Blood Pressure Monitoring Registry cohort (mean age 59.6 years, 54.9% men) were analyzed. Patients were classified according to estimated glomerular filtration rate (eGFR), as ≥60 or <60 mL/min/1.73 m2 (low eGFR), and urine albumin-to-creatinine ratio, as normoalbuminuria (<30 mg/g), high albuminuria (30–300 mg/g), or very high albuminuria (>300 mg/g). Office and 24-h BP were determined with standardized methods and conditions. RESULTS High albuminuria was associated with a statistically significant and clinically substantial higher nighttime SBP (6.8 mmHg higher than with normoalbuminuria, P < 0.001). This association was particularly striking at very high albuminuria among patients with diabetes and low eGFR (16.5 mmHg, P < 0.001). Generalized linear models showed that after full adjustment for demographic, lifestyles, and clinical characteristics, nighttime SBP was 4.8 mmHg higher in patients with high albuminuria than in those with normoalbuminuria (P < 0.001), and patients with very high albuminuria had a 6.1 mmHg greater nighttime SBP than those with high albuminuria (P < 0.001). These differences were 3.8 and 3.1 mmHg, respectively, among patients without diabetes, and 6.5 and 8 mmHg among patients with diabetes (P < 0.001). CONCLUSIONS Albuminuria in hypertensive patients is accompanied by quantitatively striking higher nighttime SBP, particularly in those with diabetes with very high albuminuria and low eGFR.

Magnitude of Hypotension Based on Office and Ambulatory Blood Pressure Monitoring: Results From a Cohort of 5066 Treated Hypertensive Patients Aged 80 Years and Older

BACKGROUND AND OBJECTIVEnElderly patients can be particularly susceptible to the adverse effects of excessive blood pressure (BP) lowering by antihypertensive treatment. The identification of hypotension is thus especially important. Ambulatory BP monitoring (ABPM) is a more accurate technique than office for classifying BP status. This study examined the prevalence of hypotension and associated demographic and clinical factors among very old treated hypertensive patients undergoing ABPM.nnnDESIGN, SETTING, AND PARTICIPANTSnCross-sectional study in which 5066 patients aged 80xa0years and older with treated hypertension drawn from the Spanish ABPM Registry were included.nnnMEASUREMENTSnOffice BP and 24-hour ambulatory BP were determined using validated devices under standardized conditions. Based on previous studies, hypotension was defined as systolic/diastolic BPxa0<110 and/or 70xa0mmHg with office measurement, <105 and/or 65xa0mmHg with daytime ABPM, <90 and/or 50xa0mmHg with nighttime ABPM, and <100 and/or 60xa0mmHg with 24-hour ABPM.nnnRESULTSnParticipants mean age was 83.2 ± 3.1xa0years (64.4% women). Overall, 22.8% of patients had office hypotension, 33.7% daytime hypotension, 9.2% nighttime hypotension, and 20.5% 24-hour ABPM hypotension. Low diastolic BP values were responsible for 90% of cases of hypotension. In addition, 59.1% of the cases of hypotension detected by daytime ABPM did not correspond to hypotension according to office BP. The variables independently associated with office and ABPM hypotension were diabetes, coronary heart disease, and a higher number of antihypertensive medications.nnnCONCLUSIONSnOne in 3 very elderly treated hypertensive patients attended in usual clinical practice were potentially at risk of having hypotension according to daytime ABPM. More than half of them had masked hypotension; that is, they were not identified if relying on office BP alone. Thus, ABPM could be especially helpful for identifying ambulatory hypotension and avoiding overtreatment, in particular, in patients with diabetes, heart disease, or on antihypertensive polytherapy.

Rapid, Automated, and Specific Immunoassay to Directly Measure Matrix Metalloproteinase-9–Tissue Inhibitor of Metalloproteinase-1 Interactions in Human Plasma Using AlphaLISA Technology: A New Alternative to Classical ELISA

The protocol describes a novel, rapid, and no-wash one-step immunoassay for highly sensitive and direct detection of the complexes between matrix metalloproteinases (MMPs) and their tissue inhibitor of metalloproteinases (TIMPs) based on AlphaLISA® technology. We describe two procedures: (i) one approach is used to analyze MMP-9–TIMP-1 interactions using recombinant human MMP-9 with its corresponding recombinant human TIMP-1 inhibitor and (ii) the second approach is used to analyze native or endogenous MMP-9–TIMP-1 protein interactions in samples of human plasma. Evaluating native MMP-9–TIMP-1 complexes using this approach avoids the use of indirect calculations of the MMP-9/TIMP-1 ratio for which independent MMP-9 and TIMP-1 quantifications by two conventional ELISAs are needed. The MMP-9–TIMP-1 AlphaLISA® assay is quick, highly simplified, and cost-effective and can be completed in less than 3u2009h. Moreover, the assay has great potential for use in basic and preclinical research as it allows direct determination of native MMP-9–TIMP-1 complexes in circulating blood as biofluid.