Blood pressure response to catheter-based renal sympathetic denervation in severe resistant hypertension: data from the Greek Renal Denervation Registry.

BACKGROUND/INTRODUCTION: The efficacy of catheter-based renal sympathetic denervation (RDN) in terms of blood pressure (BP) reduction has been questioned, while "real-world" data from registries are needed. In this study, we report the complete set of 12-month data on office and ambulatory BP changes as well as the predictors for BP response to RDN from a national registry. METHODS: In 4 Greek hospital centers, 79 patients with severe drug-resistant hypertension (age 59 ± 10 years, 53 males, body mass index 33 ± 5 kg/m2; office BP and 24-h ambulatory BP were 176 ± 15/95 ± 13 and 155 ± 14/90 ± 12 mmHg, respectively, 4.4 ± 0.9 antihypertensive drugs) underwent RDN and were followed-up for 12 months in the Greek Renal Denervation Registry. Bilateral RDN was performed using percutaneous femoral approach and standardized techniques. RESULTS: Reduction in office systolic/diastolic BP at 6 and 12 months from baseline was -30/-12 and -29/-12 mmHg, while the reduction in 24-h ambulatory BP was -16/-9 and -15/-9 mmHg, respectively (p < 0.05 for all). Patients that were RDN responders (85%, n = 58), defined as an at least 10-mmHg decrease in office systolic BP at 12 months, compared to non-responders were younger (57 ± 9 vs 65 ± 8 years, p < 0.05), had higher baseline office systolic BP (176 ± 17 vs 160 ± 11 mmHg, p < 0.05) and 24-h systolic BP (159 ± 13 vs 149 ± 11 mmHg, p < 0.05). Stepwise logistic regression analysis revealed that age, obesity parameters, and baseline office BP were independent predictors of RDN response (p < 0.05 for both), but not the type of RDN catheter or the use of aldosterone antagonists. At 12 months, there were no significant changes in renal function and any new serious device or procedure-related adverse events. CONCLUSIONS: In our "real-world" multicenter national registry, the efficacy of renal denervation in reducing BP as well as safety is confirmed during a 12-month follow-up. Moreover, younger age, obesity, and higher levels of baseline systolic BP are independently related to better BP response to RDN.

Long-term effects of multielectrode renal denervation on cardiac adaptations in resistant hypertensive patients with left ventricular hypertrophy.

Left ventricular (LV) hypertrophy and diastolic dysfunction predict long-term cardiovascular events. We evaluated whether multielectrode renal denervation (RDN) can provide beneficial cardiac adaptations in patients with resistant hypertension and LV hypertrophy long term at 24 months. Seventeen patients with true drug-resistant hypertension (age: 57±9 years, 11 men, body mass index: 33.79±5.49 kg m-2, office blood pressure (BP): 183±20/97±18 mm Hg and ambulatory BP: 152±16/86±15 mm Hg receiving 4.5 anti-hypertensive drugs per day) and LV hypertrophy underwent multielectrode RDN (EnligHTNTM, St Jude Medical). At baseline, LV mass index averaged 141.1±16.8 g m-2 (58.4±7.8 g m-2.7) and mitral lateral E/E' 14.7±6.2. At 6, 12 and 24 months after RDN, the LV mass/body surface area (LV mass per height2.7) reduced significantly by 9.1% (8.8%), 11.3% (10.5%) and 15.5% (14.1%), respectively; and the mitral lateral E/E' reduced significantly by 14.0%, 15.3% and 29.7%, respectively. At 24 months after RDN, majority (70.6%) of the patients showed regression of LV hypertrophy of at least one level; the proportion of patients with concentric LV hypertrophy had dropped by 47.1% from baseline; and the proportion of patients with office systolic BP level of ⩾160 mm Hg had dropped by 76.5% from baseline. No statistically significant association was observed between the changes in office BP and the changes in LV mass index or diastolic function. In patients with drug-resistant hypertension and LV hypertrophy, multielectrode RDN can contribute to significant and sustained improvements of diastolic dysfunction and attenuation of LV mass indices long term at 24 months.

Drug-resistant hypertensive patients responding to multielectrode renal denervation exhibit improved heart rate dynamics and reduced arrhythmia burden.

Transluminal renal sympathetic denervation (RDN) reduces blood pressure (BP) in patients with drug-resistant uncontrolled hypertension. We assessed the effect of RDN on heart rate, supraventricular and ventricular ectopic activity and indexes of heart rate variability in 14 patients with drug-resistant uncontrolled hypertension who were all responders to RDN (defined as a reduction in office systolic BP ⩾ 10 mm Hg) at baseline and at 1 and 6 months after the procedure using the multielectrode EnligHTN ablation catheter (St Jude Medical). Office and 24-h systolic and diastolic BP were significantly reduced both at 1 and 6 months after RDN and all patients were office BP responders. There was a trend toward office heart rate reduction (by 6.9 b.p.m., P=0.064) at 1 month and a significant reduction by 10 b.p.m. (P=0.004) at 6 months. Mean 24-h Holter monitoring heart rate was reduced by 6.7 b.p.m. (P=0.022) at 1 month and by 5.3 b.p.m. (P=0.010) at 6 months after RDN. The total number of premature supraventricular and ventricular contractions was significantly decreased and time- and frequency- domain indexes were increased both at 1 and at 6 months after RDN (P<0.05 for both cases). Apart from the substantial BP lowering, RDN results in significant reduction of mean heart rate and arrhythmia burden, restoring autonomic balance in responder patients with drug-resistant uncontrolled hypertension.

Renal nerve ablation for hypertensive patients with chronic kidney disease.

Among current epidemics, chronic kidney disease (CKD) is accompanied with high morbidity and mortality rates inherently associated with the thriving comorbidities of hypertension and cardiovascular disease. In this mutually reinforcing triad, adequate control of high blood pressure emerges as extremely important for decreasing patients' complication rates and prolonging life expectancy. However, hypertension control in this particular group of patients is often proven an arduous task, presenting high rates of resistance. Sympathetic nervous system (SNS) overactivity is implicated not only in the pathophysiological basis of difficult-to-treat hypertension, but also in the development and progression of renal disease, thus rendering SNS a prime therapeutic target in CKD. As renal nerve ablation (RNA) is finding its place among other invasive procedures in the cardiovascular arena, the potential therapeutic impact of this innovative treatment modality is gradually expanding from resistant hypertension to other high blood pressure-related clinical conditions like CKD. Encouraging results of clinical trials testing efficacy and safety of renal nerve ablation in resistant hypertensives provide the opportunity to apply the procedure in other subgroups of hypertensive patients. Available data regarding renal function of study participants suggest the safe implementation of RNA in patients with renal disease, but both unexplored benefits as well as potential hazards should be taken into account and critically evaluated. While renal denervation has been tested in selected cases of patients with renal disease, the results of large, multicenter trials evaluating the effects of this procedure on large cohorts of patients with CKD are eagerly anticipated.

The role of renal nerve ablation for the management of resistant hypertension and other disease conditions: benefits and concerns.

The sympathetic nervous system is overactivated in resistant hypertension and several other disease conditions. A reciprocal association between the brain and the kidney has been described, in that sympathetic overactivity affects renal function while renal injury stimulates central sympathetic drive. Renal nerve ablation has been recently introduced as a potential alternative for the management of resistant hypertension, mainly due to current limitations in pharmacologic antihypertensive therapy. Data accumulated thus far point towards an efficacious and safe interventional method for the management of treatment resistance, with additional benefits on glucose metabolism and cardiac structure and function. Furthermore, beneficial effects have been observed in patients with chronic kidney disease, obstructive sleep apnea, polycystic ovary syndrome, and sympathetically driven tachyarrhythmias. However, as with every novel technique, several questions need to be answered and concerns need to be addressed before the wide application of this interventional approach.

Carotid baroreceptor stimulation: a promising approach for the management of resistant hypertension and heart failure.

Many difficult-to-treat clinical entities in the cardiovascular field are characterized by pronounced sympathetic overactivity, including resistant hypertension and heart failure, underlining the need to explore therapeutic options beyond pharmacotherapy. Autonomic modulation via carotid baroreceptor activation has already been evaluated in clinical trials for resistant hypertension, and relevant outcomes with regard to safety and efficacy of the technique are critically presented. The pathophysiological background of heart failure renders carotid baroreceptor stimulation a potential treatment candidate for the disease. Available data from animal models with heart failure point towards significant cardioprotective benefits of this innovative technique. Accordingly, the effects of baroreceptor activation treatment (BAT) on cardiac parameters of hypertensive patients are well-promising, setting the basis for upcoming clinical trials with baroreflex activation on patients with heart failure. However, as the potential therapeutic of BAT unfolds and new perspectives are highlighted, several concerns are raised that should be meticulously addressed before the wide application of this invasive procedure is set in the limelight.

Assisted reproductive technology and pregnancy-related hypertensive complications: a systematic review.

Hypertensive complications in pregnancy are the leading cause of maternal morbidity, at least in the developed countries. In recent years, infertility issues are managed with ever growing therapeutic options namely assisted reproductive technologies (ART), which improve the ratio of successful induction of pregnancy. It is still debated whether various ART modalities are associated with adverse pregnancy outcomes, including hypertensive complications, particularly with higher incidence of preeclampsia. The main source of controversy stems from the diversity of effect modifiers modulating the association between ART-oriented pregnancy and hypertensive disorders. Indeed, women undergoing an ART procedure are affected by diverse causes of infertility, are frequently characterized by different genetic patterns with respect to their artificially conceived embryo and experienced multiple gestations. In order to investigate whether ART modalities are associated with increased incidence of hypertensive complications in pregnancy, we reviewed all published studies carried out before the end of 2010 and identified in the PubMed database. Among the 47 studies finally selected and by acknowledging the potential of shortcomings related to the different study design and populations, the overall evidence suggests that ART-oriented pregnancies-especially the in-vitro fertilization techniques-are accompanied by increased risk for gestational hypertension and preeclampsia as compared with non-ART pregnancies, even after adjustment for confounders. Multiple gestations, advanced age and underlying polycystic ovary syndrome resulted in constant confounders of the questioned association. Reducing multiple gestations by implementing single embryo techniques might be the therapeutic limiting step to lower the rate of hypertensive complications in assisted pregnancies.

Usefulness of the assessment of the appropriateness of left ventricular mass to detect left ventricular systolic and diastolic abnormalities in absence of echocardiographic left ventricular hypertrophy: the LIFE study.

Conventional definitions of left ventricular (LV) hypertrophy do not account for interindividual differences in loading conditions. We may define LV mass as inappropriately high when exceeding 128% of theoretical values predicted by gender, height(2.7), and stroke work, which explain up to 82% of the variability of LV mass in normal reference subjects. In 652 participants in the Losartan Intervention For Endpoint reduction in hypertension study without clinically overt cardiovascular disease or diabetes, we investigated whether inappropriately high LV mass is associated with relevant LV abnormalities independent of traditional definition of LV hypertrophy (ie, LV mass index >116 g/m(2) in men and >104 g/m(2) in women). The study sample was divided into three groups: patients with inappropriately high LV mass but without LV hypertrophy were compared to patients with LV hypertrophy and to patients with appropriate LV mass and without LV hypertrophy. Patients with inappropriately high but nonhypertrophic LV mass had higher body mass index and relative wall thickness, and lower LV myocardial systolic function, than patients with appropriate LV mass or patients with LV hypertrophy. In multivariate analyses, inappropriately high LV mass was independently associated with lower myocardial systolic function independent of LV hypertrophy and other covariates. Inappropriately high LV mass was also associated with prolonged isovolumic relaxation time and lower mitral E/A ratio independent of covariates. In conclusion, inappropriately high LV mass was associated with relevant, often preclinical, manifestations of cardiac disease in the absence of traditionally defined echocardiographic LV hypertrophy and concentric geometry.

Impact of valvular regurgitation on left ventricular geometry and function in hypertensive patients with left ventricular hypertrophy: the LIFE study.

Mild-to-moderate aortic and mitral regurgitation are frequently detected by echocardiogram in asymptomatic hypertensive patients. Our goal was to assess the prevalence and impact of mild-to-moderate mitral and/or aortic regurgitation on left ventricular (LV) structure and function in patients with hypertension and LV hypertrophy (LVH). Hypertensive patients with ECG LVH enrolled in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) echocardiography substudy were evaluated. Among 939 patients with needed LV measurements and Doppler data, 242 had mild (1+) valvular regurgitation, and 51 patients had moderate (2+ or 3+) regurgitation of one or both valves. In analyses adjusting for gender, patients with mild mitral and/or aortic regurgitation had larger LV internal dimensions (5.25 vs 5.33 cm, P<0.05), higher LV mass indexed for body surface area (122 vs 125 g/m(2), P<0.05) or height(2.7) (55.4 vs 57.3, P<0.05), and larger left atrial diameter. Patients with moderate regurgitation of one or both valves had larger LV chambers (5.25 vs 5.9 cm, P<0.001), greater mean LV mass (232 vs 248 g, P<0.001) and LV mass indexed for body surface area or height(2.7), and higher Doppler stroke volume. Patients with moderate valvular regurgitation also had a higher prevalence of LVH due to an increased prevalence of eccentric LVH. There were no differences among groups defined by the presence and severity of valvular regurgitation in cardiac output, total peripheral resistance, or pulse pressure/stroke volume, indicating that the observed inter-group differences in LV geometry were not due to differences in the haemodynamic severity of hypertension. Hypertensive patients with mild-to-moderate mitral or aortic valvular insufficiency have additional LV structural and functional changes that may affect prognosis.

The potential role of AT(1)-receptor blockade in the prevention and reversal of atherosclerosis.

The renin-angiotensin system may contribute to the development and progression of atherosclerosis both by increasing blood pressure and by direct effects on all phases of the atherogenic process. Genetic determinants of renin-angiotensin system activation, notably the DD genotype of angiotensin converting enzyme (ACE), are associated with an increased risk of cardiovascular events, as is increased plasma renin activity. In addition, angiotensin II has been shown to increase the uptake and oxidation of low density lipoprotein (LDL) by macrophages and endothelial cells. Angiotensin II also stimulates the production of interleukin 6 and activates the pro-inflammatory factor nuclear factor kappa(B), leading to expression of adhesion molecules and recruitment of monocytes and macrophages, and increases the production of pro-coagulatory factors. In animal experiments, treatment with ACE inhibitors or angiotensin AT(1)-receptor blockers has been shown to have anti-atherogenic effects. Studies with candesartan have shown that this agent produces a dose-dependent reduction in uptake of oxidised LDL by mouse macrophages in vitro, and reduces cholesterol accumulation and atherosclerosis development in the aorta of Watanabe rabbits. These effects were independent of changes in blood pressure. Such findings suggest that AT(1)-receptor blockers may be beneficial in reducing mortality and morbidity resulting from atherosclerotic disease, and are consistent with the findings from large outcome trials with ACE inhibitors in patients at risk of cardiovascular events.

Microalbuminuria is associated with unfavourable cardiac geometric adaptations in essential hypertensive subjects.

We sought in this study to examine the relationship between microalbuminuria and cardiac geometry since a slight increased urinary albumin excretion (UAE) and increased left ventricular (LV) mass have both been identified as predictors of cardiovascular events in hypertensive subjects. For this purpose, microalbuminuria was determined in three non-consecutive 24-h urine samples as UAE of 20-200 mg/24 h in a group of 249 untreated hypertensive subjects. Echocardiographic classification of patients into LV geometric patterns was based on relative wall thickness values and on gender-specific values for LV mass index (LVMI). The group of patients with microalbuminuria (n = 119) was matched for age, sex, body mass index, smoking status and plasma cholesterol level with the group of patients without microalbuminuria (n = 130). Subjects with microalbuminuria had significantly increased LVMI (111 vs 90 g/m(2), P < 0.0001), relative wall thickness (0.46 vs 0.41, P < 0.001) and office systolic and diastolic blood pressure (161 vs 148 and 101 vs 97 mmHg, respectively, P < 0.005). For the pooled population, UAE was positively correlated to LVMI (r = 0.46, P < 0.001) and relative wall thickness (r = 0.47, P < 0.001). In the entire population, normal LV geometry, concentric LV remodelling, eccentric and concentric LV hypertrophy was found in 34%, 33%, 12% and 21%, respectively. The prevalence of normal LV geometry was significantly higher in normoalbuminuric compared with microalbumnuric subjects (55 vs 14%, P < 0.001) while the prevalence of concentric LV hypertrophy was significantly higher in microalbuminuric compared with normoalbuminuric subjects (32 vs 5%, P < 0.0001). Multiple regression analysis revealed that concentric LV hypertrophy was significantly associated with increased values of UAE and mean arterial pressure. In conclusion, the higher prevalence of unfavourable LV geometric patterns in hypertensive subjects with microalbuminuria compared with those without microalbuminura, may account for the worse cardiovascular outcomes associated with the presence of an increased UAE in hypertensive subjects.

Relation of QT interval and QT dispersion to echocardiographic left ventricular hypertrophy and geometric pattern in hypertensive patients. The LIFE study. The Losartan Intervention For Endpoint Reduction.

OBJECTIVE: In hypertensive patients, left ventricular hypertrophy (LVH) predicts increased mortality, in part due to an increased incidence of sudden death. Repolarization-related arrhythmogenesis may be an important mechanism of sudden death in hypertensive patients with LVH. Increased QT interval and QT dispersion are electrocardiographic (ECG) measures of ventricular repolarization, and also risk markers for ventricular tachyarrhythmias. We assessed the relation of QT intervals and QT dispersion to echocardiographically determined left ventricular (LV) mass and geometry in a large population of hypertensive patients with ECG evidence of LVH. METHODS: QT intervals and QT dispersion were determined from baseline 12-lead ECGs in 577 (57% male; mean age 65 +/- 7 years) participants in the LIFE study. LV mass index (LVMI) and geometric pattern were determined by echocardiography and QT interval duration and QT dispersion were assessed in relation to gender-specific LVMI quartiles. RESULTS: In both genders, increasing LVMI was associated with longer rate-adjusted QT intervals. QT dispersion measures showed a weaker association with LVMI quartiles. Both concentric and eccentric LVH were associated with increased QT interval duration and QT dispersion. These relations remained significant after controlling for relevant clinical variables. CONCLUSIONS: In hypertensive patients with ECG evidence of LVH, increased LVMI and LVH are associated with a prolonged QT interval and increased QT dispersion. These findings suggest that an increased vulnerability to repolarization-related ventricular arrhythmias might in part explain the increased risk of sudden death in hypertensive patients with increased LV mass.

Exercise as hypertension therapy.

In conclusion, the findings of most recent studies show that moderate-intensity aerobic exercise training can lower BP in patients with stage 1 and 2 essential hypertension. The average reduction in BP is 10.5 mm Hg for systolic and 7.6 mm Hg for diastolic BP. The reductions do not appear to be gender- or age-specific. Significant reductions in BP and LVH regression in patients with stage 3 hypertension have also been reported following aerobic exercise training. Resistance training exercise has not consistently shown to significantly lower BP and is not recommended as the only form of exercise for hypertensive patients. The exercise training program for optimal benefits should consist of 3 to 5 times per week, 30 to 60 minutes per session, at 50% to 80% of PMHR. However, exercise programs should be individualized to meet the patient's needs and abilities. Exercise intensity and duration should be manipulated to promote a safe and effective antihypertensive program. Initially, the exercise intensity should be low and the duration short. Both intensity and duration should progressive increase over a period of weeks until the desired goal, is achieved. The rate of progression must be tailored to meet individual patient needs and abilities. The exercise program for overweight or obese hypertensive patients should aim to promote a caloric expenditure of 300 to 500 Kcal per day and 1000 to 2000 Kcal per week. Such an approach, combined with a prudent diet, is likely to reduce body weight. The mechanisms mediating exercise-induced BP reduction are poorly understood. BP reductions appear to be independent of changes in body weight or body composition. There are also no indications of age- or gender-related differences in BP response to exercise. The use of ambulatory blood pressure measuring devices in exercise studies is not extensive. The few studies available indicate a more moderate reduction in BP than that reported by casual observations.

Similar effects of isolated systolic and combined hypertension on left ventricular geometry and function: the LIFE Study.

Echocardiograms of 143 patients with isolated systolic hypertension were compared to 808 patients with combined (systolic and diastolic) hypertension. All patients met electrocardiographic criteria for left ventricular hypertrophy and were evaluated off medication. Patients with isolated systolic hypertension were older, shorter, weighed less, and were mostly women, but body mass index (BMI) was similar in both groups. Systolic blood pressure (SBP) was 172 mm Hg in isolated systolic hypertension, 174 mm Hg in combined (P = not significant). Diastolic blood pressure was 83 and 101 mm Hg, respectively (P < .001). Despite having mean arterial pressure 12 mm Hg lower than patients with combined hypertension, the group with isolated systolic hypertension had equally severe abnormalities of left ventricular mass, left ventricular geometric patterns, and measures of systolic and diastolic function. Peripheral resistance was lower and pulse pressure/stroke volume ratio (arterial stiffness index) was higher and the isovolumic relaxation time shorter in isolated systolic hypertension. Multiple regression analyses identified age, height, BMI, stress-corrected mid wall shortening, stroke volume, male gender, and systolic or mean blood pressure (but not isolated systolic hypertension) as independent correlates of left ventricular mass. Relative wall thickness was independently associated with isolated systolic hypertension (P = .001) in addition to mean pressure and other covariates. The present results add support to the concept that systolic blood pressure (SBP) is a stronger determinant than diastolic pressure of cardiac target organ damage in hypertension.

Echocardiographic left ventricular geometry in hypertensive patients with electrocardiographic left ventricular hypertrophy: The LIFE Study.

AIM: To assess the prevalence of echocardiographic left ventricular hypertrophy (LVH) and concentric remodeling in hypertensive patients with electrocardiographic (ECG)-LVH and to estimate the cost-effectiveness of echocardiography and ECG for detection of LVH. DESIGN: Echocardiographic LV measurements and the prevalence of abnormal LV geometric patterns were compared between 964 hypertensive patients with ECG-LVH (Cornell voltage-duration product > 2440 and/or SV1 +/- RV5-6 > 38 mm) participating in the LIFE trial and groups of 282 employed hypertensives and 366 apparently normal adults. RESULTS: Among both women and men, stepwise increases from reference subjects to employed hypertensives to LIFE patients were observed for LV wall thicknesses, chamber size and mass. Mean LV mass/body surface area (BSA) and LV mass/height(2.7) were substantially larger in LIFE patients than normal adults among women (113 vs 69 g/m2 and 55 vs 32 g/m(2.7), p <0.001) and men (127 vs 83 g/m2 and 55 vs 36 g/m(2.7), p < 0.001), with intermediate values in employed hypertensives. Compared to the latter group, LIFE patients had higher prevalences of concentric LVH (25-29% vs 3-4%) and eccentric LVH (45-51% vs 13-17%) but not concentric LV remodeling (8-11% vs 12-14%). LVH was present in 70% of LIFE patients by LV mass/BSA criteria and 76% by LV mass/height(2.7) criteria (odds ratios = 11.4 and 13.5 vs employed hypertensives). CONCLUSIONS: The ECG criteria used in LIFE identify hypertensive patients with a >70% prevalence of anatomic LVH, allowing accurate identification of high-risk status by this commonly used technique.

Reduction in stroke with gemfibrozil in men with coronary heart disease and low HDL cholesterol: The Veterans Affairs HDL Intervention Trial (VA-HIT).

BACKGROUND: A low level of HDL cholesterol has been identified as a risk factor for stroke in observational studies. METHODS AND RESULTS: Our objective was to determine whether treatment aimed at raising HDL cholesterol and lowering triglycerides reduces stroke in men with coronary heart disease and low levels of both HDL and LDL cholesterol. The study was a placebo-controlled, randomized trial conducted in 20 Veterans Affairs medical centers. A total of 2531 men with coronary heart disease, with mean HDL cholesterol 0.82 mmol/L (31.5 mg/dL) and mean LDL cholesterol 2.9 mmol/L (111 mg/dL), were randomized to gemfibrozil 1200 mg/d or placebo and were followed up for 5 years. Strokes were confirmed by a blinded adjudication committee. Relative risks were derived from Cox proportional hazards models. There were 134 confirmed strokes, 90% of which were ischemic. Seventy-six occurred in the placebo group (9 fatal) and 58 in the gemfibrozil group (3 fatal), for a relative risk reduction, adjusted for baseline variables, of 31% (95% CI, 2% to 52%, P=0.036). The reduction in risk was evident after 6 to 12 months. Patients with baseline HDL cholesterol below the median may have been more likely to benefit from treatment than those with higher HDL cholesterol. CONCLUSIONS: In men with coronary heart disease, low HDL cholesterol, and low LDL cholesterol, gemfibrozil reduces stroke incidence.