E. Koutra

Effects of multielectrode renal denervation on cardiac and neurohumoral adaptations in resistant hypertension with cardiac hypertrophy: an EnligHTN I substudy

Objective: This EnligHTN I nonrandomized substudy investigated the effect of multielectrode renal denervation (RDN) on cardiac and neurohumoral adaptations. Methods: Eighteen patients with true drug-resistant hypertension [age: 56 ± 10 years, 12 men, BMI: 33.6 ± 5.4 kg/m2, office blood pressure (BP) by automatic device (Omron): 182 ± 19/97 ± 18 mmHg and ambulatory BP (Spacelabs): 153 ± 16/87 ± 15 mmHg receiving 4.5 antihypertensive drugs/day] and left ventricular hypertrophy underwent multielectrode RDN (EnligHTN system; St. Jude Medical), whereas 10 patients served as controls. Both groups were followed-up for 6 months. Results: Demographic data were homogenous between both patient groups. In addition to reduction of office (−42/−17 mmHg, P < 0.001) and ambulatory (−19/−9 mmHg, P < 0.001) BP, RDN contributed to attenuation of left ventricular mass index from 140.0 ± 17.0 g/m2 (57.9 ± 7.9 g/m2.7) to 126.7 ± 19.2 g/m2 (52.6 ± 8.4 g/m2.7) (P < 0.01 for both) and left atrial diameter from 42.4 ± 4.3 to 40.6 ± 3.6 mm (P = 0.004) at 6 months. Up to 56% of the RDN-group patients achieved a target of less than 140/90 mmHg in the office BP; proportion of RDN-group patients with concentric left ventricular hypertrophy had decreased by 39%; mitral lateral E/E′ ratio decreased from 14.8 ± 6.1 to 12.0 ± 3.2 (P = 0.016); isovolumic relaxation time shortened from 109.8 ± 16.2 to 100.8 ± 17.1 ms (P = 0.003); and N-terminal pro B-type natriuretic peptide levels reduced from 84.9 ± 35.9 to 57.2 ± 38.8 pg/ml (P < 0.001) significantly at 6 months post-RDN. Control patients exhibited no significant changes in all the above parameters (P > 0.05) at 6 months. Conclusion: Multielectrode RDN contributes to improvement of diastolic dysfunction, reduction of left ventricular mass and attenuation of NT-proBNP, suggesting additional cardiovascular benefits in drug-resistant hypertension associated with left ventricular hypertrophy.

Effects of multielectrode renal denervation on elevated sympathetic nerve activity and insulin resistance in metabolic syndrome.

Objective: This study aimed to investigate the effects of renal denervation (RDN) on sympathetic nerve activity and insulin resistance in patients with metabolic syndrome. Methods: Seventeen patients fulfilled at least four of five criteria for metabolic syndrome and under stable use of at least two antihypertensive drugs were randomized in 3 : 1 ratio to RDN (n = 13, 12 men, age: 58 ± 7 years) and control groups (n = 4, three men, age: 60 ± 5 years) and followed up for 3 months. Muscle sympathetic nerve activity (MSNA) at rest and during standard 75 g oral glucose tolerance test (OGTT) was assessed. Results: In the RDN group, office and average 24-h blood pressures reduced by 16 ± 21/10 ± 11 mmHg (P = 0.01/0.007) and 14 ± 16/5 ± 8 mmHg (P = 0.008/0.03) respectively; waist circumference reduced by 3.1 ± 3.6 cm (P = 0.008); and resting MSNA reduced from 55 ± 9 bursts per minute to 46 ± 8 bursts per minute (P = 0.0008) at month 3 post-RDN. During OGTT, although blunted MSNA responses were noted at baseline throughout the 120-min test, improved MSNA responses with burst frequency increased to 52 ± 8 bursts per minute (P < 0.001 vs. the resting MSNA, n = 13) at 30 min and to 54 ± 8 bursts per minute (P = 0.004 vs. the resting MSNA, n = 10) at 120 min and were observed at month 3 post-RDN. No such improvements were observed in the controls. No significant change was observed in the HOMA-IR in both groups at month 3. Conclusion: In this pilot study of patients with metabolic syndrome and associated hypertension, RDN reduced elevated sympathetic nerve activity and restored the normal neural response to oral glucose loading.

[OP.7B.02] METABOLIC SYNDROME IS ASSOCIATED WITH INCREASED SYMPATHETIC NERVOUS SYSTEM ACTIVITY AND ARTERIAL STIFFNESS IN RESISTANT HYPERTENSIVE PATIENTS.

Objective: Resistant hypertension is related to sympathetic overdrive and arterial stiffening, while there are scarce data whether metabolic syndrome further potentiates sympathetic activity and vascular abnormalities in this setting. The aim of this study was to assess the effect of the metabolic syndrome on muscle sympathetic nerve activity (MSNA) and arterial stiffness in resistant hypertensive patients. Design and method: We studied 36 patients with resistant hypertension [age: 59 ± 10 years, 24 males, office blood pressure (BP): 178/93 ± 14/11 mmHg, 24-hour BP: 146/84 ± 13/11 mmHg, under 4.3 ± 0.6 drugs] that underwent transthoracic echocardiographic study and blood sampling for assessment of the metabolic profile. Metabolic syndrome was defined according to the Adult Treatment Panel III criteria and arterial stiffness was evaluated on the basis of carotid to femoral pulse wave velocity (PWV). In all participants sympathetic drive was assessed by MSNA estimations based on established methodology (microneurography). Results: Resistant hypertensive patients with metabolic syndrome (n = 16) compared to those without (n = 20) exhibited higher waist circumference (109.2 ± 5.3 vs 94.8 ± 9.1 cm, p = 0.001), fasting glucose (130.9 ± 2.2 vs 94.3 ± 2.2 mg/dl, p < 0.05), office systolic BP (185 ± 16 vs 170 ± 13 mmHg, p < 0.001) and left ventricular mass index (132.2 ± 17.1 vs 123.6 ± 16.2 g/m2, p = 0.001). Moreover, metabolic syndrome2patients compared to those without were characterized by greater levels of carotid to femoral PWV (11.8 ± 0.7 vs 9.2 ± 0.9 m/sec, p < 0.001) and sympathetic nerve traffic as reflected by MSNA levels (82.1 ± 2.5 vs 73.3 ± 2.1 bursts per 100 heart beats, p < 0.001). In all participants MSNA was related to waist circumference (r = 0.36, p = 0.004) and office systolic BP levels (r = 0.36, p < 0.05) but there was no association with PWV values (p = NS). Conclusions: In resistant hypertensive patients, metabolic syndrome is associated with high MSNA and PWV levels. These findings support that metabolic syndrome further deteriorates sympathetic activity and arterial stiffening characterizing resistant hypertension.

EXAGGERATED EXERCISE BLOOD PRESSURE RESPONSE IS ACCOMPANIED BY SYMPATHETIC OVERDRIVE AND ARTERIAL STIFFNESS IN SUBJECTS WITH HIGH NORMAL BLOOD PRESSURE

Objective: The clinical importance of a hypertensive response to exercise (HRE) in subjects with high normal blood pressure (BP) is not fully elucidated, while sympathetic overactivity and arterial stiffening are linked with adverse cardiovascular prognosis. The aim of this study was to assess the relation of HRE with sympathetic drive as assessed by muscle sympathetic nerve activity (MSNA) and arterial stiffness in subjects with high normal BP. Design and method: 42 subjects with high normal office BP [defined as office systolic BP = 130–139 mmHg and office diastolic BP = 85–89 mmHg (age: 53 ± 9 years, 29 males, office BP: 134/84 mmHg, 24-hour BP: 114/72 mmHg)] with a negative treadmill exercise test (Bruce protocol) were divided into those with HRE (n = 12) (peak exercise systolic BP > or = 210mmHg in men and > or = 190 mmHg in women) and those without HRE (n = 30). Arterial stiffness was evaluated on the basis of carotid to femoral pulse wave velocity (PWV) values. In all participants sympathetic drive was assessed by MSNA estimations based on established methodology (microneurography). Results: Subjects with a HRE compared to those without exhibited higher waist circumference (108.2 ± 5.3 vs 94.7 ± 9.2 cm, p = 0.001) and were characterized by greater levels of carotid to femoral PWV (8.5 ± 0.8 vs 7.0 ± 0.9 m/sec, p < 0.001) and sympathetic nerve traffic as reflected by MSNA levels (41.1 ± 1.5 vs 32.1 ± 1.9 bursts per 100 heart beats, p < 0.001), while did not differ regarding metabolic profile and left ventricular mass index (p = NS). In the total population, peak exercise systolic BP was related to 24-h systolic BP (r = 0.229, p < 0.05), PWV (r = 0.218, p = 0.002), and MSNA (r = 0.214, p < 0.05). Moreover, MSNA was related to waist circumference (r = 0.33, p = 0.004) and office systolic BP levels (r = 0.31, p < 0.05) but there was no association with PWV values (p = NS). Conclusions: In subjects with high normal BP, a HRE identifies a state of arterial stiffening and sympathetic overdrive, as reflected by increased PWV and MSNA levels respectively. These finding suggest that exercise testing provides additional clinical information regarding the vascular status and modulation of sympathetic tone in this setting.

ISOLATED SYSTOLIC HYPERTENSION VERSUS COMBINED SYSTOLIC-DIASTOLIC HYPERTENSION AS PREDICTORS OF NEW-ONSET DIABETES MELLITUS: DATA FROM A GREEK 8-YEARS-FOLLOW-UP STUDY

Objective: The aim of the study was to compare the predictive role of isolated systolic hypertension (ISH) and combined systolic-diastolic hypertension for the incidence of new-onset diabetes mellitus (NOD) in essential hypertensive patients. Design and method: We followed up 1435 non-diabetic essential hypertensives with office systolic blood pressure (BP)>or = 140 mmHg [mean age 57 years, 730 males, office BP = 153/92 mmHg] for a mean period of 8 years. All subjects had at least one annual visit and at baseline underwent echocardiographic study and blood sampling for estimation of metabolic profile. Patients with baseline ISH exhibited office systolic BP >or = 140 mmHg and office diastolic BP < 90 mmHg, while those with systolic-diastolic hypertension had office systolic BP >or = 140 mmHg and office diastolic BP >or = 90 mmHg. Moreover, NOD was defined if at one or more of the follow-up visits a previously non-diabetic patient reported being on insulin or an oral hypoglycemic drug or if casual plasma glucose concentration >or = 200 mg/dl or fasting glucose concentration >or = 126 mg/dl or 2-h post load glucose >or = 200 mg/dl during an oral glucose tolerance test. Results: The incidence of NOD over the follow-up period was 4.2% (n = 60). Patients with ISH (n = 460) compared to those with systolic-diastolic hypertension (n = 975) were older (65 ± 11 vs 54 ± 10 years, p < 0.0001), had at baseline lower waist circumference (94.5 ± 11 vs 99 ± 13 cm, p < 0.0001), office systolic BP (149 ± 12 vs 155 ± 13 mmHg, p < 0.0001), office diastolic BP (80 ± 8 vs 98 ± 6 mmHg, p < 0.0001), while did not differ regarding left ventricular mass index, glucose and lipid levels (p = NS for all). Univariate Cox regression analysis revealed that baseline ISH (hazard ratio = 2.143, p = 0.016) and systolic-diastolic hypertension (hazard ratio = 1.272, p = 0.029) predicted NOD. However, in multivariate Cox regression model, age (hazard ratio = 1.039, p < 0.001), baseline glucose levels (hazard ratio 1.011, p = 0.016), waist circumference (hazard ratio=1.067, p < 0.001) and ISH (hazard ratio=1.651, p = 0.029) but not systolic-diastolic hypertension were be independent predictors of NOD. Conclusions: ISH but not systolic-diastolic hypertension exhibits independent prognostic value for NOD. These findings support that ISH constitutes a hypertensive phenotype of increased metabolic risk needing careful evaluation and treatment.

ISOLATED SYSTOLIC HYPERTENSION VERSUS COMBINED SYSTOLIC-DIASTOLIC HYPERTENSION AS PREDICTORS OF ATRIAL FIBRILLATION: DATA FROM A GREEK 8-YEAR-FOLLOW-UP STUDY

Objective: The aim of the present study was to compare the predictive role of isolated systolic hypertension (ISH) and combined systolic-diastolic hypertension for the incidence of atrial fibrillation (AF) in essential hypertension. Design and method: We followed up 1605 essential hypertensives with office systolic blood pressure (BP) > or =140 mmHg [mean age 58.1 years, 842 males, office BP = 153/92 mmHg] for a mean period of 8 years. Patients with baseline ISH exhibited office systolic BP >or =140 mmHg and office diastolic BP <90 mmHg, while those with systolic-diastolic hypertension had office systolic BP > or =140 mmHg and office diastolic BP > or = 90 mmHg. Moreover, new-onset AF was defined as hospitalization for AF or compatible electrocardiographic tracings. Results: The incidence of new-onset AF over the follow-up period was 3.4% (n = 55). Patients with ISH (n = 510) compared to those with systolic-diastolic hypertension (n = 1095) were older (65 ± 10 vs 55 ± 11 years, p < 0.0001), had at baseline lower office systolic BP (149 ± 10 vs 155 ± 13 mmHg, p < 0.0001) and office diastolic BP (80 ± 5 vs 98 ± 7 mmHg, p < 0.0001), while did not differ regarding left ventricular mass index (p = NS). Univariate Cox regression analysis revealed that baseline ISH (hazard ratio = 4.612, p = 0.013) and systolic-diastolic hypertension (hazard ratio = 1.794, p = 0.036) predicted new-onset AF. However, in multivariate Cox regression model, age (hazard ratio = 1.078, p < 0.001), left atrium diameter (hazard ratio = 1.102, p < 0.001) and ISH (hazard ratio = 1.551, p = 0.035) but not systolic-diastolic hypertension turned out to be independent predictors of new-onset AF episodes. Conclusions: In hypertensive patients, ISH but not systolic-diastolic hypertension exhibits independent prognostic value for AF. These findings support that ISH constitutes a hypertensive phenotype of increased risk for AF needing careful management.

[OP.LB.02.03] EFFECTS OF MULTIELECTRODE RENAL DENERVATION ON SYMPATHETIC NERVE ACTIVITY AND INSULIN RESISTANCE IN METABOLIC SYNDROME

Objective: This study aimed to investigate the effects of renal denervation (RDN) on sympathetic nerve activity and insulin resistance in patients with metabolic syndrome at 3 months post-RDN. Design and method: Seventeen patients fulfilled 4/5 criteria for metabolic syndrome and under stable use of at least two anti-hypertensive drugs at maximum tolerated doses for at least 4 weeks were enrolled and randomized in 3:1 ratio to RDN [n = 13, 12 males, age: 58 ± 7 years] and Control groups [n = 4, 3 males, age: 60 ± 5 years]. Both groups were followed up for 3 months. Muscle sympathetic nerve activity (MSNA) measurements were performed to assess sympathetic nerve activity at fasting state and during standard 75 g oral glucose tolerance test (OGTT). Blood sampling was also performed to assess insulin resistance (HOMA-IR). Results: In the RDN group, office BP reduced by 16 ± 21/10 ± 11 mmHg (P = 0.01/0.007); average 24-hour BP reduced by 14 ± 16/5 ± 8 mmHg (P = 0.008/0.03); waist circumference reduced by 3.1 ± 3.6 cm (P = 0.008); and MSNA at fasting state reduced from 55 ± 10 bursts per minute/82 ± 15 bursts per 100 heart beats to 46 ± 8 bursts per minute/71 ± 15 bursts per 100 heart beats (P = 0.0008/0.006) at 3 months post-RDN. During OGTT, while blunted MSNA responses were noted at baseline throughout the 120-minute test (P > 0.05/0.05 vs. MSNA at fasting state), improved MSNA responses with burst frequency/burst incidence increased to 52 ± 8 bursts per minute/76 ± 12 bursts per 100 heart beats (P < 0.001/0.04 vs. the MSNA at fasting state, n = 13) at 30 minutes and to 58 ± 16 bursts per minute/80 ± 14 bursts per 100 heart beats (P = 0.04/0.008 vs. the MSNA at fasting state, n = 10) at 120 minutes were observed at 3 months post- RDN. No such improvements were observed in the 4 control group subjects at 3 months follow-up. No statistical significant change was observed in the HOMA-IR in both groups at 3 months. Conclusions: Strategies to target specifically the elevated sympathetic nerve activity may provide substantial clinical benefits to patients with metabolic syndrome and associated hypertension.

[PP.29.04] IVABRADINE THERAPY FAVORABLY MODULATES SYMPATHETIC OVERDRIVE AND ARTERIAL STIFFENING IN HYPERTENSIVE PATIENTS WITH METABOLIC SYNDROME

Objective: Hypertension and metabolic syndrome are related to sympathetic overdrive and arterial stiffening, while there are no data whether ivabradine modulates sympathetic activity and vascular abnormalities in this setting. The aim of this study was to assess the effect of ivabradine on muscle sympathetic nerve activity (MSNA) and arterial stiffness in hypertensive patients with metabolic syndrome. Design and method: We studied 36 patients with essential hypertension [age: 56 ± 10 years, 30 males, office blood pressure (BP): 148/92 ± 14/11 mmHg] on antihypertensive therapy with a fixed combination of perindopril/amlodipine. Patients were randomized with a ratio 2:1 to ivabradine (5 mg twice daily) or no ivabradine (control group). Metabolic syndrome was defined according to the Adult Treatment Panel III criteria. In all participants at baseline and at 6 months follow-up arterial stiffness was evaluated on the basis of carotid to femoral pulse wave velocity (PWV), while sympathetic drive was assessed by MSNA estimations based on established methodology (microneurography). Results: Patients on ivabradine (n = 24) compared to controls (n = 12) did not differ regarding baseline BP, creatinine, glucose and lipid profile (p = NS or all). There was no significant difference in the reduction of office BP between the two study groups (p = NS). However, hypertensive patients in the ivabradine group were characterized by a reduction in carotid to femoral PWV from 11.5 ± 0.9 m/sec to 9.8 ± 1.2 m/sec (p < 0.001) and sympathetic nerve traffic as reflected by MSNA levels from 86.2 ± 2.5 bursts per 100 heart beats to 74.8 ± 2.4 bursts per 100 heart beats (p < 0.001) at 6 months. No significant changes in PWV and MSNA were observed in the control group (p = NS). Conclusions: In hypertensive patients with metabolic syndrome, treatment with ivabradine reduces sympathetic activation and arterial stiffening as reflected by lower MSNA and PWV levels at 6 months follow-up. These findings suggest that ivabradine could exhibit additional therapeutic properties in the setting of dysmetabolic hypertension.

8A.07: NON-INVASIVE ASSESSMENT OF HAEMODYNAMICS IN RESISTANT HYPERTENSION: THE ROLE OF RENAL HAEMODYNAMICS.

Objective: Hypertension is a multisystem disease in which the kidney plays a key role in long term regulation of blood pressure and the development of hypertension. The aim of this study was to evaluate the role of intrarenal resistance indices in the renal interlobular arteries measured by Doppler ultrasound in resistant hypertensive patients. Design and method: We studied 50 patients with resistant hypertension (RH) [age: 61 ± 11 years, 31 males, office blood pressure (BP): 163/89 ± 24/15 mmHg, under 4.2 ± 0.5 drugs] and 50 hypertensive patients controlled on three or less drugs [age: 59 ± 9 years, 26 males, BP: 131/79 ± 9/8 mmHg, under 2.2 ± 0.3 drugs] that underwent transthoracic echocardiographic study for determination of mitral annular early diastolic velocity (E/e’) and blood sampling for assessment of metabolic profile. Moreover, data on renal resistive index (RRI), obtained by Doppler ultrasound sampling of the intrarenal arteries, were retrospectively analyzed. Results: Hypertensives with RH compared to those without RH exhibited higher RRI by 0.078 (p < 0.001) and E/e’ values by 3.1 (p < 0.001). In the entire study population, RRI was negatively related to office diastolic BP (r = −0.239, p < 0.05), while it was positively associated with office systolic BP (r = 0.310, p < 0.05), office PP (r = 0.583, p < 0.01), age (r = 0.322, r < 0.001), and LVMI (height) (r = 0.283, p < 0.001). Systolic BP (beta 0.864, p < 0.001) and diastolic BP (beta −0.907, p < 0.001) were the only independent predictors of RRI in linear regression analysis, while according to multivariate logistic regression analysis, the major factors influencing whether a person reported having RH were RRI, E/e’, duration of hypertension, and age. Conclusions: Increased renal and cardiac haemodynamics, as reflected by increased vascular resistance of intrarenal arteries and E/e’, are associated closely with the presence of RH. These findings imply that RRI and E/e’ values should be taken into account for the prediction of insufficient control of BP in hypertensive patients.

PREDICTORS AND CARDIOVASCULAR PROGNOSIS OF INCIDENT AND PERSISTENT RESISTANT HYPERTENSION: A 4-YEAR FOLLOW-UP STUDY

Little is known regarding the clinical course and prognosis of resistant hypertension (RHT). We evaluated predictors of persistent RHT and the associated cardiovascular risk. We studied 1,911 treated hypertensive patients (aged 59±11 years, 49% males) for a mean period of 3.9 years. At baseline,