M. Schlaich

Relation Between Cardiac Sympathetic Activity and Hypertensive Left Ventricular Hypertrophy

Background—Left ventricular (LV) hypertrophy is an independent risk factor for cardiovascular morbidity and mortality in hypertensive subjects. Sympathetic activation has been suggested to contribute to LV hypertrophy, but this has not yet been conclusively validated in humans. Methods and Results—We comprehensively assessed total systemic and regional sympathetic activity by radiotracer dilution methods and microneurography in 15 untreated hypertensive subjects with echocardiographic evidence of LV hypertrophy (EH+), 11 hypertensive subjects with similar blood pressure but without LV hypertrophy (EH−), and 10 age-matched normotensive control subjects (NT). LV mass index was 87±15 g/m2 in NT, 106±11g/m2 in EH−, and 138±17g/m2 in EH+ (P <0.001). Total body and renal norepinephrine spillover were higher in both hypertensive groups compared with NT (total norepinephrine spillover, NT 223±145 versus EH− 418±135 versus EH+ 497±303 ng/min; renal norepinephrine spillover, NT 38.8±25.3 versus EH− 88.6±58.0 versus EH+ 103.4±56.2 ng/min; both P <0.05). However, muscle sympathetic nerve activity (NT 25±6 versus EH− 38±20 versus EH+ 57±19 bursts per 100 heartbeats; P <0.01) and cardiac norepinephrine spillover (NT 11.7±6.2 versus EH− 13.1±7.2 versus EH+ 28.6±17.4 ng/min; P <0.01) were only increased in EH+. Cardiac norepinephrine spillover correlated positively with LV mass index in all subjects (r =0.52; P <0.001). Conclusions—Our findings demonstrate that hypertensive LV hypertrophy is associated with increased sympathetic activity largely confined to the heart, suggesting that increased cardiac norepinephrine release is related to the development of LV hypertrophy.

Interactions Between Leptin and the Human Sympathetic Nervous System

Abstract—Results from animal experimentation suggest a 2-way interaction between leptin and the sympathetic nervous system, with leptin causing sympathetic activation and conversely, with the sympathetic system exercising regulatory feedback inhibition over leptin release. We have now tested this hypothesis in humans. In the absence of results from leptin infusions, to test for sympathetic stimulation of leptin release, we sought a quantitative naturalistic linkage of sympathetic activity with leptin plasma concentration across a broad range of leptin values in men of widely differing adiposity. Renal norepinephrine spillover was correlated with plasma leptin (r =0.628, P <0.01), but other measures of sympathoadrenal function did not. To test for sympathetic and adrenomedullary inhibition of leptin release, we studied clinical models of high sympathetic tone, heart failure, and essential hypertension, in which lowered plasma leptin levels might have been expected but were not found; a model of low sympathetic activity, pure autonomic failure, in which plasma leptin level was normal (6.1±1.2 vs 12.8±3.1 ng/mL in healthy subjects); and a clinical model of reduced epinephrine secretion, healthy aging, in which plasma leptin level again was normal (5.7±1.1 ng/mL vs 4.0±0.9 ng/mL in men >60 years and <35 years, respectively). Paradoxically, leptin concentration was elevated in heart failure, caused entirely by reduced renal clearance of leptin release, 142.0±30.5 mL/min, compared with 56.9±18.9 mL/min (P <0.05). These results provide some support for the view that leptin stimulates the sympathetic nervous system, at least for renal sympathetic outflow, but do not confirm the concept of regulatory feedback inhibition of leptin release by the sympathetic nervous system.

Sustained Sympathetic and Blood Pressure Reduction 1 Year After Renal Denervation in Patients With Resistant Hypertension

Renal denervation (RDN) reduces muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in resistant hypertension. Although a persistent BP-lowering effect has been demonstrated, the long-term effect on MSNA remains elusive. We investigated whether RDN influences MSNA over time. Office BP and MSNA were obtained at baseline, 3, 6, and 12 months after RDN in 35 patients with resistant hypertension. Office BP averaged 166±22/88±19 mm Hg, despite the use of an average of 4.8±2.1 antihypertensive drugs. Baseline MSNA was 51±11 bursts/min ≈2- to 3-fold higher than the level observed in healthy controls. Mean office systolic and diastolic BP significantly decreased by –12.6±18.3/–6.5±9.2, –16.1±25.6/–8.6±12.9, and –21.2±29.1/–11.1±12.9 mm Hg (P<0.001 for both systolic BP and diastolic BP) with RDN at 3-, 6-, and 12-month follow-up, respectively. MSNA was reduced by –8±12, –6±12, and –6±11 bursts/min (P<0.01) at 3-, 6-, and 12-month follow-up. The reduction in MSNA was maintained, despite a progressive fall in BP over time. No such changes were observed in 7 control subjects at 6-month follow-up. These findings confirm previous reports on the favorable effects of RDN on elevated BP and demonstrate sustained reduction of central sympathetic outflow ⩽1-year follow-up in patients with resistant hypertension and high baseline MSNA. These observations are compatible with the hypothesis of a substantial contribution of afferent renal nerve signaling to increased BP in resistant hypertension and argue against a relevant reinnervation at 1 year after procedure.

Health-Related Quality of Life After Renal Denervation in Patients With Treatment-Resistant Hypertension

Recent studies have demonstrated the effectiveness of radiofrequency ablation of the renal sympathetic nerves in reducing blood pressure (BP) in patients with resistant hypertension. The effect of renal denervation on health-related quality of life (QoL) has not been evaluated. Using the Medical Outcomes Study 36-Item Short-Form Health Survey and Beck Depression Inventory-II, we examined QoL before and 3 months after renal denervation in patients with uncontrolled BP. For baseline comparisons, matched data were extracted from the Australian Diabetes, Obesity, and Lifestyle database. Before renal denervation, patients with resistant hypertension (n=62) scored significantly worse in 5 of the eight 36-Item Short-Form Health Survey domains and the Mental Component Summary score. Three months after denervation (n=40), clinic BP was reduced (change in systolic and diastolic BP, −16±4 and −6±2 mm Hg, respectively; P<0.01). The Mental Component Summary score improved (47.6±1.1 versus 52±1; P=0.001) as a result of increases in the vitality, social function, role emotion, and mental health domains. Beck Depression Inventory scores were also improved, particularly with regard to symptoms of sadness (P=0.01), tiredness (P<0.001), and libido (P<0.01). The magnitude of BP reduction or BP level achieved at 3 months bore no association to the change in QoL. Renal denervation was without a detrimental effect on any elements of the 36-Item Short-Form Health Survey. These results indicate that patients with severe hypertension resistant to therapy present with a marked reduction in subjective QoL. In this pre- and post-hypothesis generating study, several aspects of QoL were improved after renal denervation; however, this was not directly associated with the magnitude of BP reduction.

Sympathetic activation and endothelial dysfunction in polycystic ovary syndrome are not explained by either obesity or insulin resistance.

Polycystic ovary syndrome (PCOS) is a common endocrine condition underpinned by insulin resistance and associated with increased risk of obesity, type 2 diabetes and adverse cardiovascular risk profile. Previous data suggest autonomic imbalance [elevated sympathetic nervous system (SNS) activity and decreased heart rate variability (HRV)] as well as endothelial dysfunction in PCOS. However, it is not clear whether these abnormalities are driven by obesity and metabolic disturbance or whether they are independently related to PCOS.

Substantial blood pressure reduction with renal denervation in a drug-naïve patient intolerant to antihypertensive pharmacotherapy: a case report.

Substantial blood pressure reduction with renal denervation in a drug-naive patient intolerant to antihypertensive pharmacotherapy: a case report

HIGHER MICRORNA-132 IS ASSOCIATED WITH BLOOD PRESSURE AND LIVER STEATOSIS IN OBESE INDIVIDUALS

Objective: Obesity is associated with numerous comorbidities including cardiovascular disease, diabetes and non-alcoholic fatty liver disease (NAFLD). Obesity pathogenesis is complex and incompletely understood and hence therapeutic options to address the global epidemic of obesity are lacking. In addition, NAFLD is strongly linked to cardiovascular disease. Our recent findings in experimental models have shown that microRNA miR-132 is an important regulator of liver homeostasis. Here, we aimed to assess miR-132 expression in liver and fat tissue of obese individuals and its association with blood pressure and hepatic steatosis. Design and method: Obese individuals undergoing bariatric surgery for weight management (nu200a=u200a14u200afemales/5 males) comprised the cohort of this study. They were 39u200a±u200a2 years old (meanu200a±u200aSEM) with a body mass index (BMI) of 42u200a±u200a1u200akg/m2. Extensive clinical and demographic information was collected for each patient. Supine blood pressure, measured with Omron HEM-907 device, was on average 127u200a±u200a4 mmHg (systolic) and 74u200a±u200a2 mmHg (diastolic) and heart rate 67u200a±u200a24u200abeats/min. According to Adult Treatment Panel III, the participants had 2.2u200a±u200a0.3 metabolic abnormalities. Quantitative PCR was performed to determine tissue expression of miR-132 in liver and matched subcutaneous and visceral fat biopsies in these patients. Liver biopsies were read by a single hepatopathologist using a standardised pathological approach and graded in terms of steatosis, inflammation and fibrosis. Results: Hepatic and visceral fat expression of miR-132 were strongly correlated (ru200a=u200a0.729, Pu200a=u200a0.005). Hepatic miR-132 expression was also correlated with BMI (ru200a=u200a0.641, Pu200a=u200a0.018), triglycerides (ru200a=u200a0.604, Pu200a=u200a0.029), systolic blood pressure (ru200a=u200a0.577, Pu200a=u200a0.039) and heart rate (ru200a=u200a0.694, Pu200a=u200a0.009). Visceral fat miR-132 expression was associated with BMI (ru200a=u200a0.746, Pu200a<u200a0.001) and liver steatosis (ru200a=u200a0.533, Pu200a=u200a0.33). There was no correlation between subcutaneous and visceral expression of miR-132 (Pu200a=u200a0.210). Conclusions: Our data supports that miR-132 may play a causal role in the cardiovascular and metabolic implications of obesity in humans. Given the increasing public burden of obesity and associated comorbidities, novel therapeutic approaches are needed for prevention and treatment of these diseases. In addition, further targeted search for biomarkers in complex diseases such as obesity, cardiovascular disease and NAFLD are warranted.

[PP.18.22] EFFECTS OF MOXONIDINE AND LOW CALORIE DIET IN YOUNG OVERWEIGHT MALES

Objective: Elevated sympathetic nervous system activity in overweight individuals is believed to play a detrimental role in metabolic and cardiovascular health in early adulthood. We therefore aimed to compare the effects of a treatment with either a low calorie diet, a sympatholytic agent or a combination of both on hemodynamic and metabolic parameters and renal and endothelial function. Design and method: Overweight (BMI>25u200akg/m2), young (18–30 years) otherwise healthy males were randomly allocated to receive either a low calorie diet (LCD; n=10), moxonidine (MOX; nu200a=u200a10, 0.4u200amg/day), a combination of both (LCD+MOX; nu200a=u200a11) or to act as controls (CONT; nu200a=u200a6) for a period of 6 months. Muscle sympathetic nerve activity (MSNA) was measured by microneurography, endothelial function was assessed using digital pulse tonometry and renal function using creatinine clearance derived from the Cockcroft Gault formula before and after intervention. Results: Weight loss occurred in the LCD and LCD+MOX (−7.5u200a±u200a1.9 and −7.6u200a±u200a1.9u200akg). MSNA significantly decreased in the LCD, MOX and LCD+MOX groups (−14u200a±u200a3, −14u200a±u200a3, −14u200a±u200a2 bursts per 100 heartbeats) and this was associated with a decrease in systolic blood pressure (−8.9u200a±u200a3.3; −8.8u200a±u200a5.5;−9.8u200a±u200a3.2 mmHg). All other metabolic parameters for both LCD, CON and MOX groups remained unchanged. Endothelial function remained unchanged in all groups. In the LCD + MOX, additional benefits included decreased waist circumference (−8.3u200a±u200a1.9u200acm), decreased total cholesterol (−0.78u200a±u200a0.23u200ammol/l) and LDL cholesterol (−0.49u200a±u200a0.16u200ammol/l) and fasting insulin (−6.5u200a±u200a2.8u200ammol/l) and attenuated glomerular hyperfiltration from 187u200a±u200a4 to 167u200a±u200a4u200aml/min). Conclusions: The addition of moxonidine to a LCD may have beneficial effects on the metabolic profile and renal function of overweight young males.

[OP.7D.10] THE EFFECT OF RENAL DENERVATION ON ADIPOKINES IN PATIENTS WITH RESISTANT HYPERTENSION.

Objective: We have previously demonstrated the effectiveness of renal denervation (RDN) to lower blood pressure (BP) at least partially via the reduction of sympathetic stimulation to the kidney. Obesity also contributes to hypertension. A number of adipocyte-derived factors (collectively termed ‘adipokines’) have been implicated in BP control. The aim of this study was to examine the effect of RDN on adipokines. In particular, whether BP reduction, associated with RDN treatment, has a favourable outcome on adipokine profile in patients with resistant hypertension (RH). Design and method: Fifty seven patients with RH undergoing RDN have been recruited for the study (65% males, age 60.8u200a±u200a1.5 years, BMI 32.6u200a±u200a0.7u200akg/m2, meanu200a±u200aSEM). At recruitment the patients were on an average of 4.8u200a±u200a2.1 antihypertensive drugs and were asked to refrain from changing their medication regimen for the duration of the study. Automated seated office BP measurements were taken with an Omron HEM-705 monitor at baseline and 3 months follow up visit. Leptin, insulin, non-esterified fatty acids (NEFA), adiponectin and resistin were measured in plasma at baseline and 3 months after RDN. Results: There was a significant reduction in mean office systolic (168.75u200a±u200a2.57 vs 155.23u200a±u200a3.17 mmHg, pu200a<u200a0.001) and diastolic (90.68u200a±u200a2.31 vs 83.74u200a±u200a2.36 mmHg, pu200a<u200a0.001) BP 3 months after RDN. Body weight and heart rate remained unchanged. There were no significant differences in plasma leptin levels post RDN. Fasting insulin concentration significantly increased 3 months after the procedure (20.05u200a±u200a1.46 vs 29.70u200a±u200a2.51u200auU/ml, pu200a=u200a0.002). There was a significant drop in circulating NEFA at follow up (1.01u200a±u200a0.07 vs 0.47u200a±u200a0.04u200amEq/l, pu200a<u200a0.001). While there were no changes in resistin, adiponectin concentration was significantly higher after RDN (5654u200a±u200a800 vs 6644u200a±u200a967u200ang/ml, pu200a=u200a0.024). Conclusions: We have previously shown a decrease in BP following RDN. This is the first study to demonstrate that RDN is associated with potentially beneficial effects on the adipokine profile. Increased adiponectin and reduced NEFA production may contribute to BP reduction via metabolic pathways.

Restoration of blood pressure control with pacemaker implantation in a patient with bradycardia and resistant hypertension: A case report

A seventy-two year old male with a medical history of long-standingand poorly-controlled arterial hypertension, dyslipidaemia and paroxys-malatrial fibrillationwasreferredtoour hospitalscardiologyoutpatientsservice. His medications at initial assessment were: 10 mg of perindoprilonce daily; 50 mg of metoprolol twice daily; 10 mg of lercanidipine oncedaily; 2 mg of prazosin twice daily; 25 mg of hydrochlorothiazide oncedaily; 40 mg of simvastatin once dail y; and warfarin. Repeated automat-ed office blood pressure readings revealed average blood pressure(BP) levels of around 160/80 mm Hg. R epeat ambulatory blood pressuremonitoring (ABPM) confirmed uncontrolled BP with a twenty-four houraverage of 190/81 mm Hg (heart rate [HR] 41 bpm) (awake average:199/88 mm Hg (HR 46 bpm); and asleep average: 177/68 mm Hg (HR34 bpm)). An electrocardiogram showed 2:1 atrioventricular (AV)block, with a ventricular rate of 39 bpm, and right bundle branch block.The patient complained of intermittent dyspnoea and fatigue, but deniedlight-headedness, loss of consciousness or palpitations.Metoprolol was ceased immediately and additional antihyperten-sive treatment with spironolactone 12.5 mg once daily was initiated.No periods of complete heart block were recorded on a twenty-fourhour Holter monitor. A transthoracic echocardiogram (TTE) revealednormal left ventricular (LV) diameter and function with moderateconcentric hypertrophy (Fig. 1; maximum LV wall thickness of18 mm and LV mass index of 119 g/m