D. Konstantinidis

Renal denervation therapy: Can it contribute to better blood pressure control in hypertension?

INTRODUCTION Although the first results from studies suggested important benefits regarding blood pressure (BP) control in resistant hypertension by the use of diverse systems of renal denervation (RDN) in the setting of resistant hypertension, the Symplicity HTN-3, randomized sham-controlled trial reduced the enthusiasm and led to a more critical approach towards this neuromodulation innovative therapy. Nowadays there is an ongoing research attempt to justify the pathophysiological background of RDN since overdrive of the sympathetic nervous system is one of the key mechanisms leading to the development and progression of the hypertensive and cardiovascular diseases. CONCLUSION Future RDN trials based on the clinical findings and gaps from previous works will try to identify those parameters to help identify better BP response, target the most suitable population and conclude whether this interventional approach can contribute to the clinical problem of uncontrolled hypertension.

Noninvasive assessment of haemodynamics in resistant hypertension: the role of the renal resistive index

Objective: The association of resistant hypertension (RHTN) with renal haemodynamics is unclear. Our aim was to evaluate differences in haemodynamic characteristics of patients with RHTN compared with patients with controlled hypertension (HTN) at the level of the heart, kidney and aorta. Methods: We studied 50 patients with RHTN confirmed by ambulatory blood pressure monitoring and 50 controlled hypertensive patients matched for age and sex. All participants underwent renal Doppler ultrasound to determine the renal resistive index (RRI), a complete echocardiographic study including measurements of diastolic function and evaluation of augmentation index. Results: Hypertensive patients with RHTN compared with those without RHTN had a significantly decreased E/A ratio (by 0.12, P = 0.043), an increased E/e′ ratio (by 3.1, P < 0.001), increased albumin-to-creatinine ratio levels (by 49 mg/g, P = 0.023) and a significantly higher RRI (by 0.078, P < 0.001) but similar augmentation index values (P = 0.79). Logistic regression revealed that presence of RHTN was the strongest predictor of an RRI more than 0.7 after controlling for other haemodynamic variables including blood pressure levels. Receiver-operator characteristic analysis revealed an area under the curve for prediction of RHTN by the RRI alone of 80.3% (95% confidence interval: 0.72–0.89, P < 0.001). An RRI cut-point of 0.648 has a sensitivity of 78% and a specificity of 72% for prediction of RHTN. Conclusion: In a well treated hypertensive population, patients with RHTN show more pronounced renal and cardiac haemodynamic dysfunction compared with patients with controlled HTN. A greater RRI seems to be associated with RHTN and may help identify such patients.

ConfidenHT™ System for Diagnostic Mapping of Renal Nerves

Purpose of ReviewTo summarize the evidence regarding the distribution of renal nerves and their patterns of anatomic variations in animal and human settings. Moreover, the methodology and results of studies regarding renal nerve stimulation (RNS) in both preclinical and clinical models are presented.Recent FindingsThere are differences regarding the number and the size of renal fibers, as well as their distance from the lumen in the diverse parts of the main renal arteries and the branches. In both animals and humans, RNS is safe and results in an increase of blood pressure (BP) while the effect on heart rate varies. In this context, the ConfidenHT™ system constitutes an integrated solution for effective RNS in humans.SummaryDue to the diversity of renal nerve anatomy in humans, arterial areas for more effective renal denervation cannot be homogenously defined. The concept of mapping of renal nerves can improve completeness of renal denervation therapies by means of integrated RNS solutions such as the ConfidenHT™ system.

ACUTE DETRIMENTAL EFFECTS OF E-CIGARETTE AND TOBACCO CIGARETTE SMOKING ON BLOOD PRESSURE AND SYMPATHETIC NERVE ACTIVITY IN HEALTHY SUBJECTS

Objective: This study aimed to assess the acute effects of tobacco cigarettes, e-cigarettes and sham smoking on blood pressure and sympathetic nervous system in healthy subjects. Design and method: We studied 10 normotensive male habitual smokers (mean age 33 years, body mass index: 24.1 kg/m2, office blood pressure = 117/72 mmHg) free of cardiovascular disease. The study design was randomized and placebo controlled with 3 experimental sessions. Subjects smoked 2 tobacco cigarettes containing 1.1 mg nicotine or simulate smoking (sham smoking) with the 2 cigarettes separated by 5 minutes, while 45 minutes after finishing the second cigarette, subjects smoked a third cigarette or sham cigarette. Additionally, participants smoked e-cigarettes for a period of 5 and 30 minutes. Sympathetic drive was assessed by muscle sympathetic nerve activity (MSNA) (baroreflex-dependent) and skin sympathetic nerve activity (SSNA) (baroreflex-independent). Results: After the first, second and third tobacco cigarette smoking there was an increase in mean arterial pressure (by 11.2 ± 1.4%, 12.3 ± 1.3% and 13.1 ± 1.4%, respectively, p < 0.05 for all) and heart rate (by 25.1 ± 3.7%, 26.3 ± 2.7% and 25.9 ± 3.7%, respectively, p < 0.05 for all). Similarly e-cigarette smoking at 5 and 30 minutes was accompanied by augmentation of mean arterial pressure (by 10.9 ± 1.2% and 12.8 ± 1.4%, respectively, p < 0.05 for both) and heart rate (by 22.5 ± 3.3% and 23.9 ± 3.8%, respectively, p < 0.05 for both). The first, second and third tobacco cigarette smoking was accompanied by lower MSNA (by 28.1 ± 4.4%, 29.6 ± 5.3% and 30.1 ± 5.2%, respectively, p < 0.05 for all), whereas SSNA was increased (by 98.2 ± 19.4%, 100.2 ± 22.7% and 101.5 ± 21.6%, respectively, p < 0.05 for all). Additionally, e-cigarette smoking at 5 and 30 minutes caused a decrease in MSNA (by 26.9 ± 3.6%, and 28.3 ± 5.1%, respectively, p < 0.05 for both), and an augmentation in SSNA (by 97.9 ± 20.1% and 100.9 ± 20.6%, respectively, p < 0.05 for both). Sham smoking was devoid of any effects on blood pressure, MSNA and SSNA. Conclusions: E-cigarette smoking acutely increases blood pressure and has a detrimental effect on sympathetic nerve activity regulation similar to tobacco smoking in healthy subjects.

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.

URIC ACID PREDICTS CORONARY ARTERY DISEASE BUT NOT STROKE IN ESSENTIAL HYPERTENSION: DATA FROM A GREEK 8-YEAR-FOLLOW-UP STUDY

Objective: The aim of the present study was to assess the predictive role of uric acid for the incidence of coronary artery disease (CAD) as well as stroke in essential hypertensive patients. Design and method: We followed up 2415 essential hypertensives (mean age 58.4 years, 1208 males, office blood pressure (BP) = 143/88 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. Moreover, CAD was defined as the history of myocardial infarction or significant coronary artery stenosis and stroke was defined as rapid onset of a new neurological deficit persisting at least 24 hours unless death supervened confirmed by imaging findings. Results: The incidence of CAD and stroke was 2.2% and 1% respectively. Hypertensives who developed CAD (n = 53) compared to those without CAD at follow-up (n = 2362) had at baseline higher baseline uric acid levels (5.8 ± 1.8 vs 5.2 ± 1.5 mg/dl, p = 0.011) and left ventricular mass index (LVMI) (115.7 ± 27.1 vs 103.7 ± 27.1 g/m2, p = 0.001), whereas no difference was observed with respect to baseline office BP, renal function and lipid levels (p = NS for all). Hypertensives who developed stroke (n = 24) compared to those without CAD at follow-up (n = 2391) were older (63 ± 8 vs 58 ± 11 years, p = 0.006), whereas no difference was observed with respect to baseline office BP, uric acid, renal function and lipid levels (p = NS for all). Univariate Cox regression analysis revealed that baseline uric acid levels predicted CAD (hazard ratio = 1.219, p = 0.013) but not stroke. In multivariate Cox regression model baseline glomerular filtration rate (hazard ratio = 1.018, p = 0.017) LVMI (hazard ratio = 1.010, p = 0.026) and uric acid (hazard ratio = 1.226, p = 0.016) turned out to be independent predictors of CAD, while age (hazard ratio = 1.058, p = 0.014) predicted stroke. Conclusions: In essential hypertensive patients uric acid predicts future development of CAD, whereas exhibits no prognostic value for stroke. These findings further support that uric acid estimation could improve overall risk stratification in essential hypertension.

EXERCISE HEART RATE DURING TREADMILL TEST IS RELATED TO RENAL FUNCTIONAL RESERVE IN ESSENTIAL HYPERTENSIVE PATIENTS: A NOVEL LINK BETWEEN THE HEART AND THE KIDNEYS

Objective: Renal functional reserve (RFR) refers to the capacity of the kidney to augment its level of function under the influence of certain stimuli and it constitutes a valuable diagnostic tool for recognizing high risk patients for acute kidney injury and chronic kidney disease. The aim of our study was to assess the relation of RFR with diverse clinical parameters in patients with essential hypertension and glomerular filtration rate (GFR) > 60 ml/min/1.73m2. Design and method: 15 hypertensive subjects [mean age = 57 years, body mass index = 28.5 kg/m2, office systolic/diastolic blood pressure (BP) = 148/90 mmHg] were included and underwent exercise treadmill stress test, 24-hour ambulatory BP and echocardiographic examination. All subjects were fasted for 8 hours and then baseline hydration status was recorded using bioimpedance analysis. Basal GFR was measured after hydration and stress GFR was achieved after ingestion of oral protein 1 g/kg as cooked meal. Basal and Stress GFR were determined by Creatinine Clearance = Urine Creatinine/Serum Creatinine x Urine Volume/time x 1.73/body surface area. RFR was calculated as Stress GFR – Basal GFR. Results: Patients with a history of hypertension greater than 10 years, had lower RFR values (-14.59 ± 43.26vs 21.35 ± 28.19 ml/min/1.73m2, p < 0.001). There was no correlation of RFR values with respect to age, family history, smoking, dipping status and office BP. In contrast, a statistically significant positive correlation was found between RFR and maximum heart rate during treadmill test (r = 0.880, p = 0.009). Hypertensives with high RFR were also characterized by higher maximum HR during treadmill test (157 ± 22 vs 142 ± 20 bpm, p < 0.05). Conclusions: RFR is related to treadmill exercise heart rate in essential hypertension, suggesting a link between the dynamic regulation of renal function and sympathetic overdrives influence on the heart rate. These findings suggest that treadmill test may be used to identify hypertensive patients with unfavorable RFR, thus more susceptible to kidney damage.

Renal resistive index in hypertensive patients

Spectral Doppler ultrasonography provides the evaluation of renal resistive index (RRI), a noninvasive and reproducible measure to investigate arterial compliance and/or resistance. RRI seems to possess an important role in the evaluation of diverse cases of secondary hypertension. In essential hypertension, RRI is associated with subclinical markers of target organ damage and reflects renal disease progression beyond albuminuria and creatinine clearance. Also, RRI can estimate cardiovascular and renal risk. The evaluation of RRI may also help the therapeutic decisions. Given its simple assessment, RRI emerges as a simple method and a “multifunctional” tool that could help on the cardiovascular risk evaluation of the hypertensive patient.