Athanasios Kordalis

Pathophysiology of resistant hypertension: the role of sympathetic nervous system.

Resistant hypertension (RH) is a powerful risk factor for cardiovascular morbidity and mortality. Among the characteristics of patients with RH, obesity, obstructive sleep apnea, and aldosterone excess are covering a great area of the mosaic of RH phenotype. Increased sympathetic nervous system (SNS) activity is present in all these underlying conditions, supporting its crucial role in the pathophysiology of antihypertensive treatment resistance. Current clinical and experimental knowledge points towards an impact of several factors on SNS activation, namely, insulin resistance, adipokines, endothelial dysfunction, cyclic intermittent hypoxaemia, aldosterone effects on central nervous system, chemoreceptors, and baroreceptors dysregulation. The further investigation and understanding of the mechanisms leading to SNS activation could reveal novel therapeutic targets and expand our treatment options in the challenging management of RH.

Dynamic resistant hypertension patterns as predictors of cardiovascular morbidity: a 4-year prospective study.

Objective: Little is known regarding the clinical course and prognosis of resistant hypertension (RHT). We evaluated predictors of persistent RHT and the associated cardiovascular risk. Methods: We studied 1911 treated hypertensive patients (aged 59±11 years, 49% men) for a mean period of 3.9 years. At baseline, clinical data were collected and patients underwent echocardiographic measurements, routine blood testing and additional workup for exclusion of secondary causes of RHT (office-based uncontrolled hypertension under at least three drugs including a diuretic or controlled hypertension under four or more drugs). Endpoint of interest was the composite of coronary artery disease and stroke. Main results: Four groups were identified depending on presence or absence of RHT at baseline and follow-up: 1153 patients (60%) never having RHT, 189 (10%) with resolved RHT, 204 (11%) with incident RHT and 365 (19%) with persistent RHT. Two-thirds of the patients with RHT at baseline remained resistant at the end of the study. Independent variables associated with both incident and persistent RHT were diabetes mellitus, history of cardiovascular disease, hypertension duration, SBP, left ventricular hypertrophy and glomerular filtration rate. Persistent RHT compared with never-having RHT was associated with a 2.2-fold increased risk for cardiovascular morbidity (95% CI: 1.21–4.05, P = 0.01) after adjustment for risk factors. Conclusion: In treated hypertensive patients, among prospective RHT dynamic patterns, persistent RHT is frequent and independently associated with adverse cardiovascular prognosis.

Waist circumference compared with other obesity parameters as determinants of coronary artery disease in essential hypertension: a 6-year follow-up study

This study aimed to assess the predictive role of body mass index (BMI), waist circumference (WC) and the waist-to-hip ratio (WHR) for the incidence of coronary artery disease (CAD) in a cohort of essential hypertensive patients. We followed up 2266 essential hypertensive individuals (mean age, 57.8 years; males, 1083; office blood pressure (BP), 143/89 mm Hg) who were free of cardiovascular disease for a mean period of 6 years. All subjects had at least one annual visit and, at baseline, underwent blood sampling and a complete echocardiographic study to determine the left ventricular (LV) mass index. CAD was defined as a history of myocardial infarction or significant coronary artery stenosis that was revealed by angiography or a coronary revascularization procedure. The incidence of CAD throughout the follow-up period was 2.33%. Hypertensive individuals who developed CAD (n=53) had a greater baseline WC (101.1±11.7 vs. 96.4±12 cm, P=0.005), WHR (0.94±0.07 vs. 0.89±0.08 cm, P<0.0001) and LV mass index (117±26.8 vs. 103.3±27 g m−2, P<0.0001) compared with those without CAD at follow-up (n=2213), whereas no difference was observed compared with the baseline office BP and BMI values (P=NS for all). Using a multivariate Cox regression model, WC (hazard ratio (HR) 1.037, P=0.002) and LV mass index (HR 1.010, P=0.044) were found to be independent predictors of CAD. In essential hypertensive patients, WC could predict the future development of CAD, whereas BMI and WHR showed no independent prognostic value. These findings suggest that WC constitutes an easy clinical tool to assess risk in hypertension among individuals with obesity.

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.

Impact of multi-electrode renal sympathetic denervation on short-term blood pressure variability in patients with drug-resistant hypertension. Insights from the EnligHTN I study☆

BACKGROUND Transluminal renal sympathetic denervation (RDN) has been shown to reduce blood pressure (BP) in patients with treatment-resistant hypertension. METHODS We assessed the effect of multi-electrode RDN on short-term BP variability indexes in resistant hypertensives. Thirty-one patients with drug-resistant uncontrolled hypertension, participants in the EnligHTN I study, underwent ambulatory BP measurements at baseline and 6months after RDN using the EnligHTN ablation catheter (St. Jude Medical). Twelve resistant hypertensives matched for office BP served as control group. RESULTS At 6months post-RDN, office BP and 24-hour BP were reduced by 25.6/10.3mmHg and by 10.2/6mmHg (p<0.001 for all cases), respectively. No significant changes were observed 6months post-RDN in standard short-term BP variability indexes including 24-hour systolic and diastolic average real variability. The rates of systolic and diastolic 24-hour BP variation were decreased 6months after RDN, (from 0.40/0.30 to 0.34/0.24, p=0.030/0.006, respectively), especially in the responders group (n=23, 74.2%). No significant differences in BP and BP variability parameters in the control group were detected. ROC analysis revealed an area under the curve for prediction of response to RDN by systolic time rate of 66.8% (95% CI: 46.7% to 87%; p=0.16) and by diastolic time rate of 76.1% (95% CI: 58.2% to 93.9%; p=0.030). CONCLUSIONS Although standard BP variability indexes remained unchanged, the rate of systolic and diastolic BP variation was significantly decreased 6months after RDN in patients with drug-resistant hypertension. These novel indexes might also be useful as predictors of response.

Metabolic syndrome and exaggerated blood pressure response to exercise in newly diagnosed hypertensive patients

Background: Running evidence supports a prognostic value of an exaggerated blood pressure response to exercise (EBPR). The impact of the metabolic syndrome (MS) on EBPR in hypertensive patients has not been investigated. Design: A cross-sectional study in the setting of an outpatient hypertension clinic. Methods: In total, 325 non-diabetic patients with newly diagnosed hypertension were divided into two groups based on the presence (n = 95) or absence (n = 230) of the MS as defined with NCEP-ATP III criteria. All subjects underwent ambulatory blood pressure monitoring, echocardiography and exercise treadmill testing. Results: Hypertensive patients with MS exhibited higher prevalence of EBPR (by 17%, p = 0.002) and peak exercise systolic BP (by 10.4 mmHg, p = 0.001) irrespectively of confounders. Metabolic equivalents were higher in hypertensives with MS (by 0.6 ml/kg/min, p = 0.048), but the difference lost significance after adjusting for confounders, including body mass index. Logistic regression analysis identified the MS as an independent predictor of an EBPR (p = 0.016). Hypertensive patients with MS had a 2.3-fold risk of exhibiting EBPR compared to those without MS. However, individual components of MS altogether as well as each one separately failed to predict EBPR. Conclusions: Presence of MS in newly diagnosed hypertensive patients is associated with increased peak exercise BP and a higher frequency of EBPR over and above its separate elements.

Effects of hypertension, diabetes mellitus, obesity and other factors on kidney haemodynamics.

INTRODUCTION Kidney flow assessment and its haemodynamic surrogates, namely resistive index and renal flow reserve, may improve our understanding of the natural history of kidney dysfunction. METHODS We reviewed the literature on the common and differential effects of traditional risk factors such as essential hypertension, diabetes mellitus, dyslipidaemia, smoking, obesity and metabolic syndrome on human kidney haemodynamics. RESULTS AND CONCLUSIONS Aging, duration of a prevalent single cardiovascular risk factor and co-existence of multiple risk factors may further accelerate the deterioration of kidney haemodynamics. Sympathetic and renin-angiotensin-aldosterone axis activation is implicated in the pathophysiology leading to kidney function decline. Prevention of kidney disease progression includes the blockade of the renin-angiotensin-aldosterone axis, lipid lowering drugs, smoking cessation and glycaemic control as well as novel interventional methods like transluminal kidney sympathetic denervation.

Left Ventricular Mass Index as a Predictor of New-Onset Microalbuminuria in Hypertensive Subjects: A Prospective Study

BACKGROUND We aimed to investigate the predictive role of left ventricular mass and its reduction on the development of new-onset microalbuminuria (MA) in newly diagnosed hypertensive patients. METHODS A total of 207 nondiabetic, normoalbuminuric patients without clinical organ damage (aged 50.8 ± 10.1 years, 132 male, 84 smokers) with baseline office blood pressure (BP) 148/96 mm Hg were followed for a mean period of 3.3 ± 1.3 years. At baseline and last follow-up visit, all patients underwent office and 24-h ambulatory BP monitoring, albumin to creatinine ratio (ACR) determination, and echocardiographic assessment of left ventricular mass index (LVMI). All patients were treated with antihypertensive therapy during the follow-up period. We defined MA as ACR between 20 and 300 mg/g for men and 30-300 mg/g for women, effective BP control as office BP <140/90 mm Hg in ≥75% of total number of visits, and LVMI reduction as the decline of LVMI at end-follow-up of ≥15% with respect to the baseline value. RESULTS Between baseline and last follow-up visit, LVMI decreased by 6.84 ± 21.5 g/m(2) (P < 0.01); 64.3% (n = 133) of participants achieved BP control during the follow-up period. Of the total population, 5.8% (n = 12) developed MA during follow-up. Cox-regression analysis, after adjustment for clinical variables, revealed that increase of LVMI by 1 s.d. (23.3 g/m(2)) conferred a 15% increased risk of new-onset MA, while LVMI reduction and BP control were both associated with almost 100% reduced risk of MA development. CONCLUSIONS LVMI and its reduction were qualified as predictors of new-onset MA in newly diagnosed hypertensive patients, beyond BP control.

Periodontal disease severity and urinary albumin excretion in middle-aged hypertensive patients.

To address whether periodontal disease indexes are associated with urinary albumin-to-creatinine ratio (UACR) in conditions of high and low systemic inflammation as reflected by levels of high-sensitivity C-reactive protein (hs-CRP) in untreated hypertensive patients, we studied 242 hypertensive patients 51 ± 9 years old (24-hour systolic/diastolic blood pressure [BP] 132 ± 10/83 ± 8 mm Hg) with varying severity of periodontal disease evaluated by 3 periodontal disease indexes (PDIs) (i.e., mean clinical loss of attachment, maximum probe depth, and gingival bleeding index). Patients underwent BP measurements, echocardiography, and periodontal examination, and from fasting blood samples we assessed metabolic profile and hs-CRP. From 2 nonconsecutive overnight spot urine samples we evaluated UACR. With respect to median hs-CRP and UACR levels (1.67 mg/L and 10 mg/g, respectively), the total population was divided into patients with low-UACR/low-hs-CRP (n = 65), low-UACR/high-hs-CRP (n = 63), high-UACR/low-hs-CRP (n = 51), and high-UACR/high-hs-CRP (n = 63). PDIs differed among the 4 groups, and those with high UACR had significantly higher 24-hour systolic BP compared to those with low UACR. UACR was determined by all periodontal disease indexes, hs-CRP, and the interaction of each periodontal disease index with hs-CRP. In addition, mean clinical loss of attachment was the strongest determinant of the high-UACR/high-hs-CRP pattern among all studied periodontal disease indexes. In conclusion, in untreated middle-aged hypertensive patients, periodontal disease indexes and hs-CRP have a synergistic effect on UACR levels independently of the underlying hemodynamic load.

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.