Wilko Spiering

The Glu298Asp polymorphism of the NOS 3 gene as a determinant of the baseline production of nitric oxide

Rationale The endothelial nitric oxide synthase Glu298Asp polymorphism has been suggested to play a role in the development of hypertension, atherosclerosis and coronary artery disease. Objective To investigate functional differences between the various genotypes with respect to basal nitric oxide (NO) production, we estimated the response to endothelial NO synthase (ecNOS) inhibition by infusion of increasing doses of NG–monomethyl-l-arginine (l-NMMA) into the brachial artery during venous occlusion plethysmography. Methods In 41 healthy subjects forearm blood flow responses to intra-arterial infusion of increasing doses of l-NMMA (0.05, 0.1 and 0.2 mg/min per dl) and norepinephrine (10, 20 and 40 ng/min per dl) were measured. The genotype of the ecNOS Glu298Asp polymorphism was assessed. Results Nineteen subjects had the Glu/Glu genotype, 19 subjects had the Glu/Asp genotype and three subjects had the Asp/Asp genotype. Groups were comparable concerning demographic, hemodynamic and possible confounding factors. Subjects with the Asp allele showed a reduced response to infusion of l-NMMA as compared to subjects with the Glu/Glu genotype (ANOVA, P = 0.01). There was no significant difference in the response to infusion of the NO-independent vasoconstrictor, norepinephrine, between both groups. Conclusions The ecNOS Glu298Asp polymorphism is associated with reduced basal NO production and might therefore have functional implications in the development of atherosclerosis or hypertension.

Mechanisms linking obesity to hypertension

Obesity‐related hypertension is increasingly recognized as a distinct hypertensive phenotype requiring a modified approach to diagnosis and management. In this review rapidly evolving insights into the complex and interdependent mechanisms linking obesity to hypertension are discussed. Overweight and obesity are associated with adipose tissue dysfunction, characterized by enlarged hypertrophied adipocytes, increased infiltration by macrophages and marked changes in secretion of adipokines and free fatty acids. This results in chronic vascular inflammation, oxidative stress, activation of the renin‐angiotensin‐aldosterone system and sympathetic overdrive, eventually leading to hypertension. These mechanisms may provide novel targets for anti‐hypertensive drug treatment. Recognition of obesity‐related hypertension as a distinct diagnosis enables tailored therapy in clinical practice. This includes lifestyle modification and accommodated choice of blood pressure‐lowering drugs.

Relation Between Blood Pressure and Vascular Events and Mortality in Patients With Manifest Vascular Disease: J-Curve Revisited

Recent studies have challenged the notion that “lower is better” for blood pressure in relation to vascular events and mortality in patients with vascular disease, whereas practice guidelines currently recommend to lower blood pressure to <130/80 mm Hg. We reassessed this J-curved relationship between blood pressure and cardiovascular events and all-cause mortality in patients with various manifestations of vascular disease. For this purpose, 5788 patients with symptomatic vascular disease enrolled in the Secondary Manifestations of Arterial Disease Study were followed-up for the occurrence of new vascular events (ie, myocardial infarction, stroke, or vascular death) and all-cause mortality. During a median of 5.0 years (interquartile range: 2.6–8.1 years), 788 patients experienced a new vascular event, and 779 died. Overall, the covariate-adjusted relationship between mean baseline systolic, diastolic, or pulse pressure and the occurrence of vascular events followed a J-curve with increased event rates above and below the nadir blood pressure of 143/82 mm Hg. A similar nonlinear relationship was found for diastolic pressure and all-cause mortality. Elevated blood pressure was not associated with increased morbidity and mortality in patients with recently diagnosed coronary artery disease, ≥65 years, and having >60 mm Hg pulse pressure. Importantly, especially in these subgroups, low blood pressure could also be a symptom rather than a cause of disease. Blood pressure level below and above 143/82 mm Hg is, thus, an independent risk factor for recurrent events in patients with manifest vascular disease. Uncertainty of whether this association is causal provides a strong rationale for trials evaluating blood pressure treatment targets.

Eligibility for percutaneous renal denervation: the importance of a systematic screening.

Objective: Percutaneous renal denervation (pRDN) is a new and promising therapy for resistant hypertension. Among patients suspected of having resistant hypertension, the actual presence of this condition needs to be well established; pseudoresistant hypertension and significant white-coat effect (WCE) should be excluded. This analysis presents the results of a standardized screening programme for patients referred for pRDN. Methods: All patients referred to our centre for pRDN underwent a standardized stepwise screening and were subsequently discussed in a multidisciplinary team. The screening included a 24-h ambulatory blood pressure measurement (ABPM), collection of plasma, urine and saliva, and finally imaging of the renal arteries. Results: From August 2010 till October 2012, 181 patients were referred for pRDN. Mean blood pressure (BP) was 182/100 mmHg, and median use was three antihypertensives. Ultimately, 121 patients (67%) were excluded from pRDN. Main reasons for exclusion were BP-related. Twenty-three patients (19%) had an office SBP less than 160 mmHg and 26 patients (22%) showed a WCE. Fourteen patients (12%) had a so far undetected underlying cause of hypertension, the majority being primary aldosteronism (n = 11). Nine patients had an ineligible renal anatomy. Conclusion: A high percentage of patients were excluded from treatment with pRDN due to secondary causes of hypertension, WCE or a BP below the currently advised thresholds. Treatment of these excluded patients would lead to inappropriate use of pRDN, leading most likely to little benefit for the patients and a burden to healthcare. Therefore, it is recommended to use a standardized screening before treatment with pRDN.

Polymorphisms in human connexin40 gene promoter are associated with increased risk of hypertension in men.

Objective Gap junctions, formed by connexins (Cx), are important in the regulation of vascular tone. Previously, we reported two closely linked polymorphisms (−44G → A and +71A → G) within regulatory regions of the gene for Cx40, a major connexin in the vascular wall and the kidney. In the present study, we examined the hypothesis that these polymorphic variants are associated with hypertension and that they interact with blood pressure in healthy individuals. Methods Cx40 genotypes were determined in 191 subjects with essential hypertension, 198 normotensive individuals, and a healthy control population (178 twin pairs, 108 monozygotic, 70 dizygotic). Results We found a significant contribution of the minor Cx40 allele or genotype (−44AA/+71GG) to the risk of hypertension in men (P = 0.013 or P = 0.035; odds ratio, 1.87 or 2.10, respectively), but not in women. Moreover, in the healthy control population a significant effect of Cx40 genotype and sex on systolic blood pressure was found (P < 0.05 and P < 0.0001, respectively). Women carrying the minor Cx40 genotype had significantly higher systolic blood pressure compared with non-carriers (P < 0.05). In men, systolic blood pressure in carriers of the minor Cx40 genotype was not significantly different from the other two genotypes, possibly because of the small number of men in this group. However, men carrying the −44GA/+71AG genotype had higher standing systolic blood pressure compared with the more common Cx40 genotype (−44GG; P = 0.033). Conclusion These findings suggest that the Cx40 polymorphisms may form a genetic susceptibility factor for essential hypertension in men.

Persisting gender differences and attenuating age differences in cardiovascular drug use for prevention and treatment of coronary heart disease, 1998-2010.

BACKGROUND Evidence on recent time trends in age-gender differences in cardiovascular drug use is scarce. We studied time trends in age-gender-specific cardiovascular drug use for primary prevention, secondary prevention, and in-hospital treatment of coronary heart disease. METHODS AND RESULTS The PHARMO database was used for record linkage of drug dispensing, hospitalization, and population data to identify drug use between 1998 and 2010 in 1 203 290 persons ≥25 years eligible for primary prevention, 84 621 persons hospitalized for an acute coronary syndrome (ACS), and 15 651 persons eligible for secondary prevention. The use of cardiovascular drugs increased over time in all three settings. In primary prevention, the proportion of women that used lipid-lowering drugs was lower than men between 2003 and 2010 (5.7 vs. 7.3% in 2010). The higher proportion of women that used blood pressure-lowering drugs for primary prevention, compared with men, attenuated over time (15.1 vs. 13.8% in 2010). During hospital admission for an ACS, the proportion of women that used cardiovascular drugs was lower than men. In secondary prevention (36 months after hospital discharge), drug use was lowest in young women. The proportion receiving lipid-lowering drugs declined after the age of 75 in all three settings. This age difference attenuated over time. CONCLUSION Age differences in drug use tended to attenuate over time, whereas gender differences persisted. Areas potentially for improvement are in the hospital treatment of ACS in young women, in secondary prevention among young women and the elderly, and in the continuity of drug use in secondary prevention.

Adrenal vein sampling versus CT scan to determine treatment in primary aldosteronism: an outcome-based randomised diagnostic trial

BACKGROUND The distinction between unilateral aldosterone-producing adenoma or bilateral adrenal hyperplasia as causes of primary aldosteronism is usually made by adrenal CT or by adrenal vein sampling (AVS). Whether CT or AVS represents the best test for diagnosis remains unknown. We aimed to compare the outcome of CT-based management with AVS-based management for patients with primary aldosteronism. METHODS In a randomised controlled trial, we randomly assigned patients with aldosteronism to undergo either adrenal CT or AVS to determine the presence of aldosterone-producing adenoma (with subsequent treatment consisting of adrenalectomy) or bilateral adrenal hyperplasia (subsequent treatment with mineralocorticoid receptor antagonists). The primary endpoint was the intensity of drug treatment for obtaining target blood pressure after 1 year of follow-up, in the intention-to-diagnose population. Intensity of drug treatment was expressed as daily defined doses. Key secondary endpoints included biochemical outcome in patients who received adrenalectomy, health-related quality of life, cost-effectiveness, and adverse events. This trial is registered with ClinicalTrials.gov, number NCT01096654. FINDINGS We recruited 200 patients between July 6, 2010, and May 30, 2013. Of the 184 patients that completed follow-up, 92 received CT-based treatment (46 adrenalectomy and 46 mineralocorticoid receptor antagonist) and 92 received AVS-based treatment (46 adrenalectomy and 46 mineralocorticoid receptor antagonist). We found no differences in the intensity of antihypertensive medication required to control blood pressure between patients with CT-based treatment and those with AVS-based treatment (median daily defined doses 3·0 [IQR 1·0-5·0] vs 3·0 [1·1-5·9], p=0·52; median number of drugs 2 [IQR 1-3] vs 2 [1-3], p=0·87). Target blood pressure was reached in 39 (42%) patients and 41 (45%) patients, respectively (p=0·82). On secondary endpoints we found no differences in health-related quality of life (median RAND-36 physical scores 52·7 [IQR 43·9-56·8] vs 53·2 [44·0-56·8], p=0·83; RAND-36 mental scores 49·8 [43·1-54·6] vs 52·7 [44·9-55·5], p=0·17) for CT-based and AVS-based treatment. Biochemically, 37 (80%) of patients with CT-based adrenalectomy and 41 (89%) of those with AVS-based adrenalectomy had resolved hyperaldosteronism (p=0·25). A non-significant mean difference of 0·05 (95% CI -0·04 to 0·13) in quality-adjusted life-years (QALYs) was found to the advantage of the AVS group, associated with a significant increase in mean health-care costs of €2285 per patient (95% CI 1323-3248). At a willingness-to-pay value of €30 000 per QALY, the probability that AVS compared with CT constitutes an efficient use of health-care resources in the diagnostic work-up of patients with primary aldosteronism is less than 0·2. There was no difference in adverse events between groups (159 events of which nine were serious vs 187 events of which 12 were serious) for CT-based and AVS-based treatment. INTERPRETATION Treatment of primary aldosteronism based on CT or AVS did not show significant differences in intensity of antihypertensive medication or clinical benefits for patients after 1 year of follow-up. This finding challenges the current recommendation to perform AVS in all patients with primary aldosteronism. FUNDING Netherlands Organisation for Health Research and Development-Medical Sciences, Institute of Cardiology, Warsaw.

Eligibility for Renal Denervation: Experience at 11 European Expert Centers

Based on the SYMPLICITY studies and CE (Conformité Européenne) certification, renal denervation is currently applied as a novel treatment of resistant hypertension in Europe. However, information on the proportion of patients with resistant hypertension qualifying for renal denervation after a thorough work-up and treatment adjustment remains scarce. The aim of this study was to investigate the proportion of patients eligible for renal denervation and the reasons for noneligibility at 11 expert centers participating in the European Network COordinating Research on renal Denervation in treatment-resistant hypertension (ENCOReD). The analysis included 731 patients. Age averaged 61.6 years, office blood pressure at screening was 177/96 mm Hg, and the number of blood pressure–lowering drugs taken was 4.1. Specialists referred 75.6% of patients. The proportion of patients eligible for renal denervation according to the SYMPLICITY HTN-2 criteria and each center’s criteria was 42.5% (95% confidence interval, 38.0%–47.0%) and 39.7% (36.2%–43.2%), respectively. The main reasons of noneligibility were normalization of blood pressure after treatment adjustment (46.9%), unsuitable renal arterial anatomy (17.0%), and previously undetected secondary causes of hypertension (11.1%). In conclusion, after careful screening and treatment adjustment at hypertension expert centers, only ≈40% of patients referred for renal denervation, mostly by specialists, were eligible for the procedure. The most frequent cause of ineligibility (approximately half of cases) was blood pressure normalization after treatment adjustment by a hypertension specialist. Our findings highlight that hypertension centers with a record in clinical experience and research should remain the gatekeepers before renal denervation is considered.Based on the SYMPLICITY studies and CE (Conformite Europeenne) certification, renal denervation is currently applied as a novel treatment of resistant hypertension in Europe. However, information on the proportion of patients with resistant hypertension qualifying for renal denervation after a thorough work-up and treatment adjustment remains scarce. The aim of this study was to investigate the proportion of patients eligible for renal denervation and the reasons for noneligibility at 11 expert centers participating in the European Network COordinating Research on renal Denervation in treatment-resistant hypertension (ENCOReD). The analysis included 731 patients. Age averaged 61.6 years, office blood pressure at screening was 177/96 mm Hg, and the number of blood pressure–lowering drugs taken was 4.1. Specialists referred 75.6% of patients. The proportion of patients eligible for renal denervation according to the SYMPLICITY HTN-2 criteria and each center’s criteria was 42.5% (95% confidence interval, 38.0%–47.0%) and 39.7% (36.2%–43.2%), respectively. The main reasons of noneligibility were normalization of blood pressure after treatment adjustment (46.9%), unsuitable renal arterial anatomy (17.0%), and previously undetected secondary causes of hypertension (11.1%). In conclusion, after careful screening and treatment adjustment at hypertension expert centers, only ≈40% of patients referred for renal denervation, mostly by specialists, were eligible for the procedure. The most frequent cause of ineligibility (approximately half of cases) was blood pressure normalization after treatment adjustment by a hypertension specialist. Our findings highlight that hypertension centers with a record in clinical experience and research should remain the gatekeepers before renal denervation is considered. # Novelty and Significance {#article-title-32}

Molecular genetics and gene expression in atherosclerosis

Although molecular cardiology is a relative young discipline, the impact of the new techniques on diagnosis and therapy in cardiovascular disease are extensive. Our insight into pathophysiological mechanisms is rapidly expanding and is changing our understanding of cardiovascular disease radically and irrevocably. Molecular cardiology has many different aspects. In this paper the importance of molecular cardiology and genetics for every day clinical practice are briefly outlined. It is expected that in the genetic predisposition for atherosclerotic disease multiple genes are involved (genetics). The role of only a minority of genes involved in the atherosclerotic process is known. Far less is known about particular gene-gene and gene-environment interactions. In some families disease can be explained mostly by a single, major gene (monogenic), of which the lipid disorder Familial Hypercholesterolemia is an example. In other cases, one or several variations in minor genes (multigenic) contribute to an atherosclerotic predisposition, for instance the lipoprotein lipase gene. Although mutations in this gene influence lipoprotein levels, disease development is predominantly depending on environmental influences. Recently several additional genetic risk factors were identified including elevated levels of lipoprotein (a) [Lp(a)], the DD genotype of angiotensin converting enzyme (ACE), and elevated levels of homocysteine. This illustrates the complexity of genetics in relation to atherosclerosis and the difficulty to assign predictive values to separate genetic risk factors. Furthermore, little attention has been given to protective genes thus far, explaining why some high risk patients are protected from vascular disease. Genetics based treatment or elimination of the genetic risk factor requires complete understanding of the pathogenic molecular basis. Once this requirement is fulfilled, disease management can be strived for, provided that adequate medical management is available. Recent studies suggest that such treatment should be genotype specific, as the genetic makeup can determine the outcome of a pharmacological intervention (pharmacogenetics). Once the trigger for atherosclerosis has initiated disease development, various genes are activated or silenced and contribute to lesion progression. Every stage of lesion development depends on a different gene expression programme (genomics). In this review paper an introduction is provided into genetics, pharmacogenetics and gene expression with respect to atherosclerotic disease.

Prediction of Cerebral Hyperperfusion after Carotid Endarterectomy with Transcranial Doppler

OBJECTIVES To determine the diagnostic value for predicting cerebral hyperperfusion syndrome (CHS) by adding a transcranial Doppler (TCD) measurement in the early postoperative phase after carotid endarterectomy (CEA). DESIGN Patients who underwent carotid endarterectomy between January 2004 and August 2010 and in whom both intra- and postoperative TCD monitoring were performed were included. METHODS In 184 CEA patients the mean velocity (V(mean)) preoperatively (V1), pre-clamping (V2), post-declamping (V3) and postoperatively (V4) was measured using TCD. The intra-operative V(mean) increase ((V3 - V2)/V2) was compared to the postoperative increase ((V4 - V1)/V1) in relation to CHS. CHS was diagnosed if the patient developed neurological complaints in the presence of a preoperative V(mean) increase >100%. RESULTS Sixteen patients (9%) had an intra-operative V(mean) increase >100% and 22 patients (12%) a postoperative V(mean) increase of >100%. In 10 patients (5%) CHS was diagnosed; two of those had an intra-operative V(mean) increase of >100% and nine postoperative V(mean) increase >100%. This results in a positive predictive value of 13% for the intra-operative and 41% for the postoperative measurement. CONCLUSIONS Besides the commonly used intra-operative TCD monitoring additional TCD measurement in the early postoperative phase is useful to more accurately predict CHS after CEA.