Gert Jensen

Increased cardiovascular mortality in hypertensive patients with renal artery stenosis. Relation to sympathetic activation, renal function and treatment regimens.

BACKGROUND Previous studies in hypertensive patients with renovascular disease have shown both elevated sympathetic nerve activity and increased cardiovascular mortality. OBJECTIVE The aim of the present study was to assess long-term survival in hypertensive patients with renal artery stenosis in relation to sympathetic activation, renal function and treatment regimens. SUBJECTS AND METHODS A total of 169 consecutive patients aged 54 +/- 1 years with hypertension underwent a clinical investigation for renovascular hypertension including renal angiography and measurement of bilateral renal renin secretion. In 107 of these patients, arterial plasma concentrations of noradrenaline were measured. The mean follow-up time was 7.1 +/- 0.3 years and survival data were available in all patients up to May 1997. For comparison, healthy age-matched normotensive controls were examined. RESULTS Arterial noradrenaline concentrations were threefold elevated in hypertensive patients with renal artery stenosis compared to healthy controls (P < 0.01). During the follow-up time, 44 patients died. Cardiovascular mortality accounted for 75% of all deaths. The risk ratio for overall mortality in hypertensive patients with renal artery stenosis compared to the normal population of Sweden, matched for age, was 3.3 (2.4-4.4), whereas the risk ratio for cardiovascular mortality was 5.7 (3.9-8.0). The arterial plasma concentration of noradrenaline was 3.11 +/- 0.30 pmol/ml in patients who died compared to 3.84 +/- 0.26 pmol/ml in survivors. Reduced renal function and age were independent predictors of death. Survival did not differ between patients undergoing intervention with either renal angioplasty or surgical reconstruction for renal artery stenosis and patients not undergoing intervention. CONCLUSIONS Although sympathetic nerve activity is elevated in hypertensive patients with renal artery stenosis, our results do not suggest that this adrenergic over-activity is directly linked to the observed high cardiovascular mortality. Mortality in hypertensive patients with renovascular disease remains high whether an interventional treatment is performed or not, possibly due to the concomitant coronary disease.

Baroreflex effectiveness index and baroreflex sensitivity predict all-cause mortality and sudden death in hypertensive patients with chronic renal failure.

Objectives Impaired arterial baroreflex sensitivity (BRS) has been associated with cardiac mortality and non-fatal cardiac arrests after a myocardial infarction. Patients with chronic renal failure (CRF) have a poor prognosis because of cardiovascular diseases, and sudden death is common. The aim of this study was to assess whether BRS or the baroreflex effectiveness index (BEI), a novel index reflecting the number of times the baroreflex is active in controlling the heart rate in response to blood pressure fluctuations, is associated with prognosis in CRF. Methods Hypertensive patients with CRF who were treated conservatively, by haemodialysis or peritoneal dialysis were studied. Electrocardiogram and beat-to-beat blood pressures were recorded continuously and BRS and BEI were calculated. Patients were then followed prospectively for 41 ± 15 months (range 1–64). Results During follow-up 69 patients died. Cardiovascular diseases and uraemia accounted for the majority of deaths (60 and 20%, respectively), whereas sudden death occurred in 15 patients. In adjunct with established risk factors such as age, diabetes, congestive heart failure and diastolic blood pressure, reduced BEI was an independent predictor of all-cause mortality among CRF patients [relative risk (RR) 0.50, 95% confidence interval (CI) 0.33–0.71 for an increase of one standard deviation in BEI, P < 0.001]. Diabetes and reduced BRS were independent predictors of sudden death (RR 0.29, 95% CI 0.09–0.86 for an increase of one standard deviation in BRS, P = 0.022). Conclusions Both BEI and BRS convey prognostic information that may have clinical implications for patients with cardiovascular diseases in general.

Increased cardiac sympathetic drive in renovascular hypertension

Background Patients with renovascular hypertension (RVH) have high cardiovascular mortality and morbidity. In these patients, overall sympathetic nerve activity is increased. It is unknown, however, whether this increase also involves the heart. Objective We tested the hypothesis that cardiac sympathetic activity is increased in patients with hypertension and renal artery stenosis. Methods and results A total of 14 patients with hypertension were studied before angioplasty of angiographically identified renal artery stenosis. Nine out of 14 patients had renovascular hypertension proven at the 1-year follow-up visit. A total of 19 healthy subjects served as a control group. A right heart catheterization, including the positioning of a coronary sinus thermodilution catheter was performed for hemodynamic recordings and blood sampling. Using a radiotracer dilution technique with infusion of tritiated noradrenaline ([3H]NA) and adrenaline ([3H]A), fractional extraction and clearance were calculated. Total body and cardiac NA spillovers were used as indices of systemic and cardiac sympathetic nervous activity. The study group had normal left ventricular ejection fraction and cardiac pressures. Cardiac NA spillover was increased by 127% in the hypertensive patients compared with healthy subjects (200 ± 53 versus 88 ± 10 pmol/min in controls, P < 0.05). Total body NA spillover was similar in both groups. Cardiac fractional extraction of [3H]NA and [3H]A was decreased by 26 and 47%, respectively, compared with normotensive subjects (P < 0.01 for both). Conclusions Patients with renovascular hypertension have altered cardiac sympathetic function with increased sympathetic drive and impaired catecholamine extraction. The increased cardiac sympathetic drive may have adverse long-term effects on prognosis in this patient group with high cardiovascular mortality.

Non-invasive ultrasound assessment of renal artery stenosis by means of the gosling pulsatility index

OBJECTIVE To gauge the effectiveness of a new Doppler test for renal artery stenosis (RAS), based on the pulsatility index of the blood flow velocity spectrum within several interlobar arteries of both kidneys. METHODS Twenty normotensive volunteers and 49 hypertensive patients were investigated with ultrasound. Patients with angiographic signs of RAS underwent bilateral renal vein catheterization for renin measurement. Significant RAS was assumed if lateralization of renal vein renin to the stenotic side was proven. RESULTS The pulsatility index was higher in the hypertensives without RAS than in normal volunteers. Side differences between both kidneys were within methodological variations with the exception of one case, in whom side difference was > 0.12. The pulsatility index was lower in kidneys with significant RAS than in kidneys without RAS. In most patients with significant unilateral RAS the side difference was < 0.12. In the other patients with a low pulsatility index and a side difference < 0.12 RAS was found to be bilateral upon angiography. Doppler signals were absent in all kidneys with renal occlusion. CONCLUSIONS A side difference of > or = 0.12 predicts unilateral RAS, whereas the absence of parenchymal Doppler signals indicate occlusive RAS. A low pulsatility index combined with normal side difference may, in hypertensive patients, indicate bilateral RAS. Renovascular hypertension was correctly diagnosed in 84% of the patients and the presence of RAS in 94%.

Reduced spontaneous baroreceptor sensitivity in patients with renovascular hypertension.

Objective Sympathetic nerve activity is increased in hypertensive patients with renal artery stenosis. Less is known about cardiac vagal function in these patients before and after renal angioplasty. The aim of the present study was to investigate cardiac baroreceptor reflex sensitivity together with total body noradrenaline (NA) spillover in hypertensive patients with renal artery stenosis before, and in some patients, 1 year after renal angioplasty. Material and methods Spontaneous baroreceptor reflex sensitivity and total body noradrenaline (NA) spillover were measured in patients with renovascular hypertension before intervention (n = 18), patients being cured/improved 1 year after renal angioplasty (n = 5) and age-matched healthy subjects (n = 25). Results Hypertensive patients with renal artery stenosis had higher total body NA spillover (4630 ± 619 versus 3132 ± 210 pmol/min, P < 0.05) and reduced cardiac baroreceptor reflex sensitivity (6.1 ± 1.0 versus 10.7 ± 1.0 ms/mmHg, P < 0.01) compared with healthy subjects. Similar results were obtained (before intervention) in a subgroup of patients (n = 9) with renovascular hypertension defined as cured/improved 1 year following renal angioplasty. Baroreceptor reflex sensitivity improved after renal angioplasty in a subset of patients showing good blood pressure control 1 year after intervention (6.4 ± 0.7 to 9.4 ± 1.7 ms/mmHg, P < 0.05). Conclusions Patients with renovascular hypertension showed reduced cardiac baroreceptor reflex sensitivity and increased noradrenergic activity, which to some extent was reversed 1 year following successful renal angioplasty.

Differentiated Response of the Sympathetic Nervous System to Angiotensin-Converting Enzyme Inhibition in Hypertension

Hypertension with renal artery stenosis is associated with both an activated renin-angiotensin system and elevated sympathetic activity. Therefore, in this condition it may be favorable to use a therapeutic modality that does not reflexly increase heart rate, renin secretion, and sympathetic nervous activity. The purpose of the present study was to assess overall, renal, and muscle sympathetic activity after short-term administration of an angiotensin-converting enzyme inhibitor (enalaprilat) and a nonspecific vasodilator (dihydralazine) to hypertensive patients with renal artery stenosis. Forty-eight patients undergoing a clinical investigation for renovascular hypertension were included in the study. An isotope dilution technique for assessing norepinephrine spillover was used to estimate overall and bilateral renal sympathetic nerve activity. In 11 patients simultaneous intraneural recordings of efferent muscle sympathetic nerve activity were performed. Thirty minutes after dihydralazine administration, mean arterial pressure fell by 15%, whereas plasma angiotensin II, muscle sympathetic nerve activity, heart rate, and total body norepinephrine spillover increased (P <0.05 for all). In contrast, after enalaprilat administration a fall in arterial pressure similar to that for dihydralazine was followed by decreased angiotensin II levels and unchanged muscle sympathetic nerve activity, heart rate, and total body norepinephrine spillover, whereas renal norepinephrine spillover increased by 44% (P <0.05). Acute blood pressure reduction by an angiotensin-converting enzyme inhibitor provokes a differentiated sympathetic response in patients with hypertension and renal artery stenosis, inasmuch that overall and muscle sympathetic reflex activation are blunted, whereas the reflex renal sympathetic response to blood pressure reduction is preserved.

Renovascular resistance in primary hypertension: experimental variations detected by means of Doppler ultrasound

Objective To gauge the influence of renovascular resistance changes on blood flow velocity pulsatility in kidneys of hypertensive patients by means of the ultrasonic colour and pulsed-wave Doppler method, since we have previously shown in normotensive subjects that the blood flow velocity pulsatility in renal interlobar arteries varies with changes in renovascular resistance. Methods In six male patients with primary hypertension, renal blood flow velocity profiles were investigated by means of duplex ultrasound. Single-kidney renovascular resistance was assessed by measurements of split renal function (γ-camera renography), renal plasma flow (steady-state para-aminohippurate clearance) and cuff blood pressure. The pulsatility index of the blood flow velocity spectrum in the renal interlobar artery and renovascular resistance were measured either at rest, during infusion of angiotensin II, or after angiotensin converting enzyme inhibition. Results A significant correlation existed between pulsatility index and renovascular resistance (r = 0.50, P< 0.002), which did not improve after correction for the blood pressure pulsatility. Changes of pulsatility index were more closely related (r = 0.64, P< 0.001) to the corresponding changes in renovascular resistance. Conclusions With the two-dimensional image-guided colour and pulsed-wave Doppler method it is possible to assess semiquantitatively small intra-individual changes in renovascular resistance in hypertensive patients by means of pulsatility index measurements. Pharmacologically induced alterations in renovascular haemo-dynamics may therefore be evaluated with this technique.

A study of clinical complications and risk factors in 1001 native and transplant kidney biopsies in Sweden

Background In Sweden, native and transplant kidney biopsies are usually performed in major renal medical centers. Purpose To clarify risk factors in native and transplant kidney biopsies to improve patient safety. Material and Methods A total of 1001 biopsies (in 352 women and 565 men) were included. The median age was 54 years (range, 16–90 years). Data were derived from 826 native kidney biopsies (640 prospective and 186 retrospective) and 175 transplant kidney biopsies (170 prospective and 5 retrospective). Various factors and complications were registered while performing native and transplant kidney biopsies, focusing on major (e.g. blood transfusions, invasive procedures) and minor complications. The prospective protocol was used at six centers and at one center data were obtained retrospectively. Results Women were at greater risk of overall complications than men (12.2% vs. 6.5%; P = 0.003; odds ratio [OR], 2.0; confidence interval [CI], 1.3–3.1) as well as of major complications (9.6% vs. 4.5%; P = 0.002; OR, 2.2, CI 1.3–3.7). Major complications occurred more commonly after biopsies from the right kidney, in women than in men (10.8% vs. 3.1%; P = 0.005; OR, 3.7; CI, 1.5–9.5), and in patients with lower BMI (25.5 vs. 27.3, P = 0.016) and of younger age (45 years vs. 52.5 years; P = 0.001). Lower mean arterial pressure in transplant kidney biopsies indicated a risk of major complications (90 mmHg vs. 98 mmHg; P = 0.039). Factors such as needle size, number of passes, serum creatinine, and eGFR did not influence complication rates. Conclusion The present findings motivate greater attention being paid to the risk of major side-effects after right-side biopsies from women’s kidneys, as well as after biopsies from younger patients and patients with lower BMI.

Increased myocardial repolarization lability and reduced cardiac baroreflex sensitivity in individuals with high-normal blood pressure.

Background Recent guidelines for the management of arterial hypertension have proposed that, to prevent cardiovascular disease, lifestyle modifications are required even in the case of high-normal blood pressure (HNBP). Objective To assess myocardial repolarization and spontaneous cardiac baroreflex sensitivity (BRS) in newly diagnosed and never-treated individuals. Design and participants We studied healthy individuals with HNBP according to the 2003 European Society of Hypertension–ESC guidelines and, for comparison, patients with renovascular hypertension (RVH) and healthy individuals with normal blood pressure (NBP). Main outcome measures Electrocardiogram and beat-to-beat blood pressure were recorded and spontaneous cardiac baroreflex sensitivity and the temporal QT interval variability index (QTVI) were calculated. Results Individuals with HNBP had increased QTVI values compared with those with NBP (−1.23 ± 0.37 compared with −1.52 ± 0.26; P < 0.05), whereas patients with RVH had additionally increased QTVI values that were greater than those in healthy individuals with NBP or HNBP (−0.81 ± 0.75; P < 0.05 compared with both groups). BRS was reduced in both groups of individuals with increased blood pressures compared with NBP (8.2 ± 4.1 ms/mmHg for individuals with HNBP, 6.1 ± 4.3 ms/mmHg for patients with RVH and 10.8 ± 3.5 ms/mmHg for NBP; P < 0.05 for both). Conclusion In otherwise healthy individuals, even a moderate blood pressure increase is associated with increased myocardial repolarization lability and reduced baroreflex sensitivity (BRS). Patients with RVH have an additionally increased QTVI, with values similar to those reported in congestive heart failure. Future studies are needed to establish the value of QTVI and BRS measurements among individuals with HNBP in predicting the risk of progression to hypertension and end-organ damage.

Renal angioplasty causes a rapid transient increase in inflammatory biomarkers, but reduced levels of interleukin-6 and endothelin-1 1 month after intervention.

Objective To examine prospectively whether inflammatory biomarkers and endothelin (ET)-1 are increased in patients with renal artery stenosis (RAS), and to investigate how treatment with percutaneous transluminal renal angioplasty (PTRA) affects these variables during the first month after intervention. Methods One hundred patients with suspected RAS undergoing renal angiography were included. PTRA was performed if the trans-stenotic mean arterial pressure gradient was ≥10 mmHg. High-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNFα), neopterin, CD40 ligand (CD40L) and endothelin-1 (ET-1) were measured before, and 1 day and 1 month after PTRA (n = 61) or diagnostic angiography only (n = 39). Results At baseline there were no significant differences in inflammatory biomarkers or ET-1 levels between patients subsequently undergoing PTRA or angiography only. After angiography, IL-6 and hs-CRP had increased in both groups compared to baseline (P < 0.001). At this time point hs-CRP (10.90 ± 1.48 versus 6.37 ± 1.61 mg/l; P < 0.05) and IL-6 (13.70 ± 0.94 versus 13.00 ± 0.17 pg/ml; P < 0.01) were higher in the PTRA group than in patients subjected to angiography only. One month after PTRA, systolic blood pressure and levels of IL-6 and ET-1 were lower than before intervention (P < 0.05), whereas CD40L had increased compared to baseline (P < 0.01). Conclusion In patients with RAS, PTRA triggers rapid transient increases in hs-CRP and IL-6; however, 1 month after PTRA, both IL-6 and ET-1 had decreased compared to before intervention, indicating beneficial effects of PTRA on inflammation and the endothelin system.