Richard E. Katholi

Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the Symplicity HTN-1 study

BACKGROUND Renal denervation (RDN) with radiofrequency ablation substantially reduces blood pressure in patients with treatment-resistant hypertension. We assessed the long-term antihypertensive effects and safety. METHODS Symplicity HTN-1 is an open-label study that enrolled 153 patients, of whom 111 consented to follow-up for 36 months. Eligible patients had a systolic blood pressure of at least 160 mm Hg and were taking at least three antihypertensive drugs, including a diuretic, at the optimum doses. Changes in office systolic blood pressure and safety were assessed every 6 months and reported every 12 months. This study is registered with ClinicalTrials.gov, numbers NCT00483808, NCT00664638, and NCT00753285. FINDINGS 88 patients had complete data at 36 months. At baseline the mean age was 57 (SD 11) years, 37 (42%) patients were women, 25 (28%) had type 2 diabetes mellitus, the mean estimated glomerular filtration rate was 85 (SD 19) mL/min per 1·73 m(2), and mean blood pressure was 175/98 (SD 16/14) mm Hg. At 36 months significant changes were seen in systolic (-32·0 mm Hg, 95% CI -35·7 to -28·2) and diastolic blood pressure (-14·4 mm Hg, -16·9 to -11·9). Drops of 10 mm Hg or more in systolic blood pressure were seen in 69% of patients at 1 month, 81% at 6 months, 85% at 12 months, 83% at 24 months, and 93% at 36 months. One new renal artery stenosis requiring stenting and three deaths unrelated to RDN occurred during follow-up. INTERPRETATION Changes in blood pressure after RDN persist long term in patients with treatment-resistant hypertension, with good safety. FUNDING Ardian LLC/Medtronic Inc.

Role of the Renal Sympathetic Nerves in the Development and Maintenance of Hypertension in the Spontaneously Hypertensive Rat

Neurogenic factors and, in particular, enhanced renal sympathetic tone, have been implicated in the pathogenesis of hypertension in the spontaneously hypertensive rat of the Okamoto strain. To examine the hypothesis that the renal sympathetic nerves contribute to the development and maintenance of hypertension by causing urinary sodium retention, 7-wk-old (early hypertensive) and 18-wk-old (established hypertensive) male spontaneously hypertensive rats were subjected to bilateral renal denervation and compared with sham-operated controls. In 7-wk-old animals renal denervation delayed the onset and slowed the rate of development of hypertension. These alterations were associated with a significantly greater fractional excretion of sodium (percentage of sodium intake excreted) during the first 3 wk after denervation. Blood pressure 2 wk after surgery was 169+/-3.5 (sham) vs. 150+/-2.4 mm Hg (denervated) (P < 0.001), corresponding to fractional sodium excretions of 65+/-1.3% (sham) vs. 80+/-2.3% (denervated) (P < 0.001). By the 5th wk after surgery, at which time an increase in renal norepinephrine content of denervated animals suggested reinnervation, blood pressures in the two groups converged (sham, 199+/-6.5 mm Hg vs. denervated 180+/-3.5 mm Hg, NS) and there was no difference in sodium excretion (sham, 77+/-2.5% vs. denervated 79+/-2.3%). Plasma and kidney renin activity of denervated animals did not differ significantly from that of sham-operated controls. In 18-wk-old rats renal denervation did not alter blood pressure or urinary sodium excretion. These data indicate that the renal sympathetic nerves contribute to the development of hypertension in the spontaneously hypertensive rat in part by causing enhanced sodium retention. Once hypertension is established the renal nerves do not play a significant role in the maintenance of increased blood pressure.

Intrarenal adenosine produces hypertension by activating the sympathetic nervous system via the renal nerves in the dog.

Studies from our laboratory suggest that the afferent renal nerves from the clipped kidney enhance sympathetic nervous system activity in established one-kidney, one clip and two-kidney, one clip Goldblatt hypertension. Because adenosine is released during renal ischaemia and adenosine has been shown to increase the frequency of afferent renal nerve signals, we proposed the hypothesis that intrarenal adenosine might produce hypertension by activating the sympathetic nervous system via the afferent renal nerves. To examine this hypothesis, changes in arterial pressure and activity of the sympathetic nervous system were measured during renal artery infusion of adenosine before and after renal denervation in uninephrectomized sodium replete conscious dogs. Intrarenal adenosine infusion produced a 21 +/- 3 mmHg mean arterial pressure rise in association with an increase in plasma norepinephrine. Ganglionic blockade during intrarenal adenosine infusion resulted in a significantly greater decrease in arterial pressure compared to control responses. After renal denervation, intrarenal adenosine infusion resulted in no change in arterial pressure, plasma norepinephrine or arterial pressure response to ganglionic blockade. To further assess sympathetic activity changes, right renal norepinephrine secretion and multifibre efferent neural traffic were measured during left renal artery adenosine infusion in alpha-chloralose-anaesthetized dogs. Left renal artery adenosine infusion resulted in increased right renal vascular resistance in association with increased renal norepinephrine secretion and increased efferent neural activity. The data indicate that in the dog with intact renal nerves, intrarenal adenosine produces hypertension by activating the sympathetic nervous system.

International expert consensus statement: Percutaneous transluminal renal denervation for the treatment of resistant hypertension.

Catheter-based radiofrequency ablation technology to disrupt both efferent and afferent renal nerves has recently been introduced to clinical medicine after the demonstration of significant systolic and diastolic blood pressure reductions. Clinical trial data available thus far have been obtained primarily in patients with resistant hypertension, defined as standardized systolic clinic blood pressure ≥ 160 mm Hg (or ≥ 150 mm Hg in patients with type 2 diabetes) despite appropriate pharmacologic treatment with at least 3 antihypertensive drugs, including a diuretic agent. Accordingly, these criteria and blood pressure thresholds should be borne in mind when selecting patients for renal nerve ablation. Secondary forms of hypertension and pseudoresistance, such as nonadherence to medication, intolerance of medication, and white coat hypertension, should have been ruled out, and 24-h ambulatory blood pressure monitoring is mandatory in this context. Because there are theoretical concerns with regard to renal safety, selected patients should have preserved renal function, with an estimated glomerular filtration rate ≥ 45 ml/min/1.73 m(2). Optimal periprocedural management of volume status and medication regimens at specialized and experienced centers equipped with adequate infrastructure to cope with potential procedural complications will minimize potential patient risks. Long-term safety and efficacy data are limited to 3 years of follow-up in small patient cohorts, so efforts to monitor treated patients are crucial to define the long-term performance of the procedure. Although renal nerve ablation could have beneficial effects in other conditions characterized by elevated renal sympathetic nerve activity, its potential use for such indications should currently be limited to formal research studies of its safety and efficacy.

Decrease in Peripheral Sympathetic Nervous System Activity following Renal Denervation or Unclipping in the One-Kidney One-Clip Goldblatt Hypertensive Rat

Increased sympathetic nervous system activity has been demonstrated in established one-kidney one-clip hypertension in the rat. We have found that renal denervation in this model results in an attenuation of hypertension, unassociated with alterations in sodium or water balance or renin activity. To determine whether the depressor effect of renal denervation is associated with changes in peripheral sympathetic nervous system activity, sham operation (n = 12), renal denervation (n = 13), or unclipping (n = 13) was carried out 2 wk after the onset of one-kidney one-clip hypertension. Normotensive unine-phrectomized age- and sex-matched rats were used as controls (n = 14). Renal denervation resulted in a significant decrease in systolic blood pressure (201+/-7 to 151+/-6 mm Hg), while unclipping lowered systolic blood pressure to normotensive levels (130+/-6 mm Hg). 8 d after operation plasma norepinephrine and mean arterial pressure before and after ganglionic blockade with 30 mg/kg hexamethonium bromide were measured in conscious, unrestrained, resting animals, as indices of peripheral sympathetic nervous system activity. Plasma norepinephrine was significantly higher in hypertensive sham-operated rats (422+/-42 pg/ml) compared with normotensive controls (282+/-25 pg/ml) (P < 0.01). Both renal denervation and unclipping restored plasma norepinephrine to normal levels (273+/-22 and 294+/-24 pg/ml, respectively). Ganglionic blockade in hypertensive sham-operated animals resulted in a significantly greater decrease in mean arterial pressure than occurred in renal denervated, unclipped, or control rats. The data suggest that the depressor effect of renal denervation or unclipping in the one-kidney one-clip hypertensive rat is associated with a decrease in peripheral sympathetic nervous system activity.

Role of the renal nerves in the pathogenesis of one-kidney renal hypertension in the rat.

SUMMARY Increased sympathetic nerrous system actirity has been demonstrated in established onekidney one dip hypertension in the rat. To determine the importance of the renal nerves in this model of hypertension, renal denervation or sham operation was carried out 2 weeks after clipping. Systolic blood pressure (BP) after clipping the renal artery In 27 nninephrectomlzed male Charles Rlrer rats increased significantly from 125 ± 3 mm Hg to a stable level of 185 ± 7 mm Hg by 2 weeks, in association with a positive sodium balance. Renal denervation in 13 animals resulted in a significant decrease in BP to 137 ± 7 mm Hg, while no change in BP was seen after sham operation in 14 »ntmal«- There was no difference in mean daily water intake, mean dally sodium intake, mean daily urine volume, or mean fractional urinary sodium excretion between sham-operated and renal-denervated animals during the 2 weeks after operation. Plasma renin activity (PRA) and creatinine clearance were not significantly different at sacrifice 2 weeks after operation. Six of the renaldenervated rats were followed for 11 weeks after surgery. The BP rose again to hypertensive levels (187 ± 8 mm Hg) by 5 weeks after renal denervation. Repeat renal denervation resulted in a significant decrease to 142 ± 8 mm Hg. Renal denervation in eight rats with established one-kidney Grollman hypertension (185 ± 8 mm Hg) also resulted in a significant decrease in systolic BP (143 ± 8 mm Hg). The data demonstrate the importance of intact renal nerves in the maintenance of hypertension in the one-kidney renal hypertensive rat. The depressor effect of renal denervation is not mediated by alterations in sodium intake or excretion, water intake or excretion, creatinine clearance or PRA.

Decrease in hypothalamic norepinephrine content following renal denervation in the one-kidney, one clip Goldblatt hypertensive rat.

Peripheral and central sympathetic mechanisms have been shown to contribute to the development and maintenance of increased blood pressure in the one-kidney model of renal hypertension in the rat. Previous studies from our laboratory have demonstrated that the renal sympathetic nerves, in particular, contribute to the maintenance of hypertension in this model. In those studies, renal denervation, performed 2 weeks after renal artery clipping, resulted in a significant decrement in blood pressure that was associated with a decrease in peripheral sympathetic activity. To further define the role of the renal nerves in the pathogenesis of hypertension in this model, we determined the systolic blood pressure and norepinephrine and dopamine content of the hypothalamus, midbrain, pons medulla, and spinal cord at 1 week following renal denervation or sham operation of rats with early established one-kidney one clip hypertension. Age-matched uninephrectomized rats were controls. The blood pressure of denervated animals decreased significantly from 189 ± 9.21 to 151 ± 6.5 mm Hg (p < 0.001), while that of sham-operated animals did not change. Hypothalamic norepinephrine content of sham-operated animals was significantly greater than that of controls (2.24 ± 0.8 μg/g sham vs 1.84 ± 0.12 μg/g controls, p < 0.01). Renal denervation resulted in a decrease in hypothalamic norepinephrine content to control levels (1.72 ± 0.11 μg/g)- There was a significant (r = 0.65, p < 0.01) positive correlation between systolic blood pressure and hypothalamic norepinephrine content of renaldenervated and sham-operated animals. The norepinephrine content of other brain regions was not different between groups. The results suggest that the renal nerves contribute to the maintenance of hypertension in the one-kidney one clip rat by modulating central sympathetic nervous system activity. (Hypertension 4: 369–373, 1982)

Differential effect of β‐blocker therapy on insulin resistance as a function of insulin sensitizer use: results from GEMINI

Aims  To determine whether the beneficial effects of carvedilol on insulin resistance (IR) are affected by the concomitant use of insulin sensitizers [thiazolidinediones (TZDs) and metformin].

Reducing delay in the emergency room in administration of thrombolytic therapy for myocardial infarction associated with ST elevation

Thrombolytic therapy reduces mortality and improves left ventricular function in patients with acute myocardial infarction (AMI).1–5 Our review of 816 patients treated in community hospitals showed that the primary care or emergency physician can use these drugs effectively, but we also found that the average delay from arrival in the emergency department to institution of thrombolytic therapy was 86 minutes.6 This is similar to other cities, in which an average time from arrival in the emergency department to time of treatment was 84 minutes.7 We began this study to see if the time delay between patient presentation to emergency department and institution of thrombolytic therapy could be reduced.

β-Blocker use and diabetes symptom score: Results from the GEMINI study

Aim:  The Glycemic Effect in Diabetes Mellitus: Carvedilol–Metoprolol Comparison in Hypertensives (GEMINI) trial compared the metabolic effects of two β‐blockers in people with type 2 diabetes and hypertension treated with renin–angiotensin system (RAS) blockade and found differences in metabolic outcomes. In this paper, we report the results of a prespecified secondary analysis of GEMINI that sought to determine the effect of these two β‐blockers on commonly reported symptoms.