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Resistant hypertension is a growing problem in the United States and around the world. Although its pathophysiology is multifactorial and poorly understood, it is invariably associated with increased renal sympathetic activation and central sympathoexcitation.[1-3] Sympathetic nervous system (SNS) regulation is complex and several mechanisms modulate its activity,[4-6] with accumulating evidence pointing to the kidney as a key contributor. The kidney, through efferent and afferent sympathetic fibers, acts as both a generator and a recipient of sympathetic signals.[7]

A great deal of basic research[8-11] has pointed out for decades that efferent fibers can modulate sodium and fluid retention by the kidney, control renin release and plasma renin activity, and regulate renal blood flow. On the other hand, afferent fibers can transfer signals generated by mechanoreceptors and chemoreceptors in the kidney to the brain and sequentially modulate heart rate (HR), heart function, and peripheral resistance.[9, 10] Recent advances in technology made it possible to percutaneously approach and interrupt transvascularly the sympathetic fibers coursing in the adventitia of the renal artery. A first-in-man study,[12] using a single tip radiofrequency ablation catheter, suggested impressive reductions in office blood pressure (OBP), sustained and improved over time. Other follow-up studies demonstrated similar results, with durable long-term blood pressure (BP) reduction,[13-15] although all published data consistently indicate that response varies among patients. Some patients demonstrate adequate response, some partial response, and some no response at all.[16] It is therefore important to focus our research on response indicators in order to better tailor our therapies. In this brief article we describe a case with impressive BP response early on after sympathetic renal denervation using a multi-electrode ablation catheter. The patient had clinical evidence of sympathetic activation, ie, persistently high BP and HR despite the use of multiple drugs including sympatholytics.

Case

  1. Top of page
  2. Case
  3. Renal Denervation Procedure
  4. Effect on BP and HR
  5. Comment
  6. References

The patient was a 52-year-old morbidly obese (body mass index = 43.4 kg/m2) woman with a history of smoking of more than 30 years and uncontrolled severe drug-resistant hypertension diagnosed more than 5 years prior to presentation. She also had a history of hypothyroidism and received levothyroxin replacement therapy, being eythyroid at last follow-up. Extensive workup for secondary causes of hypertension had been negative. On presentation, the patient was treated with 6 antihypertensive medications as follows: olmesartan 40 mg, chlorthalidone 25 mg, nifedipine 60 mg, bisoprolol 15 mg, and eplerenone 50 mg once a day and clonidine 0.15 mg 3 times a day. Systolic OBP was consistently >160 mm Hg despite use of a multidrug regimen and she was referred for renal denervation. During baseline evaluation, office systolic and diastolic OBP were 223 mm Hg and 131 mm Hg, respectively. HR was 97 beats per minute and 24-hour ambulatory BP monitoring (ABPM) averaged 178/102 mm Hg. Laboratory results showed normal complete blood cell count and chemistry, and glomerular filtration rate was estimated at 93 mL/min/1.73 m2. Target organ damage was indicated by an albumin to creatinine ratio of 101 mg/g, while findings from transthoracic echocardiography revealed concentric left ventricular hypertrophy (left ventricular mass indexed for body surface area equal to 148.6 g/m2).

Renal Denervation Procedure

  1. Top of page
  2. Case
  3. Renal Denervation Procedure
  4. Effect on BP and HR
  5. Comment
  6. References

Preprocedure evaluation, including anatomic eligibility of renal vasculature confirmed by computed tomography angiography (CTA), was completed and the patient was admitted to the cardiac catheterization laboratory for renal denervation. Following standard procedures, the patient underwent conscious sedation (intravenous fentanyl 100 µg and intravenous midazolam 4 mg) under rhythm and pulse oxymetry monitoring. Access was obtained from the right groin using the Seldinger technique.

Findings from renal angiography prior to renal denervation procedure demonstrated normal renal artery lumen bilaterally with sharp take off from the aorta (Figure 1). The right renal artery (RRA) measured 6.2 mm in diameter and 37 mm in length while the left renal artery (LRA) measured 5.5 mm in diameter and 38 mm in length. There were no other anatomic abnormalities, no accessory arteries, and no evidence of atherosclerotic disease confirming the CTA findings (Figure 1). The EnligHTN Multi-Electrode Renal Denervation System (St Jude Medical, Saint Paul, MN) was used. Because of sharp take off of the renal arteries, engagement of the guide catheter was challenging, but appropriate maneuvering of the guide catheter achieved good engagement and the lumen of the guide became co-axial with the lumen of the renal artery, making delivery of the ablation system easy and safe. Occasionally in such cases, guide wire would be helpful in achieving good deep engagement in order to safely deliver the ablation system. Renal denervation was successfully performed using the standardized procedure for the EnligHTN device. Initially the ablation catheter was placed at the bifurcation of the first major branch of the LRA and the basket deployed with no difficulty (Figure 1). After a diagnostic check to confirm electrode contact, energy was delivered through each electrode for 90 seconds sequentially. Then the basket was collapsed, withdrawn about 1 cm, turned 45 degrees, expanded, and the procedure repeated. After delivering 8 lesions in the LRA, the basket was withdrawn in the guide and the RRA was engaged to repeat the same steps (Figure 1). Eight lesions were placed in the RRA in a similar fashion. The duration of the procedure was 35 minutes from access to ablation completion. The patient developed flank pain during the energy delivery, but it was controlled with administration of additional doses of intravenous midazolam and fentanyl. Figure 1 shows the different phases of the denervation procedure. Note the configuration of the guide catheter, bow-like appearance, caused by exerted pressure to achieve coaxial lumen of the guide and the renal artery.

image

Figure 1. Baseline renal angiograms with sharp take off of renal arteries from the aorta (A, D); guide catheter engagement and deployment of the EnligHTN ablation system (B, E); post-ablation angiograms showing normal renal arteries with no evidence of dissection, stenosis, or spasm (C, F).

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Effect on BP and HR

  1. Top of page
  2. Case
  3. Renal Denervation Procedure
  4. Effect on BP and HR
  5. Comment
  6. References

Renal denervation resulted in a dramatic reduction of BP in this patient. Office systolic/diastolic BP decreased from 223/131 mm Hg at baseline to 110/69 mm Hg at 1 month and remained low, within normal range despite significant reduction in antihypertensive medication. At 3 months, OBP averaged 122/74 mm Hg and at 6 months 113/77 mm Hg. There was some gradual increase in office BP after 6 months, and at 12 months averaged 156/96 mm Hg. At this point, medication was readjusted to achieve better BP control. At the same time, average 24-hour ABPM decreased from 178/102 mm Hg at baseline to 102/66 mm Hg at 1 month (the patient became symptomatic and medication was decreased, see below). At 3 months, 24-hour ABPM averaged 119/70 mm Hg and at 6 months 131/73 mm Hg. Similar to OBP, 24-hour average ABPM also increased at 12 months to 163/87 mm Hg, justifying medication adjustment for better control. Along with office BP and 24-hour ABPM, HR decreased substantially after renal denervation from 95 to 60 beats per minute (office) and from 97 to 57 beats per minute (ABPM). HR remained low despite decrease in HR-reducing medication (bisoprolol and clonidine), indicating a substantial reduction of sympathetic outflow to the heart (Figure 2 and Figure 3). Following renal denervation, the patient was closely followed and in addition to office and ABPM pressure measurements, as per protocol, had interim visits and home BP measurements. Her pressures were found to be low on several occasions and she reported persistently low BP at home. The patient complained of dizziness and lightheadedness and for this reason the antihypertensive regimen was modified to improve symptoms as follows: bisoprolol was reduced from 15 mg daily to 10 mg, chlorthalidone was decreased from 25 mg to 15 mg daily, and clonidine was reduced from 0.45 mg daily to 0.225 mg. Eplerinone from 50 mg to 25 mg and nifedipine 60 mg daily was discontinued. Olmesartan 40 mg daily remained the same. The modified reduced medication regimen remained unchanged until the 12-month visit, when BPs were found to be above normal and medications were re-adjusted (upwards to improve BP control).

image

Figure 2. Change in office blood pressure (BP) and heart rate (HR) at 1 month and 3, 6, and 12 months. DBP indicates diastolic BP; SBP, systolic BP.

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image

Figure 3. Change in ambulatory blood pressure (BP) and heart rate (HR) at 1 month and 3, 6, and 12 months. DBP indicates diastolic BP; SBP, systolic BP.

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This patient experienced a dramatic reduction in BP (>120/60 mm Hg reduction in OBP) and became symptomatic, reporting dizziness and lightheadedness. This should not be considered a serious adverse event of the procedure, however, since the patient was also taking 6 antihypertensive medications at the same time. Medication adjustment resolved the symptoms and stabilized BP for more than 12 months. This information is useful for renal denervation operators, since patients such as this with sympathetic hyperactivity may require medication adjustment early on after the procedure to avoid hypotension and/or symptoms.

Of note and of major clinical importance in this patient is the noted regression of microalbuminuria (A/C from 101 mg/g to 12 mg/g) and left ventricular hypertrophy (left ventricular mass index from 148 to at 115 g/m2 at 6 months of follow-up).

In summary, BP control in this high-risk, morbidly obese hypertensive patient with target organ damage taking multiple antihypertensive medications was achieved early on, from the first month following renal denervation. BP remained reasonably well controlled and target organ damage regression was noted.

It should be noted that in these patients following renal denervation, medication adjustment may be required to avoid orthostatic symptoms or to normalize BP.

Comment

  1. Top of page
  2. Case
  3. Renal Denervation Procedure
  4. Effect on BP and HR
  5. Comment
  6. References

This case demonstrates a number of important points:

  • The procedure is feasible and safe even in patients with sharp take off of the renal arteries. Guide catheter manipulation can be done safely to make the deployment of the device possible.
  • Marked BP reduction was noted early and medication decrease was necessary to avoid patient symptoms (dizziness). Effective lowering of BP and HR was sustained long-term and was accompanied by regression in target organ damage.
  • In this patient there was marked BP reduction, but there was also considerable HR reduction by >30 beats per minute. Of note, the HR was elevated (along with BP) even though the patient was receiving bisoprolol and clonidine, both of which can affect sympathetic nerve activation. Although the standardized markers of sympathetic activation (muscle sympathetic nerve activity and norepinephrine spillover) were not available in this patient, clinical markers of sympathoexcitation, including hemodynamic parameters (BP and HR) and obesity, indicated marked sympathetic activation and make this patient ideal for renal denervation.[11]

Several clinical studies published to date[12-15, 17, 18] indicate that sympathetic renal denervation can reduce BP in most patients. In about one third of treated patients, sympathetic denervation results in BP normalization and about two thirds of treated patients are responders (at least 10 mm Hg reduction in systolic BP). Yet, there is a small number of patients who show no response at all. In fact, in at least one study, none of 12 patients treated with renal denervation responded.[17] Of note, in that study, markers of sympathetic activity at baseline were within normal limits (muscle sympathetic nerve activity was normal and HR was 60 beats per minute at baseline). It seems possible that these patients with no evidence of sympathetic activation will be nonresponders. In fact, early assessment of available results indicates a strong correlation of BP response to baseline HR and baseline BP.

The above case had very high BP (223/131 mm Hg) and high HR (97 beats per minute) at baseline despite treatment with sympatholytic medication. It is possible that patients such as this would be ideal candidates for renal denervation as additional data continues to be collected in this promising new therapy.

References

  1. Top of page
  2. Case
  3. Renal Denervation Procedure
  4. Effect on BP and HR
  5. Comment
  6. References
  • 1
    Joyner MJ, Charkoudian N, Wallin BG. A sympathetic view of the sympathetic nervous system and human blood pressure regulation. Exp Physiol. 2008;93:715724.
  • 2
    Wallin BG, Charkoudian N. Sympathetic neural control of integrated cardiovascular function: insights from measurement of human sympathetic nerve activity. Muscle Nerve. 2007;36:595614.
  • 3
    Charkoudian N, Rabbitts JA. Sympathetic neural mechanisms in human cardiovascular health and disease. Mayo Clin Proc. 2009;84:822830.
  • 4
    Esler M. Pathophysiology of the human sympathetic nervous system in cardiovascular diseases: the transition from mechanisms to medical management. J Appl Physiol. 2010;108:227237.
  • 5
    Grassi G, Seravalle G, Quarti-Trevano F. The ‘neuro-adrenergic’ hypothesis in hypertension. Current evidence. Exp Physiol. 2010;95:581586.
  • 6
    Fisher JP, Young CN, Fadel PJ. Central sympathetic overactivity: maladies and mechanisms. Auton Neurosci. 2009;148:515.
  • 7
    DiBona GF, Esler M. Translational medicine: the antihypertensive effect of renal denervation. Am J Physiol Regul Integr Comp Physiol. 2010;298:R245R253.
  • 8
    Stadbauer V, Wright GA, Banaji M, et al. Relationship between activation of the sympathetic nervous system and renal blood flow autoregulation in cirrhosis. Gastroenterology. 2008;134:111119.
  • 9
    Campese VM, Ku E, Park J. Sympathetic renal innervation and resistant hypertension. Int J Hypertens. 2011;2011:814354.
  • 10
    DiBona GF. Physiology in perspective: the wisdom of the body. Neural control of the kidney. Am J Physiol Regul Integr Comp Physiol. 2005;289:R633R641.
  • 11
    Tsioufis C, Kordalis A, Flessas D, et al. Pathophysiology of resistant hypertension: the role of sympathetic nervous system. Int J Hypertens. 2011;2011:642416.
  • 12
    Papademetriou V, Doumas M, Faselis C, et al. Carotid baroreceptor stimulation for the treatment of resistant hypertension. Int J Hypertens. 2011;2011:964394.
  • 13
    Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373:12751281.
  • 14
    Symplicity HTN-2 Investigators, Esler MD, Krum H, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. 2010;376:19031909.
  • 15
    Symplicity HTN-1 Investigators. Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months. Hypertension. 2011;57:911917.
  • 16
    Krum H, Barman N, Schlaich M. Long-term follow-up of catheter-based renal sympathetic denervation for resistant hypertension confirms durable blood pressure reduction. J Am Coll Cardiol. 2012;59:E1704.
  • 17
    Brinkmann J, Heusser K, Schmidt BM, et al. Catheter-based renal nerve ablation and centrally generated sympathetic activity in difficult-to-control hypertensive patients: prospective case series. Hypertension. 2012;60:14851490.
  • 18
    Papademetriou V, Worthley S, Tsioufis C, et al. EnligHTN™ I, First-in-Human Multicenter Study of a Multi-Electrode Renal Denervation Catheter in Patients with Drug-Resistant Hypertension: Circulation (A) Presentation at 2012 scientific session-Special Sessions.