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Renal denervation not only reduces resistant hypertension but also decreases left ventricular (LV) mass and improves diastolic function in patients with hypertensive heart disease, according to a new analysis stemming from the Symplicity HTN-2 trial. The findings, which could add another feather to the cap of the innovative interventional procedure, were published in the March 6, 2012, issue of the Journal of the American College of Cardiology. 

In the original Symplicity HTN-2 trial, patients with resistant hypertension (office systolic pressure of ≥ 160 mm Hg despite treatment with 3 or more antihypertensive agents) were randomized to bilateral renal denervation by catheter-based radiofrequency ablation or control. All patients were instructed to continue on their standard antihypertensive regimen. At 6 months, systolic blood pressure in the renal denervation group was reduced by 32 mm Hg and diastolic pressure by 12 mm Hg.

For the current study, investigators led by Uta C. Hoppe, MD, of Paracelsus Medical University Salzburg (Salzburg, Austria), compared outcomes of 46 renal denervation patients with those of 18 controls, looking at changes not only in blood pressure but also LV hypertrophy and diastolic function as assessed by transthoracic echocardiography. Demographic and clinical characteristics were similar between the groups. The cohort included patients enrolled in Symplicity HTN-2 as well as additional subjects.

Dual Benefit

As in the Symplicity HTN-2 trial, renal denervation substantially reduced blood pressure, yielding decreases from baseline of 22.5 mm Hg systolic and 7.2 mm Hg diastolic at 1 month and 27.8 mm Hg systolic and 8.8 mm Hg at 6 months (P < 0.001 for each time point). Blood pressure did not change in controls.

At 6 months, echocardiography showed improvements in several measures of ventricular mass and function in treated patients, while controls experienced worsening dysfunction or no change (table 1).

Table 1. Echocardiographic Parameters of LV Mass and Function

^a P value for treatment vs. control groups.

To assess the potential impact of the blood pressure reduction on improvement in LV hypertrophy and diastolic function, patients were divided into tertiles of systolic reduction. Regression in both metrics was most pronounced in subjects with the largest declines in systolic pressure. On the other hand, 5 of 6 patients classified as denervation nonresponders (defined as < 10 mm Hg decline in systolic pressure at 6 months) nonetheless saw a marked reduction in LV mass index (-8.8 ± 6.6 g/m^2.7) and ratio of mitral inflow velocity to annular relaxation velocity (-4.9 ± 5.2), suggesting that the effects were largely independent of blood pressure changes.

The authors acknowledge that the small study cohort and short follow-up do not permit assessment of clinical outcomes. Even so, they say, “[e]xtrapolating from drug trials, the effect on cardiac remodeling documented in our study suggests a prognostic benefit of [renal denervation] in patients with refractory hypertension, which should be evaluated in future trials.”

Potential Mechanisms

In an accompanying editorial, Michael R. Zile, MD, of the Medical University of South Carolina (Charleston, SC), and William C. Little, MD, of Wake Forest University School of Medicine (Winston-Salem, NC), address the question of how renal denervation might counter LV remodeling and dysfunction. “It seems likely that both a decrease in LV myocardial load and a decrease in activation of the sympathetic nervous system contribute to these outcomes,” they write.

Dr. Hoppe and colleagues explain that current pharmacological treatments for hypertensive heart disease block individual components of the sympathetic nervous system and prevent overactivation of the renin-angiotensin-aldosterone system.

Renal denervation, on the other hand, “may provide a more integrated approach to normalizing autonomic activity. By altering both afferent and efferent renal nerve signaling, [renal denervation] appears to decrease afferent sympathetic signals from the kidney to the brain, reducing systemic sympathetic activation, and to decrease efferent sympathetic signals from the brain to the kidneys, reducing vasoconstriction and [renin-angiotensin-aldosterone] activation,” they say.

According to the editorial, “patients across the spectrum of [hypertensive heart disease] may represent reasonable target populations for the treatment,” including those with resistant hypertension, hypertensive LV hypertrophy, and hypertension-related heart disease. In the future, even patients with hypertension not refractory to drug treatment may be candidates, Drs. Zile and Little assert.

LV Mass Reduction Suggests Better Prognosis

In a telephone interview with TCTMD, Suzanne Oparil, MD, of the University of Alabama (Birmingham, AL), observed that sympathetic nerve activity probably has a parallel effect on both blood pressure and cardiac remodeling. “The sympathetic nervous system releases mainly norepinephrine, which like angiotensin II stimulates cardiomyocyte growth and cardiac fibrosis. And medicines don’t work very well in countering this mechanism.”

Renal denervation’s positive effect on LV hypertrophy is “a big plus” for renal denervation, Dr. Oparil said, pointing to results of the LIFE trial comparing a beta blocker with an angiotensin receptor blocker (ARB) in patients with hypertension and LV hypertrophy.

“The ARB reduced LV hypertrophy, while the beta blocker didn’t do much, although blood pressure was lowered comparably between the two,” she said. “And there was a 25% reduction in stroke in the ARB arm vs. the beta blocker arm. So improvement in LV hypertrophy is an important index of success with antihypertensive treatment.”

Renal denervation may be especially useful for patients with diastolic heart failure, Dr. Oparil indicated. “These people have big, thick hearts that don’t relax normally in diastole, although contractile function is okay,” she said. “If you can get rid of some of that mass, the heart comes back functioning well. But there’s no satisfactory medical treatment for that, so [renal denervation] is very exciting.” On the other hand, the procedure is unlikely to help much if the heart is scarred from multiple heart attacks, she added.

Dr. Oparil cautioned that renal denervation requires further validation. “Right now the world is having a love affair with this procedure, and undoubtedly as it becomes more disseminated, there will be some problems,” she said. “But everything we have seen so far is positive.”

Study Details

On average, patients were taking 4.7 different antihypertensive drugs. Patients with secondary causes of hypertension or renal atherosclerosis or abnormal vascular anatomy were excluded.

Renal denervation was performed with Symplicity (Ardian [now Medtronic], Palo Alto, CA) or Flex (St. Jude Medical, St. Paul, MN) ablation catheters. In the overall Symplicity HTN-2 trial, the procedure was performed using only the Symplicity catheter.

2. Zile MR, Little WC. Effects of autonomic modulation: More than just blood pressure. J Am Coll Cardiol. 2012;59:910-912.

Related Stories:

1. Symplicity Itself: Endovascular RF Ablation Lowers Resistant Hypertension
2. Endovascular Renal Nerve Ablation Safely Reduces BP During Exercise

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