Author + information
- †Department of Medicine, ASH Comprehensive Hypertension Center, University of Chicago Medicine, Chicago, Illinois
- ‡Department of Medicine, Section of Cardiology, University of Chicago Medicine, Chicago, Illinois
- ↵∗Reprint requests and correspondence:
Dr. George Bakris, University of Chicago Medicine, 5841 South Maryland Avenue, MC 1027, Chicago, Illinois 60637.
Population studies indicate a continuous association between an increase in attributable risk for cardiovascular disease with increasing blood pressure (BP) and age (1). Resistant hypertension, by definition, is the inability to reduce BP to levels <140/90 mm Hg, despite adequate combinations of maximally tolerated doses of antihypertensive medications and lifestyle modifications (2). The longer history of higher sustained pressures, relative to those without resistant hypertension, increases the likelihood of end-organ injury such as left ventricular (LV) hypertrophy, subsequent heart failure, and progression of kidney disease.
The pathophysiology of resistant hypertension is not well understood, but the sympathetic nervous system (SNS) has a central role in its genesis (3). Antihypertensive medications that inhibit the beta- or alpha-adrenoreceptors are only partially effective in inhibiting the SNS effects of primary hypertension and relatively ineffective in true resistant hypertension. New interventional techniques in man help attenuate the effects of the SNS on BP, with 1 such technique being renal denervation. Renal denervation has now garnered a reasonable database demonstrating improvement, not only in BP control among patients with true resistance, but also in other comorbid conditions such as glycemic control, LV hypertrophy, and sleep apnea (4). Specifically, recent reports have linked renal denervation with reduction in LV mass and improved cardiac performance (5).
In this issue of the Journal, Schirmer et al. (6) report reductions in LV mass and improved diastolic relaxation realized within 6 months following renal denervation in 66 patients prospectively studied who underwent planned renal denervation at a single European center (using the Medtronic Flex catheter system; Medtronic, Santa Rosa, California) (6). These improvements in cardiac function and ventricular size were documented by changes in echocardiography and independent of the magnitude of BP reduction. Unlike previous studies on LV mass regression, the novelty of this study was that neither BP at baseline nor degree to which BP was reduced had an impact on the degree of LV mass regression or diastolic improvement (6). The authors therefore concluded that renal denervation results in amelioration of not only BP load, but other unexplained variables that contribute to ventricular hypertrophy.
The findings of this study, although intriguing, raise a number of issues. First, the present study drew its conclusions from a relatively small sample size of patients, all undergoing open-label catheter renal denervation at a single center, without a sham control for comparison. This problem is offset, partially, by a subset of patients with 24-h ambulatory monitoring data.
The authors presented medications used at baseline but did not present data on kidney function. It is well known that chronic kidney disease (i.e., estimated glomerular filtration rate <60 ml/min/1.73 m2) is strongly associated with increases in LV mass and is a contributing factor to resistant hypertension (7). Online Table 1 in the article by Schirmer et al. (6) lists the patients as requiring a mean of 4.3 antihypertensive medications at baseline, with higher usage of beta-blockers (89%) and diuretics (100%), and proportionally lower use of angiotensin receptor blockers (55%). An early meta-analysis demonstrated that beta-blockers have little to no effect on regression of LV mass (8). A more recent meta-analysis of 4,000 patients further supports these earlier findings by showing differences between drug classes on LV mass reduction, after adjustment for the degree and duration of BP reduction. This meta-analysis noted an 11% regression with calcium channel blockers, 10% with angiotensin-converting enzyme inhibitors, 8% with diuretics, and 6% with beta-blockers (9). This lack of effect on LV mass regression by beta-blockers, however, is only seen when BP levels are approximately 140/90 mm Hg. A recent randomized multicenter trial of patients with BP <130/80 mm Hg showed comparable LV mass regression using magnetic resonance imaging in patients randomized to carvedilol CR/lisinopril versus atenolol/lisinopril versus high-dose lisinopril (10). Thus, although the investigators of the present study indicated that there were no significant adjustments to medication regimens between the start and conclusion of the study, detailed information stratified by tertile of treatment response was not provided. Consequently, given the small sample size, the benefit seen in the lowest BP tertile may be attributable to better BP control.
Another acknowledged limitation is the use of echocardiography, rather than magnetic resonance imaging, widely regarded as the reference standard for LV mass quantification, especially at 6 months. One may presume, however, that differences between these assessment methodologies should not have had a significant impact on the findings because echocardiography for all assessments was performed by a single blinded operator, and so limitations of assessment should have uniformly carried through the study.
Another consideration relates to renovascular anatomy and the actual performance of the renal denervation procedure, details of which are limited in the report. The quality of denervation may have also contributed to a more effective ablation of sympathetic traffic and hence, a greater LV mass regression. Recommendations relating to anatomic suitability put forth by the expert consensus document from the European Society of Cardiology include selection of renal arteries with an ablatable segment >20 mm in length and a diameter of >4 mm (11). We assume from the paucity of detail that all 66 patients conformed to these recommendations, but information on the presence of accessory renal arteries, early branching of main renal arteries, and sizing of branches not intervened upon would all be relevant. Additionally, the specifics of radiofrequency ablation were not provided vis-à-vis the number of ablation sites per vessel and per patient, catheter tip temperature, and total energy delivered. These variables could potentially serve as surrogates for the adequacy of interruption in renal sympathetic signaling and thus, bear great relevance to the observed results. Even if this information were in hand, an admitted limitation to the denervation system employed in this study is interoperator variability introduced by the requisite manipulation of a single-tip, unipolar device in a spiral fashion within each renal artery and fluctuation of electrical impedance during delivery of radiofrequency energy. Thus, these results may not be generalizable to all centers doing the procedure.
Finally, the SNS does interact with the renin-angiotensin system, and activation of one system is usually associated with activation of the other, with the converse also being true (12,13). Hence, it is possible that renal denervation reduced the renin-angiotensin system, thus acting like a renin-angiotensin system blocker and providing this additional benefit on LV mass regression.
In summary, Schirmer et al. (6) should be commended for providing promising early benefit of catheter-based renal denervation and for highlighting a possible BP-independent facet of this technique. These observations need confirmation before acceptance in clinical practice for the reasons enumerated previously and can only be applied to those with inclusion criteria used in their study.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Bakris is a consultant to Abbvie, Takeda, Daiichi-Sankyo, Medtronic, Relypsa, Bristol-Myers Squibb, and Jansson. Dr. Nathan is a consultant and proctor for Medtronic.
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