Baroreflex activation as a novel therapeutic strategy for diastolic heart failure
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- Brandt, M.C., Madershahian, N., Velden, R. et al. Clin Res Cardiol (2011) 100: 249. doi:10.1007/s00392-010-0249-0
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Diastolic heart failure is a common clinical finding in patients with severe arterial hypertension. While heart failure patients with reduced ejection fraction benefit from improved medical and device therapy, the prognosis of diastolic heart failure has not changed over the last decades and no therapeutic strategy has proven effective to significantly improve the outcome [1–4]. Sympathetic hyperactivity has been implicated in the occurrence of hypertrophy and diastolic heart failure [5, 6]. Moreover, clinically discernible hypertrophy may blunt sympathoinhibitory reflexes in its own right, thus possibly leading to increased sympathetic drive and progressive symptoms in a circulus vitiosus .
A 47-year-old female with a long history of arterial hypertension presented to our clinic after recurrent pulmonary edema. The patient showed a markedly reduced exercise capacity consistent with NYHA class III. Her 6-min walking distance was 235 m. Despite a combination of nine different antihypertensive drugs (hydrochlorothiazide, torasemide, ramipril, candesartan, nebivolol, lecarnidipin, spironolactone, moxonidin and minoxidil), she still measured systolic home blood pressure values between 170 and 210 mmHg. 24-h ambulatory blood pressure recordings confirmed drug-refractory hypertension (Fig. 1a). A wide range of potential causes of secondary refractory hypertension (including renal artery stenosis and endocrine disorders) had been excluded in the past. The renal function was normal with a GFR of 140 ml/min. Transthoracic echocardiography showed myocardial hypertrophy (interventricular septum diastolic diameter 15 mm) with an ejection fraction of 46% and marked diastolic dysfunction (E/E′ lateral 13.3) with a restrictive ventricular filling pattern (mitral valve E/A 3.9, deceleration time 148 ms, isovolumic relaxation time IVRT 90 ms). Severe pulmonary arterial hypertension was present with a tricuspid dPmax of 65 mmHg. An elevated NT-pro-BNP level of 983 ng/l further supported the diagnosis of DHF. The patient’s exercise capacity was markedly reduced, consistent with NYHA class III.
To improve blood pressure control, a device which provided Baroreflex Activation Therapy® as detailed above was implanted.
The Rheos® System effectively decreased blood pressure minutes after activation to the extent that four antihypertensive drugs could be discontinued. From discharge onwards, the blood pressure was treated with beta-blocker, ramipril, and the diuretics, which remained unchanged from baseline.
24-h blood pressure monitoring confirmed sufficient ambulatory device function and blood pressure control (Fig. 1b). After 3 months of device therapy, the mean blood pressure was 123/80 mmHg (daytime) and 117/65 mmHg (night). The heart rate was reduced from mean values of 90/min (daytime) and 85/min (night) before implantation to 77/min and 75/min, respectively. Notably, diastolic function had normalized (E/E′ lateral 4.7, IVRT 83 ms) at 3 months (Fig. 1e). While severe pulmonary hypertension had been present before implantation, the tricuspid dPmax was also normalized (18 and 16 mmHg) after 3 and 6 months, respectively. Moreover, left ventricular ejection fraction increased to 57%. The left ventricular mass index showed a marked decrease from 170.4 g/m2 at baseline to 95.7 g/m2 after 6 months. Blood pressure remained controlled after 6 months (Fig. 1c). Importantly, normalization of echocardiographic parameters was associated with a decrease of the NT-pro-BNP value to 42 ng/l, which now was also within the normal range. Consistently, the patient reported marked improvement of her exercise capacity (NYHA class II). The 6-min walking distance increased to 315 m.
This novel baroreflex activation therapy resulted in substantial and sustained reduction in blood pressure and effective treatment of overt severe diastolic heart failure, accompanied by a decreased requirement for antihypertensive medication. Already 3 months after device activation functional parameters, exercise capacity, clinical presentation and biomarkers consistently demonstrated normalization of diastolic function; notably despite a withdrawal of four antihypertensive drugs. Moreover, the elevated heart rate at baseline, which has been recognized as prognostic marker in hypertension and heart failure , was markedly reduced, most likely due to device-mediated increased parasympathetic nervous activity . These results indicate that further evaluation of the long-term clinical and potentially prognostic effect of continuous Baroreflex Activation Therapy for the treatment of hypertension and diastolic heart failure is of interest and warranted.
CVRx Inc. provided financial support of the study and supported device implantation and programming.
Conflict of interest
M.C.B., N.M., and U.C.H. report no conflicts of interest. R.V. is an employee of CVRx Inc.