Effects of baroreflex activation therapy on cardiac function and morphology

Abstract

Aims

Arterial hypertension (aHTN) plays a fundamental role in the pathogenesis and prognosis of heart failure with preserved ejection fraction (HFpEF). The risk of heart failure increases with therapy‐resistant arterial hypertension (trHTN), defined as inadequate blood pressure (BP) control ≥140/90 mmHg despite taking ≥3 antihypertensive medications including a diuretic. This study investigates the effects of the BP lowering baroreflex activation therapy (BAT) on cardiac function and morphology in patients with trHTN with and without HFpEF.

Methods

Sixty‐four consecutive patients who had been diagnosed with trHTN and received BAT implantation between 2012 and 2016 were prospectively observed. Office BP, electrocardiographic and echocardiographic data were collected before and after BAT implantation.

Results

Mean patients' age was 59.1 years, 46.9% were male, and mean body mass index (BMI) was 33.2 kg/m². The prevalence of diabetes mellitus was 38.8%, atrial fibrillation was 12.2%, and chronic kidney disease (CKD) stage ≥3 was 40.8%. Twenty‐eight patients had trHTN with HFpEF, and 21 patients had trHTN without HFpEF. Patients with HFpEF were significantly older (64.7 vs. 51.6 years, P < 0.0001), had a lower BMI (30.0 vs. 37.2 kg/m², P < 0.0001), and suffered more often from CKD‐stage ≥3 (64 vs. 20%, P = 0.0032). After BAT implantation, mean office BP dropped in patients with and without HFpEF (from 169 ± 5/86 ± 4 to 143 ± 4/77 ± 3 mmHg [P = 0.0019 for systolic BP and 0.0403 for diastolic BP] and from 170 ± 5/95 ± 4 to 149 ± 6/88 ± 5 mmHg [P = 0.0019 for systolic BP and 0.0763 for diastolic BP]), while a significant reduction of the intake of calcium‐antagonists, α₂‐agonists and direct vasodilators, as well as a decrease in average dosage of ACE‐inhibitors and α₂‐agonists could be seen. Within the study population, a decrease in heart rate from 74 ± 2 to 67 ± 2 min⁻¹ (P = 0.0062) and lengthening of QRS‐time from 96 ± 3 to 106 ± 4 ms (P = 0.0027) and QTc‐duration from 422 ± 5 to 432 ± 5 ms (P = 0.0184) were detectable. The PQ duration was virtually unchanged. In patients without HF, no significant changes of echocardiographic parameters could be seen. In patients with HFpEF, posterior wall diameter decreased significantly from 14.0 ± 0.5 to 12.7 ± 0.3 mm (P = 0.0125), left ventricular mass (LVM) declined from 278.1 ± 15.8 to 243.9 ± 13.4 g (P = 0.0203), and e′ lateral increased from 8.2 ± 0.4 to 9.0 ± 0.4 cm/s (P = 0.0471).

Conclusions

BAT reduced systolic and diastolic BP and was associated with morphological and functional improvement of HFpEF.

Introduction

A number of cardiovascular risk factors are associated with heart failure with preserved ejection fraction (HFpEF), including diabetes mellitus, chronic lung disease, chronic kidney disease (CKD), atrial fibrillation, obesity, and arterial hypertension (aHTN).^1–4 With a prevalence of 90% in HFpEF, aHTN is the main risk factor, which is strongly involved in the aetiology and in the prognosis of HFpEF.^3,5,6 The occurrence of incident heart failure (HF) increases with poor blood pressure (BP) control, especially in cases of therapy-resistant arterial hypertension (trHTN),^7–10 defined as insufficient BP control ≥140/90 mmHg despite taking ≥3 antihypertensive medications including a diuretic.^11,12

Two interacting biohumoral systems, the renin-angiotensin-aldosterone and the sympathetic nervous system, are involved in the pathophysiology of aHTN and development of HF.^4,13 Comparative studies in hypertensive patients with and without diastolic dysfunction revealed a higher sympathetic modulation of the sinus node and an abnormal baroreflex modulation and sensitivity in patients with diastolic dysfunction.^14–16 Grassi and colleagues showed muscle sympathetic nerve activity to be significantly greater in patients with aHTN and left ventricular diastolic dysfunction than in hypertensive individuals without diastolic dysfunction,¹⁴ indicating that sympathetic nerve activation played a crucial role in the pathogenesis of diastolic dysfunction and HFpEF.

In HF, the efferent signal of arterial baroreceptors to control sympathetic nerve activation seems to be intact, whereas the afferent, inhibitory input decreases.^17,18 So therapies that activate the baroreflex are expected to suppress prognostic adverse sympathetic excess, restoring reflex modulation and autonomic balance.^19,20

Baroreflex activation therapy (BAT) is a device-based method to stimulate baroreceptors on the carotid glomus, activating vegetative feedback loops and resulting in an inhibition of the sympathetic nervous system.²¹ BAT is approved in cases of trHTN and provides beneficial effects on the vascular system as well.^22–25 Furthermore, it has been shown to improve the functional status and quality of life in patients with HF with reduced ejection fraction (HFrEF)^26,27 and is approved by the Food and Drug Administration (FDA) for an intended group of patients with HFrEF.²⁸ But so far, effects in cases of trHTN with diastolic dysfunction or HFpEF are limited to case reports only.^29,30 This study investigates the effects of the BAT neo system on BP and cardiac parameters in patients with trHTN with and without HFpEF.

Methods

Sixty-four consecutive adult patients visiting the certified hypertension clinic of the University Medical Centre Göttingen were enrolled from 2012 to 2016 and prospectively observed. Patients fulfilled the diagnosis of trHTN with BP above national and international targets,³¹ had been treated for aHTN for at least 1 year, and received optimal therapy for secondary reasons.

Exclusion criteria were pregnancy, unstable angina, acute myocardial infarction, transitory ischaemic attack or stroke within the previous 6 months, untreated secondary cause for aHTN or stenosis of the carotid artery >70%.

The study was performed as an uncontrolled observational study with data obtained before and after BAT implantation. All patients provided informed consent before the initiation of protocol-mandated procedures. The study was approved by the local Ethical Committee of Göttingen (19/9/2011). The investigation conforms to the principles outlined in the Declaration of Helsinki.

Office blood pressure measurements

Office BP measurement was performed as described in detail before.²⁴ Initially, BP was measured on both upper arms. The arm with the higher value was used for all following measurements throughout the study. After 10 min of rest, BP was measured twice within a 3-min interval using a semiautomatic oscillometric device (Bosch und Sohn GmbH u. Co. KG, Jungingen, Germany). Results were averaged.

Twenty-four hours ambulatory BP was investigated using an oscillometric Spacelabs Model 90s207 Recorder (Spacelabs Healthcare GmbH, Nürnberg, Germany) with readings every 15 min in the daytime and every 30 min at night-time. Measurements were averaged after 24 h.

Cardiac parameters

Cardiac parameters were investigated by analysing electrocardiograms of 33 patients before and 6 ± 1 months after BAT implantation. Assessed parameters were heart rate (HR), PQ-time, QRS-time, QT-time, and QTc-time. Four patients were excluded from the analysis: Two because they had a pacemaker and two due to missing follow-up values. Because of atrial fibrillation, atrial flutter and one missing value, four more patients were excluded from PQ-time analysis.

Echocardiographic data were collected before BAT implantation and at the latest follow-up available. Investigated parameters were septal and posterior wall thickness, left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left atrium (LA), left atrial volume index (LAVI), left ventricular ejection fraction (LVEF), e′ septal, e′ lateral, average E/e′, and tricuspid annular plane systolic excursion (TAPSE). Left ventricular mass (LVM) was calculated by Devereux formula.

The mean values of each parameter were compared between the two analysed time points and between patients with and without HFpEF. Patients were classified using the definition of HF and HFpEF of 2016, which was valid during data acquisition. According to this classification, patients with no elevation of brain natriuretic peptide (BNP) and preserved LVEF before BAT implantation were classified as patients without HF, whereas patients with symptoms and signs of HF and elevated BNP > 35 ng/L and LAVI > 34 mL/m² and/or LVMI ≥ 115 g/m² (men) or 95 g/m² (women) and/or E/e′ ≥ 13 and average (medial and lateral) e′ velocity < 9 cm/s and preserved LVEF before BAT implantation were classified as patients with HFpEF.³² The BNP level was measured before BAT implantation from patients' blood.

Statistical analysis

Data were evaluated using the statistical Software GraphPad Prism 9 and Microsoft Excel 2010. To analyse differences in the investigated variables between baseline and follow-up data, the paired t-test or Wilcoxon signed rank test was used. To analyse differences in the investigated variables between patients with and without HFpEF the unpaired t-test, Mann–Whitney or chi square test was used. For the analysis of antihypertensives, the Mann–Whitney and Fisher's exact test were used. Results are expressed as mean values ± SEM or median and interquartile range (IQR). The threshold for statistical significance was chosen to be P < 0.05.

Results

Baseline characteristics of patients with and without heart failure with preserved ejection fraction

Sixty-four patients were included: 21 patients showed no symptoms or signs of HF and 28 patients met the criteria for HFpEF. The remaining 15 patients were excluded for different reasons: two patients had a LVEF of <50%, five patients could not be classified due to incongruent values (elevated BNP, but no structural or diastolic echocardiographic aberrations), and eight patients could not be classified due to missing values. Mean patients' age was 59.1 years, 46.9% were male, and mean body mass index (BMI) was 33.2 kg/m². Prevalence of diabetes mellitus was 38.8%, atrial fibrillation was 12.2%, and CKD stage ≥3 was 40.8%.

The 28 patients with HFpEF receiving BAT for trHTN were significantly older (64.7 vs. 51.6 years, P < 0.0001), had a lower BMI (30.0 vs. 37.2 kg/m², P < 0.0001), and suffered more often from CKD-stage ≥3 (64 vs. 20%, P = 0.0032). By definition, they had higher BNP levels. Although not significant, they tended to have a lower diastolic office BP (85.9 vs. 94.5 mmHg, P = 0.0980) and took less antihypertensive drugs (6.4 vs. 7.1, P = 0.1069). There were no significant differences concerning gender (60.7 vs. 42.9% male patients), pre-existing diabetes mellitus (38.5 vs. 45%) or atrial fibrillation (17.9 vs. 4.8%), smoking state (65.4 vs. 65% [ex-]smokers), prior renal denervation (23 vs. 35%), mean office systolic BP (168.8 vs. 169.7 mmHg) or 24 h mean arterial pressure (103.0 vs. 105.4 mmHg) (Table 1).

Table 1 Baseline characteristics of patients with and without HFpEF

Parameter	No HF (n = 21)	HFpEF (n = 28)	P-value
Mean age (years)	51.6	64.7	<0.0001
Male (%)	42.9	60.7	0.2152
Diabetes mellitus (%)	45	38.5	0.6553
Mean BMI (kg/m2)	37.2	30.0	<0.0001
History of smoking (%)	65.0	65.4	0.8857
CKD-stage ≥ 3 (%)	20	64	0.0032
Atrial fibrillation (%)	4.8	17.9	0.1664
Mean BNP (ng/L)	18.6	436.7	<0.0001
Number of BP medication	7.1	6.4	0.1069
Prior renal denervation (%)	35	23	0.3733
Mean systolic office BP (mmHg)	169.7	168.6	0.8808
Mean diastolic office BP (mmHg)	94.5	85.9	0.0980
Mean 24 h-MAP (mmHg)	105.4	103.0	0.4701

Blood pressure development of patients with and without heart failure with preserved ejection fraction

At a median of 24 months (IQR 24–24 months) after BAT implantation, mean office BP decreased significantly in patients with and without HFpEF. In patients without HF, mean BP dropped from an average of 170 ± 5/95 ± 4 to 149 ± 6/88 ± 5 mmHg (P = 0.0019 for systolic BP and 0.0763 for diastolic BP). In patients with HFpEF, mean BP lowered from 169 ± 5/86 ± 4 to 143 ± 4/77 ± 3 mmHg (P = 0.0019 for systolic BP and 0.0403 for diastolic BP; see Table 2). The medication intake of ACE-inhibitors, angiotensin-receptor-blockers (ARBs), calcium-antagonists, thiazides, loop diuretics, aldosterone-antagonists, beta-blockers, α-blockers, α₂-agonists, and direct vasodilators was analysed. There was no relevant increased usage or dosage with any of these drugs. In contrast, significantly less patients took calcium-antagonists, α₂-agonists, and direct vasodilators after receiving BAT. Further, the average dosage of ACE-inhibitors and α₂-agonists declined. The development of antihypertensive medication usage is shown in Table 3.

Table 2 Course of blood pressure in patients with and without HFpEF

	Office SBP (mmHg)	Office DBP (mmHg)
Before BAT implantation	Follow-up	P-value	Before BAT implantation	Follow-up	P-value
No HF (n = 20a)	170 ± 5	149 ± 6	0.0019	95 ± 4	88 ± 5	0.0763
HFpEF (n = 26a)	169 ± 5	143 ± 4	0.0019	86 ± 4	77 ± 3	0.0403

Table 3 Course of antihypertensive medication

	Number of patients before BAT implantation	Number of patients at follow-up	P-value	Taken proportion of maximum dosage before BAT implantation (%)	Taken proportion of maximum dosage at follow-up (%)	P-value
ACE-inhibitors	24	16	0.4301	113.5	76.7	0.0434
ARBs	35	25	0.4437	86.0	90.6	0.3680
Calcium-antagonists	50	31	0.0164	110.6	95.7	0.1878
Thiazides	41	25	0.0780	25.5	35.1	0.0980
Loop diuretics	32	29	0.7014	53.0	63.8	0.9016
Aldosterone Antagonists	20	16	>0.9999	45.8	40.8	0.5443
Beta-blockers	51	41	0.7970	77.9	68.8	0.1426
α-blockers	40	28	0.3248	52.5	50.1	0.7987
α2-agonists	51	25	0.0001	88.9	71.4	0.0427
Direct vasodilators	33	14	0.0065	57.1	58.9	0.7671

Electrocardiogram data

After 6 ± 1 months of BAT, there was a significant reduction of HR from 74 ± 2 to 67 ± 2 min⁻¹ (P = 0.0062). Additionally, there was an increase in QRS-time from 96 ± 3 to 106 ± 4 ms (P = 0.0027), in QT-time from 384 ± 5 to 411 ± 5 ms (P < 0.0001) and in QTc-duration from 422 ± 5 to 432 ± 5 ms (P = 0.0184), but well within normal limits of QT-time. PQ duration was virtually unchanged (from 172 ± 6 to 173 ± 5 ms). For detailed electrocardiogram information, see Table 4.

Table 4 Electrocardiogram data of all patients

Parameter	n	Baseline	6 ± 1 months after BAT implantation	P-value
HR (min−1)	29a	74 ± 2	67 ± 2	0.0062
PQ-time (ms)	25a	172 ± 6	173 ± 5	0.4641
QRS-time (ms)	29a	96 ± 3	106 ± 4	0.0027
QT-time (ms)	29a	384 ± 5	411 ± 5	<0.0001
QTc-time (ms)	29a	422 ± 5	432 ± 5	0.0184

One patient had developed a de novo AV block I°, and one patient had received a pacemaker by the time of follow-up.

Echocardiographic data

At a median follow-up duration of 24 months (IQR 7.4–28 months) after BAT implantation in patients without HF, no significant changes of echocardiographic parameters could be seen.

In contrast, in patients with HFpEF a significant reduction of posterior wall diameter from 14.0 ± 0.5 to 12.7 ± 0.3 mm (P = 0.0125) was detectable. Moreover, in these patients, LVM declined significantly from 278.1 ± 15.8 to 243.9 ± 13.4 g (P = 0.0203; see Figure 1), and e′ lateral increased from 8.2 ± 0.4 to 9.0 ± 0.4 cm/s (P = 0.0471). Results on the development of echocardiographic parameters in patients with and without HFpEF are presented in Table 5. Due to missing values, not all parameters could be analysed for all patients.

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Table 5 Echocardiography data of patients with and without HFpEF

	No HF	HFpEF
na	Baseline	Follow-up	P-value	na	Baseline	Follow-up	P-value
Septum (mm)	18	13.1 ± 0.5	13.8 ± 0.5	0.1758	25	13.9 ± 0.5	13.4 ± 0.4	0.2199
Posterior Wall (mm)	18	12.4 ± 0.4	12.2 ± 0.6	0.5977	25	14.0 ± 0.5	12.7 ± 0.3	0.0125
LVEDD (mm)	18	50.5 ± 1.4	49.9 ± 2.0	0.0855	25	48.19 ± 1.4	47.2 ± 1.5	0.5756
LVESD (mm)	10	32.8 ± 1.0	30.8 ± 1.3	0.0812	16	31.4 ± 1.0	27.5 ± 2.2	0.1147
LVM (g)	18	260.5 ± 13.1	264.4 ± 19.1	0.8317	25	278.1 ± 15.8	243.9 ± 13.4	0.0203
LA (mm)	15	42.3 ± 1.5	40.9 ± 1.4	0.3705	21	44.0 ± 1.5	43.8 ± 1.1	0.8838
LAVI (ml/m2)	14	35.6 ± 3.2	33.5 ± 2.5	0.6257	18	45.6 ± 2.7	44.2 ± 3.8	0.5433
LVEF visuell (%)	18	59.9 ± 1.2	61.0 ± 1.6	0.5783	25	62.2 ± 1.6	59.6 ± 1.5	0.2067
e′ septal (cm/s)	15	6.9 ± 0.4	6.7 ± 0.5	0.7445	20	5.8 ± 0.3	6.1 ± 0.3	0.3897
e′ lateral (cm/s)	14	9.1 ± 1.1	8.5 ± 0.9	0.3479	18	8.2 ± 0.4	9.0 ± 0.4	0.0471
E/e′	14	11.2 ± 0.9	10.8 ± 0.9	0.5016	17	12.3 ± 0.9	12.3 ± 0.9	0.7730

Discussion

BAT has proven to reduce office and ambulatory BP^24,33,34 and to exert protective effects on kidney³⁵ and vasculature²⁵ in patients with trHTN. Moreover, BAT has been shown to improve the functional status and quality of life in patients with HFrEF^26,27 and is approved by the FDA for a specific group of patients with HFrEF.²⁸ However, data on the effects of this device therapy on diastolic dysfunction or HFpEF are currently limited to case reports only. The present study compared the baseline characteristics, BP and cardiac parameters in patients with and without HFpEF, who underwent BAT for trHTN. HFpEF state was defined according to the criteria of 2016, as these were the current guideline criteria at study inclusion and data acquisition.

After BAT implantation, mean office BP dropped significantly in patients with and without HFpEF, while a reduction in antihypertensive medication was observed. Additionally, in patients with HFpEF, posterior wall diameter and LVM, markers of left ventricular (LV) hypertrophy, decreased, and e′ lateral, a parameter of diastolic function, increased.

Consistent with the usual risk factors for HFpEF, such as age and CKD,^1,4 in our study population, patients with HFpEF were significantly older and more likely to have CKD-stage ≥3 than patients without HF. In contrast to the common observations,⁴ patients with HFpEF in our study population had a lower BMI and consequently no increased incidence of diabetes mellitus. This may be due to our study population consisting of patients selected for BAT, as weight reduction as a lifestyle change to achieve BP control is attempted before interventional methods are used.

After a median follow-up duration of 24 months, patients with and without HFpEF experienced a significant reduction in office BP with concurrent reduction of antihypertensive medication. This reduction in BP could be an essential benefit of BAT in managing trHTN in both groups. As BP control is the major preventive and treatment strategy in HFpEF,⁵ BAT seems to be a therapeutic approach in patients with HFpEF and accompanying trHTN.

Following BAT implantation, there was a significant reduction in HR detectable, and the QRS-, QT-, and QTc-intervals were lengthened, albeit without reaching pathological levels. Although one patient developed de novo AV block I°, this seems to be an individual development, as no lengthening of PQ-time could be seen in the overall population. The significant reduction of HR can be seen as a surrogate for reduced sympathetic excess, and normalization of HR might lead to an improvement of coronary blood circulation and left ventricular filling. However, the extent of HR reduction for the best benefit in patients with HFpEF is unclear.³⁶

Regarding echocardiographic parameters, posterior cardiac wall diameter and LVM, surrogate parameters of LV hypertrophy, were significantly reduced in patients with HFpEF. Notably, the reduction of LV hypertrophy was observed especially in patients with HFpEF, whereas there was no change in patients without HF. As Okin et al. showed that a reduction of LV hypertrophy is associated with fewer hospitalizations for HF in hypertensive patients,³⁷ the remarkable reduction of LVM by BAT might be a meaningful effect of this therapy on HF outcomes. A decreasing thickness of the posterior wall by BAT was also detected in a case report of a hypertensive female with diastolic dysfunction.²⁹ Notably, the group saw a normalization of echocardiographic diastolic dysfunction parameters, such as E/e′ lateral.²⁹ Similarly, we could detect an improvement of e′ lateral in patients with HFpEF, which might indicate a beginning improvement of early diastolic, passive ventricular filling. Further, Segers et al. described a reduction of LV afterload and a concomitant positive effect on LV filling dynamics in a male patient with trHTN and clinical symptoms of HF treated with BAT.³⁰

These positive effects of BAT on morphological and functional cardiac parameters in patients with HFpEF might be due to a suppression of HF-associated sympathetic overdrive.^19,28 Cardiac damage linked to the intrinsic cardiac nervous system causes a sympathetic excess that leads to baroreflex dysfunction and drives further cardiac damage with progressive HF.¹³ By restoring baroreflex function, BAT helps to suppress this sympathetic overdrive which leads to diastolic dysfunction.^14,19,28 Accordingly, in animal models of HF, BAT was proven to reduce neurohormonal activation and improve LV function and remodelling.^28,38,39

Limitations

Being a single-centre evaluation in a rare indication, the study was limited to a small sample size with missing data. Moreover, due to its observational nature, it lacks a control group. Electrocardiograms were available for only 33 patients. As ECG data were derived from single ECG measurements at baseline and follow-up, HR variability during the day may lead to incorrect data. The Devereux formula was used to calculate LVM. This formula is based on linear measurements of ventricular wall and internal diameters without taking into account the three-dimensional ventricular structure, asymmetric changes or interindividual differences in LV morphology. Also, the formula might underestimate LV hypertrophy. Therefore, magnetic resonance imaging would have allowed a better assessment of LVM. Nevertheless, estimation of LVM by Devereux formula is an accepted tool, and a possible underestimation of LVM in our study affects both baseline and follow-up data, so the change of LVM should be valid. It would have been of interest to correlate cardiac morphological changes with clinical outcome. Unfortunately, no data on clinical endpoints were available.

Conclusions

BAT reduced systolic and diastolic BP in patients with and without HFpEF and was associated with morphological and functional cardiac improvement in patients with HFpEF. In these patients, posterior wall diameter and LVM decreased significantly, whereas e′ lateral increased. This study highlights the potential benefits of BAT in managing aHTN and improving cardiac parameters in patients with HFpEF. The findings contribute to the growing understanding of the interplay between aHTN, HFpEF and the potential therapeutic impact of BAT in patients with trHTN beyond its BP-lowering effects by modulation of sympathetic nerve activity. However, further research and larger-scale studies are needed to confirm these findings and to evaluate whether the particular effect of BAT on diastolic function in patients with HFpEF can be verified.

Funding

This study was a prospectively designed cohort study planned by an interdisciplinary team of nephrologists and cardiologists. The analysis of the data was financially supported by CVRx but without any insight into, or influence on, the data. No other funding was provided.

Acknowledgements

The authors thank Mrs. C. Biegler for assistance, Dr. D. Zenker, Department of Thoracic-Cardiac-and-Vascular-Surgery, for BAT implantation, and the employees of CVRx for technical support. We acknowledge support by the Open Access Publication Funds of the Göttingen University.

Open access funding enabled and organized by Projekt DEAL.

Conflict of interest

MK, MW, and RW have received speaking honoraria and research grants from CVRx. MK is a member of the CVRx Barostim Hypertension Registry Steering Committee. RW declares to have received lecture fees and enumeration for including subjects into clinical trials from CVRx. RW has received consultant fees from CVRx. AKS, CS, LL, SL, and GH declare no relevant financial or non-financial interests to disclose.

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