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Baroreflex activation therapy: a new approach to the management of advanced heart failure with reduced ejection fraction.

ABSTRACT: : Chronic heart failure is a common clinical condition characterized by persistent excessive sympathetic nervous system activation. The derangement of the sympathetic activity has relevant implications for disease progression and patient survival. Aiming to positively impact patient outcome, autonomic nervous system modulatory therapies have been developed and tested in animal and clinical studies. As a general gross assumption, direct vagal stimulation and baroreflex activation are considered equivalent. This assumption does not take into account the fact that direct cervical vagal nerve stimulation involves activation of both afferent and efferent fibers innervating not only the heart, but the entire visceral system, leading to undesired responses to and from this compartment. The different action of baroreflex activation is based on generating a centrally mediated reduction of sympathetic outflow and increasing parasympathetic activity to the heart via a physiological reflex pathway. Thus, baroreflex activation rebalances the unbalanced autonomic nervous system via a specific path. Independent and complementary investigations have shown that sympathetic nerve activity can be rebalanced via control of the arterial baroreflex in heart failure patients.Results from recent pioneering research studies support the hypothesis that baroreflex activation can add significant therapeutic benefit on top of guideline-directed medical therapy in patients with advanced heart failure. In the present review, baroreflex activation therapy results are discussed, focusing on critical aspects like patient selection rationale to support clinician orientation in opting for baroreflex activation therapy when, on top of current guideline-directed medical treatment, other therapies are to be considered.

SUBMITTER: Gronda E

PROVIDER: S-EPMC5555968 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Baroreflex activation therapy: a new approach to the management of advanced heart failure with reduced ejection fraction.

Gronda Edoardo E Francis Darrel D Zannad Faiez F Hamm Christian C Brugada Josep J Vanoli Emilio E

Journal of cardiovascular medicine (Hagerstown, Md.) 20170901 9

: Chronic heart failure is a common clinical condition characterized by persistent excessive sympathetic nervous system activation. The derangement of the sympathetic activity has relevant implications for disease progression and patient survival. Aiming to positively impact patient outcome, autonomic nervous system modulatory therapies have been developed and tested in animal and clinical studies. As a general gross assumption, direct vagal stimulation and baroreflex activation are considered e ...[more]

PMID: 28737621

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Project description:BackgroundLifetime risk of heart failure has been estimated to range from 20% to 46% in diverse sex and race groups. However, lifetime risk estimates for the 2 HF phenotypes, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF), are not known.MethodsParticipant-level data from 2 large prospective cohort studies, the CHS (Cardiovascular Health Study) and MESA (Multiethnic Study of Atherosclerosis), were pooled, excluding individuals with prevalent HF at baseline. Remaining lifetime risk estimates for HFpEF (EF ≥45%) and HFrEF (EF <45%) were determined at different index ages with the use of a modified Kaplan-Meier method with mortality and the other HF subtype as competing risks.ResultsWe included 12 417 participants >45 years of age (22.2% blacks, 44.8% men) who were followed up for median duration of 11.6 years with 2178 overall incident HF events with 561 HFrEF events and 726 HFpEF events. At the index age of 45 years, the lifetime risk for any HF through 90 years of age was higher in men than women (27.4% versus 23.8%). Among HF subtypes, the lifetime risk for HFrEF was higher in men than women (10.6% versus 5.8%). In contrast, the lifetime risk for HFpEF was similar in men and women. In race-stratified analyses, lifetime risk for overall HF was higher in nonblacks than blacks (25.9% versus 22.4%). Among HF subtypes, the lifetime risk for HFpEF was higher in nonblacks than blacks (11.2% versus 7.7%), whereas that for HFrEF was similar across the 2 groups. Among participants with antecedent myocardial infarction before HF diagnosis, the remaining lifetime risks for HFpEF and HFrEF were up to 2.5-fold and 4-fold higher, respectively, compared with those without antecedent myocardial infarction.ConclusionsLifetime risks for HFpEF and HFrEF vary by sex, race, and history of antecedent myocardial infarction. These insights into the distribution of HF risk and its subtypes could inform the development of targeted strategies to improve population-level HF prevention and control.

Project description:BackgroundMicrovascular dysfunction plays an important role in the pathogenesis of heart failure with preserved ejection fraction (HFpEF). However, no mechanistic link between systemic microvasculature and congestion, a central feature of the syndrome, has yet been investigated.ObjectivesThis study aimed to investigate capillary-interstitium fluid exchange in HFpEF, including lymphatic drainage and the potential osmotic forces exerted by any hypertonic tissue Na+ excess.MethodsPatients with HFpEF and healthy control subjects of similar age and sex distributions (n = 16 per group) underwent: 1) a skin biopsy for vascular immunohistochemistry, gene expression, and chemical (water, Na+, and K+) analyses; and 2) venous occlusion plethysmography to assess peripheral microvascular filtration coefficient (measuring capillary fluid extravasation) and isovolumetric pressure (above which lymphatic drainage cannot compensate for fluid extravasation).ResultsSkin biopsies in patients with HFpEF showed rarefaction of small blood and lymphatic vessels (p = 0.003 and p = 0.012, respectively); residual skin lymphatics showed a larger diameter (p = 0.007) and lower expression of lymphatic differentiation and function markers (LYVE-1 [lymphatic vessel endothelial hyaluronan receptor 1]: p < 0.05; PROX-1 [prospero homeobox protein 1]: p < 0.001) compared with control subjects. In patients with HFpEF, microvascular filtration coefficient was lower (calf: 3.30 [interquartile range (IQR): 2.33 to 3.88] l × 100 ml of tissue-1 × min-1 × mm Hg-1 vs. 4.66 [IQR: 3.70 to 6.15] μl × 100 ml of tissue-1 × min-1 × mm Hg-1; p < 0.01; forearm: 5.16 [IQR: 3.86 to 5.43] l × 100 ml of tissue-1 × min-1 × mm Hg-1 vs. 5.66 [IQR: 4.69 to 8.38] μl × 100 ml of tissue-1 × min-1 × mm Hg-1; p > 0.05), in keeping with blood vascular rarefaction and the lack of any observed hypertonic skin Na+ excess, but the lymphatic drainage was impaired (isovolumetric pressure in patients with HFpEF vs. control subjects: calf 16 ± 4 mm Hg vs. 22 ± 4 mm Hg; p < 0.005; forearm 17 ± 4 mm Hg vs. 25 ± 5 mm Hg; p < 0.001).ConclusionsPeripheral lymphatic vessels in patients with HFpEF exhibit structural and molecular alterations and cannot effectively compensate for fluid extravasation and interstitial accumulation by commensurate drainage. Reduced lymphatic reserve may represent a novel therapeutic target.

Project description:INTRODUCTION:The pathophysiology of heart failure with preserved ejection fraction (HFpEF) remains incompletely defined. We aimed to characterize HFpEF compared to heart failure with reduced ejection fraction (HFrEF) and asymptomatic hypertensive or non-hypertensive controls. MATERIALS AND METHODS:Prospective, observational study of 234 subjects (HFpEF n = 140; HFrEF n = 46, controls n = 48, age 73±8, males 49%) who underwent echocardiography, cardiovascular magnetic resonance imaging (CMR), plasma biomarker analysis (panel of 22) and 6-minute walk testing (6MWT). The primary end-point was the composite of all-cause mortality and/or HF hospitalization. RESULTS:Compared to controls both HF groups had lower exercise capacity, lower left ventricular (LV) EF, higher LV filling pressures (E/E', B-type natriuretic peptide [BNP], left atrial [LA] volumes), more right ventricular (RV) systolic dysfunction, more focal and diffuse fibrosis and higher levels of all plasma markers. LV remodeling (mass/volume) was different between HFpEF (concentric, 0.68±0.16) and HFrEF (eccentric, 0.47±0.15); p<0.0001. Compared to controls, HFpEF was characterized by (mild) reductions in LVEF, more myocardial fibrosis, LA remodeling/dysfunction and RV dysfunction. HFrEF patients had lower LVEF, increased LV volumes, greater burden of focal and diffuse fibrosis, more RV remodeling, lower LAEF and higher LA volumes compared to HFpEF. Inflammatory/fibrotic/renal dysfunction plasma markers were similarly elevated in both HF groups but markers of cardiomyocyte stretch/damage (BNP, pro-BNP, N-terminal pro-atrial natriuretic peptide and troponin-I) were higher in HFrEF compared to HFpEF; p<0.0001. Focal fibrosis was associated with galectin3, GDF-15, MMP-3, MMP-7, MMP-8, BNP, pro-BNP and NTproANP; p<0.05. Diffuse fibrosis was associated with GDF-15, Tenascin-C, MMP-2, MMP-3, MMP-7, BNP, proBNP and NTproANP; p<0.05. Composite event rates (median 1446 days follow-up) did not differ between HFpEF and HFrEF (Log-Rank p = 0.784). CONCLUSIONS:HFpEF is a distinct pathophysiological entity compared to age- and sex-matched HFrEF and controls. HFpEF and HFrEF are associated with similar adverse outcomes. Inflammation is common in both HF phenotypes but cardiomyocyte stretch/stress is greater in HFrEF.

Dataset Information

Baroreflex activation therapy: a new approach to the management of advanced heart failure with reduced ejection fraction.

Publications

Baroreflex activation therapy: a new approach to the management of advanced heart failure with reduced ejection fraction.

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