Baroreflex Activation Therapy for the Treatment of Heart Failure With a Reduced Ejection Fraction

AbstractObjectivesThe objective of this clinical trial was to assess the safety and efficacy of carotid BAT in advanced HF.BackgroundIncreased sympathetic and decreased parasympathetic activity contribute to heart failure (HF) symptoms and disease progression. Baroreflex activation therapy (BAT) results in centrally mediated reduction of sympathetic outflow and increased parasympathetic activity.MethodsPatients with New York Heart Association (NYHA) functional class III HF and ejection fractions ≤35% on chronic stable guideline-directed medical therapy (GDMT) were enrolled at 45 centers in the United States, Canada, and Europe. They were randomly assigned to receive ongoing GDMT alone (control group) or ongoing GDMT plus BAT (treatment group) for 6 months. The primary safety end point was system- and procedure-related major adverse neurological and cardiovascular events. The primary efficacy end points were changes in NYHA functional class, quality-of-life score, and 6-minute hall walk distance.ResultsOne hundred forty-six patients were randomized, 70 to control and 76 to treatment. The major adverse neurological and cardiovascular event–free rate was 97.2% (lower 95% confidence bound 91.4%). Patients assigned to BAT, compared with control group patients, experienced improvements in the distance walked in 6 min (59.6 ± 14 m vs. 1.5 ± 13.2 m; p = 0.004), quality-of-life score (–17.4 ± 2.8 points vs. 2.1 ± 3.1 points; p < 0.001), and NYHA functional class ranking (p = 0.002 for change in distribution). BAT significantly reduced N-terminal pro–brain natriuretic peptide (p = 0.02) and was associated with a trend toward fewer days hospitalized for HF (p = 0.08).ConclusionsBAT is safe and improves functional status, quality of life, exercise capacity, N-terminal pro–brain natriuretic peptide, and possibly the burden of heart failure hospitalizations in patients with GDMT-treated NYHA functional class III HF. (Barostim Neo System in the Treatment of Heart Failure; NCT01471860; Barostim HOPE4HF [Hope for Heart Failure] Study; NCT01720160

Transforming Growth Factor β1 Oppositely Regulates the Hypertrophic and Contractile Response to β-Adrenergic Stimulation in the Heart

BACKGROUND: Neuroendocrine activation and local mediators such as transforming growth factor-β₁ (TGF-β₁) contribute to the pathobiology of cardiac hypertrophy and failure, but the underlying mechanisms are incompletely understood. We aimed to characterize the functional network involving TGF-β₁, the renin-angiotensin system, and the β-adrenergic system in the heart. METHODS: Transgenic mice overexpressing TGF-β₁ (TGF-β₁-Tg) were treated with a β-blocker, an AT₁-receptor antagonist, or a TGF-β-antagonist (sTGFβR-Fc), were morphologically characterized. Contractile function was assessed by dobutamine stress echocardiography in vivo and isolated myocytes in vitro. Functional alterations were related to regulators of cardiac energy metabolism. RESULTS: Compared to wild-type controls, TGF-β₁-Tg mice displayed an increased heart-to-body-weight ratio involving both fibrosis and myocyte hypertrophy. TGF-β₁ overexpression increased the hypertrophic responsiveness to β-adrenergic stimulation. In contrast, the inotropic response to β-adrenergic stimulation was diminished in TGF-β₁-Tg mice, albeit unchanged basal contractility. Treatment with sTGF-βR-Fc completely prevented the cardiac phenotype in transgenic mice. Chronic β-blocker treatment also prevented hypertrophy and ANF induction by isoprenaline, and restored the inotropic response to β-adrenergic stimulation without affecting TGF-β₁ levels, whereas AT₁-receptor blockade had no effect. The impaired contractile reserve in TGF-β₁-Tg mice was accompanied by an upregulation of mitochondrial uncoupling proteins (UCPs) which was reversed by β-adrenoceptor blockade. UCP-inhibition restored the contractile response to β-adrenoceptor stimulation in vitro and in vivo. Finally, cardiac TGF-β₁ and UCP expression were elevated in heart failure in humans, and UCP--but not TGF-β₁--was downregulated by β-blocker treatment. CONCLUSIONS: Our data support the concept that TGF-β₁ acts downstream of angiotensin II in cardiomyocytes, and furthermore, highlight the critical role of the β-adrenergic system in TGF-β₁-induced cardiac phenotype. Our data indicate for the first time, that TGF-β₁ directly influences mitochondrial energy metabolism by regulating UCP3 expression. β-blockers may act beneficially by normalizing regulatory mechanisms of cellular hypertrophy and energy metabolism

Endothelial progenitor cells and integrins: adhesive needs

In the last decade there have been multiple studies concerning the contribution of endothelial progenitor cells (EPCs) to new vessel formation in different physiological and pathological settings. The process by which EPCs contribute to new vessel formation in adults is termed postnatal vasculogenesis and occurs via four inter-related steps. They must respond to chemoattractant signals and mobilize from the bone marrow to the peripheral blood; home in on sites of new vessel formation; invade and migrate at the same sites; and differentiate into mature endothelial cells (ECs) and/or regulate pre-existing ECs via paracrine or juxtacrine signals. During these four steps, EPCs interact with different physiological compartments, namely bone marrow, peripheral blood, blood vessels and homing tissues. The success of each step depends on the ability of EPCs to interact, adapt and respond to multiple molecular cues. The present review summarizes the interactions between integrins expressed by EPCs and their ligands: extracellular matrix components and cell surface proteins present at sites of postnatal vasculogenesis. The data summarized here indicate that integrins represent a major molecular determinant of EPC function, with different integrin subunits regulating different steps of EPC biology. Specifically, integrin α4β1 is a key regulator of EPC retention and/or mobilization from the bone marrow, while integrins α5β1, α6β1, αvβ3 and αvβ5 are major determinants of EPC homing, invasion, differentiation and paracrine factor production. β2 integrins are the major regulators of EPC transendothelial migration. The relevance of integrins in EPC biology is also demonstrated by many studies that use extracellular matrix-based scaffolds as a clinical tool to improve the vasculogenic functions of EPCs. We propose that targeted and tissue-specific manipulation of EPC integrin-mediated interactions may be crucial to further improve the usage of this cell population as a relevant clinical agent

Association between high-density lipoprotein-cholesterol and hypertension in relation to circulating CD34-positive cell levels

Background: Although high-density lipoprotein-cholesterol (HDL) level is inversely correlated with cardiovascular events, HDL is also reported to be positively associated with hypertension, which is a known endothelial impairment factor. Since HDL mediates important protective actions on the vascular endothelium by increasing the number of circulating endothelial progenitor cells (CD34-positive cells), the level of circulating CD34-positive cells should influence the association between HDL and hypertension. Methods: To investigate the association between HDL and hypertension in relation to the level of circulating CD34-positive cells, we conducted a cross-sectional study of 477 elderly men aged 60?69 years who participated in general health checkup. Results: HDL was found to be significantly positively associated with hypertension in subjects with a high level of circulating CD34-positive cells, while no significant association was observed for subjects with low circulating CD34-positive cells. Known cardiovascular risk factors adjusted odds (ORs) and 95% confidence intervals (CIs) of hypertension for increments of one standard deviation (SD) in HDL (13.8 mg/dL) were 1.44 (1.06, 1.96) for subjects with a high level of circulating CD34-positive cells and 0.87 (0.63, 1.19) for subjects with low circulating CD34-positive cells. We also revealed a significant association between HDL level and CD34-positive cell level on hypertension, with fully adjusted p values for the effect of this interaction on hypertension at 0.022. Conclusions: Independent of known cardiovascular risk factors, HDL was found to be positively associated with hypertension in subjects with a high level of circulating CD34-positive cells but not for subjects with low circulating CD34-positive cells