Interaction between cardiac sympathetic drive and heart rate in heart failure Modulation by adrenergic receptor genotype

ObjectivesIn the present study, we aimed to evaluate the effect of adrenergic receptor polymorphisms on the response of myocardium to measured levels of cardiac adrenergic drive, and to evaluate whether polymorphisms of presynaptic adrenoceptors modified the rate of cardiac and systemic release of norepinephrine.BackgroundHeightened sympathetic activity plays an important pathophysiologic role in congestive heart failure (CHF). Recently several functionally relevant polymorphisms of the α2-, β1-, and β2-adrenoceptors have been identified, and specific genotypes have been associated with the incidence or clinical severity of CHF. These adrenoceptors are known to be located both pre-synaptically (α2and β2) and post-synaptically (β1and β2), raising the possibility that their association with clinical measures in CHF could be mediated either by modulation of the cardiac response to a given level of adrenergic drive or by altering norepinephrine release from sympathetic nerve terminals.MethodsWe determined the β1-, β2-, and α2C-adrenoceptor genotype in 60 patients with severe CHF in conjunction with measurement of cardiac and systemic sympathetic activity using the radiotracer norepinephrine spillover method.ResultsWe showed a strong relationship (r = 0.67, p < 0.001) between heart rate and the level of cardiac adrenergic drive, and heart rate for a given level of cardiac adrenergic drive was substantially greater in patients with the Arg/Arg16 β2-adrenoceptor polymorphism (p = 0.02), whereas no such relationship existed for polymorphisms of the β1-adrenoceptor. The genotype of the α2C- and β2-adrenoceptors showed no relationship to the rate of norepinephrine release from cardiac sympathetic nerves.ConclusionsFor the first time, we show that β2-adrenoceptor polymorphisms significantly influence the relationship between heart rate and cardiac adrenergic drive in CHF, but do not affect the rate of norepinephrine release from sympathetic nerve terminals

Effects of Renal Denervation on Sympathetic Activation, Blood Pressure, and Glucose Metabolism in Patients with Resistant Hypertension

Increased central sympathetic drive is a hallmark of several important clinical conditions including essential hypertension, heart failure, chronic kidney disease, and insulin resistance. Afferent signaling from the kidneys has been identified as an important contributor to elevated central sympathetic drive and increased sympathetic outflow to the kidney and other organs is crucially involved in cardiovascular control. While the resultant effects on renal hemodynamic parameters, sodium and water retention, and renin release are particularly relevant for both acute and long term regulation of blood pressure, increased sympathetic outflow to other vascular beds may facilitate further adverse consequences of sustained sympathetic activation such as insulin resistance, which is commonly associated with hypertension. Recent clinical studies using catheter-based radiofrequency ablation technology to achieve functional renal denervation in patients with resistant hypertension have identified the renal nerves as therapeutic target and have helped to further expose the sympathetic link between hypertension and insulin resistance. Initial data from two clinical trials and several smaller mechanistic clinical studies indicate that this novel approach may indeed provide a safe and effective treatment alternative for resistant hypertension and some of its adverse consequences

SUPPRESSION OF SYMPATHETIC NERVOUS FUNCTION IN LOW-RENIN ESSENTIAL HYPERTENSION

Study of general haemodynamics in 15 patients with low-renin essential hypertension showed haemodynamic and pathophysiological heterogeneity. However, there was suppression of sympathetic nervous system function in all low-renin patients, regardless of haemodynamic pattern. Subnormal sympathetic nervous activity was manifested by a low normal mean plasma-noradrenaline concentration at rest, diminished noradrenaline responsiveness to postural stimulation, and a reduced blood-pressure response to the indirectly acting sympathomimetic amine tyramine. It is proposed that the syndrome of low-renin essential hypertension is of diverse aetiology, but with secondary sympathetic nervous system underactivity as a feature common to the various forms. The low plasmarenin activity is probably an expression of defective sympathetic nervous system stimulation of renin release.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/21720/1/0000112.pd

Renal sympathetic denervation restores aortic distensibility in patients with resistant hypertension: data from a multi-center trial

Renal sympathetic denervation (RDN) is under investigation as a treatment option in patients with resistant hypertension (RH). Determinants of arterial compliance may, however, help to predict the BP response to therapy. Aortic distensibility (AD) is a well-established parameter of aortic stiffness and can reliably be obtained by CMR. This analysis sought to investigate the effects of RDN on AD and to assess the predictive value of pre-treatment AD for BP changes. We analyzed data of 65 patients with RH included in a multicenter trial. RDN was performed in all participants. A standardized CMR protocol was utilized at baseline and at 6-month follow-up. AD was determined as the change in cross-sectional aortic area per unit change in BP. Office BP decreased significantly from 173/92 ± 24/16 mmHg at baseline to 151/85 ± 24/17 mmHg (p < 0.001) 6 months after RDN. Maximum aortic areas increased from 604.7 ± 157.7 to 621.1 ± 157.3 mm2 (p = 0.011). AD improved significantly by 33% from 1.52 ± 0.82 to 2.02 ± 0.93 × 10-3 mmHg-1 (p < 0.001). Increase of AD at follow-up was significantly more pronounced in younger patients (p = 0.005) and responders to RDN (p = 0.002). Patients with high-baseline AD were significantly younger (61.4 ± 10.1 vs. 67.1 ± 8.4 years, p = 0.022). However, there was no significant correlation of baseline AD to response to RDN. AD is improved after RDN across all age groups. Importantly, these improvements appear to be unrelated to observed BP changes, suggesting that RDN may have direct effects on the central vasculature

Renal Denervation Update From the International Sympathetic Nervous System Summit:JACC State-of-the-Art Review

Three recent renal denervation studies in both drug-naïve and drug-treated hypertensive patients demonstrated a significant reduction of ambulatory blood pressure compared with respective sham control groups. Improved trial design, selection of relevant patient cohorts, and optimized interventional procedures have likely contributed to these positive findings. However, substantial variability in the blood pressure response to renal denervation can still be observed and remains a challenging and important problem. The International Sympathetic Nervous System Summit was convened to bring together experts in both experimental and clinical medicine to discuss the current evidence base, novel developments in our understanding of neural interplay, procedural aspects, monitoring of technical success, and others. Identification of relevant trends in the field and initiation of tailored and combined experimental and clinical research efforts will help to address remaining questions and provide much-needed evidence to guide clinical use of renal denervation for hypertension treatment and other potential indications

Boosting scientific publications in Africa: which IPRs protection channels matter?

This paper examines how Africa’s share in the contribution to global scientific knowledge can be boosted with existing Intellectual Property Rights (IPRs) mechanisms. The findings which broadly indicate that tight IPRs are correlated with knowledge contribution can be summarized in two main points. First, the enshrinement of IPRs laws in a country’s Constitution is a good condition for knowledge economy. Secondly, while Main IP laws, WIPO treaties and Bilateral treaties are positively correlated with scientific publications, the IPRs law channel have a negative correlation. Whereas the study remains expositional, it does however offer interesting insights into the need for IPRs in the promotion of knowledge contribution within sampled countries of the continent. Other policy implications are discussed

The Comparative Economics of Knowledge Economy in Africa: Policy Benchmarks, Syndromes and Implications

The paper complements the scarce literature on knowledge economy (KE) in Africa by comparing KE dynamics within Africa in order to assess best and worst performers based on fundamental characteristics of the continent’s development. The five dimensions of the World Bank’s knowledge economy index (KEI) are employed, notably: education, information and communication technology, innovation and, economic incentives and institutional regime. The empirical evidence is based on a five-step novel approach with data from 53 African countries for the period 1996-2010. Limitations of the beta catch-up approach are complemented with the sigma convergence strategy. Based on the determined fundamental characteristics, computed dynamic benchmarks, policy syndromes and syndrome free scenarios we establish that: Landlocked, Low-income, Conflict-affected, sub-Saharan African, Non-oil-exporting and French civil law countries are generally more predisposed to lower levels of KE whereas; English common-law, Notlandlocked, Conflict-free, North African and middle-income countries are characteristics that predispose certain nations to higher KE. Broad and specific policy implications are discussed in detail