Vascular Biology and Hypertension

Dr Gavin Lambert
Head, Human Neurotransmitters
gavin.lambert@bakeridi.edu.au

Laboratory Research Overview

Cardiovascular neuroscience in several guises remains the focus of Gavin's team. Broadly speaking his group works on projects associated with four research themes: obesity, orthostatic intolerance (fainting), the link between stress and heart disease and, in conjunction with A/Prof Markus Schlaich, hypertension. They focus principally on the sympathetic nervous system, with a particular emphasis on neuronal activity, brain function and end organ consequences of sympathetic nervous activation.

In addition to the groundbreaking work on depression and heart disease conducted with Prof Murray Esler, Gavin's lab is investigating the way that obesity contributes to raised blood pressure. While it is well known that an excess of body fat distributed around the abdomen increases the risk of heart disease, the precise reasons for this are not yet understood. High cholesterol, high blood pressure and high blood sugar levels are all commonly found in overweight and obese people and this cluster of symptoms, referred to as "metabolic syndrome", significantly increases the risk of heart attack and the development of diabetes.

Research conducted by Gavin's team suggests that an important link between heart disease and body fat might be due to an overactive sympathetic nervous system. The sympathetic nervous system is associated with the body's response to stress and in an active state the stress hormone noradrenaline is released, which raises blood pressure. Studies conducted on overweight and obese volunteers have shown that weight loss and exercise not only improved every symptom of metabolic syndrome but also resulted in a significant reduction in the release of noradrenaline. Importantly, a recent study in young overweight subjects clearly indicated that the sympathetic excitation associated with excess weight was associated with subclinical damage to the kidneys, heart and blood vessels. Research is continuing into whether the modifying sympathetic nervous system activity in these individuals redresses the march towards organ damage.

Research Focus

• Obesity
• Depression and the heart
• Orthostatic intolerance
• Mechanisms of cardiac risk in panic disorder

Research Projects

The impact of overweight and obesity in young adults

Group leader: Dr Elisabeth Lambert

Excess weight is established as a major risk factor for cardiovascular diseases (CVD) particularly in young individuals. To get a better understanding of the pathophysiology underlying increased CVD risk, we evaluated early signs of organ damage and their possible relationship to the sympathetic nervous activity (SNA).We comprehensively assessed subclinical target organ damage including:

1. assessment of renal function,
2. left ventricular structure and systolic and diastolic function, and
3. endothelial function.

Muscle SNA (MSNA) was assessed by microneurography. Participants with excess weight had decreased endothelial function, elevated creatinine clearance, increased left ventricular mass index and left ventricular wall thickness, lower systolic and diastolic function and elevated MSNA compared to lean individuals. In multiple regression analysis, endothelial function was inversely related to MSNA, while creatinine clearance and left ventricular mass index were positively related to MSNA, after adjustment for BMI, sex and blood pressure.

This study demonstrated that excess weight in young individuals is associated with subclinical alterations in renal, endothelial function as well as in the structure of the heart, even in the absence of hypertension. Elevated sympathetic activity appears to be a major driver of cardiovascular and renal alterations observed in these subjects. The consequences of elevated SNA may, in part, explain the increased CVD risk in young individuals with excess weight. Ongoing studies are focused on the targeted reduction of the SNS in order to reverse the march towards clinical end organ disease.

A longitudinal assessment of the effect of substantial and sustained weight loss on blood pressure and target organ damage in obese subjects

Group leader: Associate Professor John Dixon

High blood pressure (hypertension) is commonly found among obese people, with more that 50% of the disease burden of hypertension attributed to overweight and obesity. Hypertension is a fundamental risk factor for cardiovascular diseases. There is a range of ways that obesity may generate raised blood pressure but the exact mechanisms are poorly understood. The precise effects of weight loss on blood pressure in the short and long term are also yet to be fully described.

We are currently in the process of recruiting over 200 obese patients who have chosen to undergo Laparoscopic Adjustable Gastric Banding (LAGB) surgery for weight loss and who are not currently using any antihypertensive therapies in order to carefully examine a range of clinical factors associated with their blood pressure, metabolic, cardiovascular, renal and psychological health and follow their progress over a two-year period as weight is lost. A range of surveys and clinical tests will be employed, including fasting blood samples, urine samples, echocardiography, ECG, non-invasive endothelial function and muscle sympathetic nerve activity recording, body composition scanning, 24-hour blood pressure and overnight sleep monitoring. Through a cross-sectional analysis of patients' baseline characteristics and longitudinal assessment of changes over two years with weight loss, we hope to gain valuable knowledge about the relationship between obesity and hypertension, to define the characteristics that place some obese patients at high risk of hypertension and the characteristics that predict a positive response to weight loss in terms of improvements in blood pressure.

Sympathetic neural responsiveness in metabolic syndrome obesity: inter-relationships with insulin resistance and cortisol

Group leader: Dr Nora Straznicky

Metabolic syndrome (MetS) obesity is an increasingly prevalent multidimensional risk factor for type 2 diabetes and cardiovascular disease. Neuroadrenergic abnormalities, comprising increased resting sympathetic nervous system (SNS) activity and blunted sympathetic neural responsiveness are recognized features of this condition which contribute importantly to both its pathophysiology and adverse clinical prognosis. The thermic effect of food is defined as the increase in resting metabolic rate after ingestion of a meal. In healthy lean persons approximately one third of the thermic effect of food is mediated by the meal-induced increment in SNS activity (facultative thermogenesis) and accounts for 3-4% (50-120 calories per day) of daily energy expenditure. Blunted nutritional sympathetic and thermogenic responsiveness are recognized characteristics of MetS obesity which may play a role in the development and/or maintenance of the obese state.

In this project we are examining whether treatments that specifically target peripheral and central insulin resistance, enhance sympathetic and thermogenic responsiveness in this clinical setting. Efforts to delineate the mechanisms of sympathetic dysfunction and its therapeutic modification are relevant to the prevention of type 2 diabetes and cardiovascular disease in this high risk obese phenotype. Our overarching hypothesis is that improvement in insulin sensitivity in peripheral tissues and the brain will be accompanied by a reversal of blunted nutritional SNS responsiveness and increased facultative thermogenesis in obese insulin resistant MetS subjects.

Depression and the heart - mechanisms of cardiac risk

Group leader: Associate Professor David Barton

There is strong evidence that patients with major depressive disorder (MDD) are at increased risk of developing coronary heart disease. While the mechanism of increased cardiac risk attributable to MDD at this stage is not known, recent work by us, and others, implicates brain serotonin, serotonin transporter genotype (5-HTT) and the sympathetic nervous system as possible candidates involved in generating increased risk.

Using high internal jugular vein blood sampling we demonstrated that brain serotonin turnover was elevated in patients with MDD and was influenced by the 5-HTT genotype, with carriage of the short allele being associated with an over 2-fold increase in brain serotonin turnover. In parallel, using direct cardiac catheterization techniques we also showed that whole body and cardiac sympathetic nervous activity in patients with MDD follows a bimodal distribution, with values in some patients being extraordinarily high and others being marginally lower than those found in healthy subjects. Further analysis indicated a link between carriage of the short allele of the 5-HTT gene and elevated sympathetic nervous activity in MDD. While at this stage MDD patients with high sympathetic activity do not present with any evidence of current clinical cardiac disease, we, and others, have provided a growing body of evidence linking elevated sympathetic activity and exaggerated sympathetic responses to stress to early stages of end organ dysfunction and markers of disease development. Of particular note is the association of chronic sympathetic nervous activation to:

1. the development of left ventricular hypertrophy (LVH) and diastolic dysfunction,
2. abnormal blood pressure regulation, and
3. the development of insulin resistance.

In this project we will determine the physiological consequences of sympathetic activation in patients with MDD.

Understanding Fontan Physiology

Group leader: Dr Gavin Lambert

Since its conception in 1971, the Fontan procedure has been used as the final stage of palliation for all children born with congenital heart disease who could not be offered a two-ventricle repair. This procedure comprises the redirecting of the systemic veins to drain directly into the pulmonary arteries, without passing through the heart. While patient selection and improved surgical techniques have improved survival, Fontan patients do develop heart failure and left ventricular dysfunction. Heart transplantation is the ultimate and only definitive treatment for Fontan failure. The mechanisms underpinning Fontan failure remain poorly understood, thereby making therapy difficult to optimise.

In this study, conducted in collaboration with Yves d'Udekem and Michael Chang of the Royal Children's' Hospital, we are examining sympathetic nervous system function in Fontan patients using direct nerve recording techniques. The study aims to determine the relationship between elevated sympathetic activity in Fontan patients and:

1. the presence and degree of diastolic dysfunction,
2. endothelial function, and
3. arterial compliance.

Knowledge of the mechanisms at play in Fontan patients may pave the way for the development of new therapies in order to improve morbidity and mortality in this vulnerable patient group.

Sympathetic activation in polycystic ovary disease - a target for therapy?

Group leader: Dr Gavin Lambert

Polycystic ovary syndrome (PCOS) affects approximately 10% of women of reproductive age, rendering it a major public health issue. Women suffering from PCOS not only experience despair and dejection, but they are also at increased risk of developing cardiovascular disease through hyperinsulinemia, insulin resistance and abdominal obesity, which are metabolic abnormalities often observed in the syndrome. The etiology of PCOS remains unknown, although the metabolic and hemodynamic profile suggests some involvement of the sympathetic nervous system.

We aim to elucidate the role of the sympathetic nervous system in the etiology of PCOS, and to examine the effect of the centrally-acting sympatholytic, moxonidine, on sympathetic nervous activation and the downstream metabolic abnormalities that are regularly observed in women with PCOS. We anticipate that moxonidine treatment will decrease sympathetic nervous system activity and have a beneficial effect on downstream metabolic abnormalities. We will achieve this by conducting a double-blind, placebo-controlled, cross-over trial in 25 women of reproductive age who suffer from PCOS. Treatment will be for a duration of three months, with a two-week wash-out period between phases. Sympathetic activity will be assessed using the technique of muscle sympathetic nerve activity, and we will also examine anthropometric measures, endothelial function as assessed by EndoPat, ambulatory blood pressure and glucose tolerance test; all downstream abnormalities that can result from elevated activation of the sympathetic nervous system.

Lab Head Profile

Dr Lambert is a neurochemist/clinical research scientist with over 20 years experience in medical research. He has worked previously in Sweden and France, has ongoing national and international collaborations and is the author of more than 200 scientific publications and has an H index over 40. He has made contributions to the understanding of brain neurotransmitter function in a variety of clinical conditions including hypertension, cardiac failure, obesity and, more recently, panic disorder and depressive illness.

Publication Highlights

• Lambert EA, Ika Sari C, Dawood T, Nguyen J, McGrane M, Eikelis E, Chopra R, Wong C, Chatzivlastou K, Head G, Straznicky N, Esler MD, Schlaich MP, Lambert GW. Sympathetic nervous system activity is associated with obesity-induced subclinical organ damage in young adults. Hypertension 2010;56:351-358.
• Straznicky NE, Lambert EA, Nestel PJ, McGrane MT, Dawood T, Schlaich MP, Masuo K, Eikelis N, de Courten B, Esler MD, Socratous F, Chopra R, Ika Sari C, Paul E, Lambert GW. Sympathetic neural adaptation to hypocaloric diet with or without exercise training in obese metabolic syndrome subjects. Diabetes 2010;59(1):71-79.
• Barton DA, Esler MD, Dawood T, Lambert EA, Haikerwal D, Brenchley C, Socratous F, Hastings J, Guo L, Wiesner G, Kaye DM, Bayles R, Schlaich MP, Lambert GW. Elevated brain serotonin turnover in patients with depression: Effect of genotype and therapy. Archives of General Psychiatry 2008;65(1):38-46.
• Dawood T, Anderson J, Barton D, Lambert E, Esler M, Hotchkin E, Haikerwal D, Kaye, D, Lambert G. Reduced overflow of BDNF from the brain is linked with suicide risk in depressive illness. Molecular Psychiatry 2007;12(11):981-983.
• Lambert GW, Reid C, Kaye DM, Jennings GL, Esler MD. Effect of sunlight and season on serotonin turnover in the brain. Lancet 2002;360:1840-1842.

Staff

Contact

Direct: +613 8532 1346
Email: gavin.lambert@bakeridi.edu.au