Chim Lang - Academia.edu (original) (raw)

Papers by Chim Lang

The health burden of Heart Failure with Preserved Ejection Fraction (HFpEF) is substantial. In so... more The health burden of Heart Failure with Preserved Ejection Fraction (HFpEF) is substantial. In some countries, HFpEF is the leading cause of hospital admission in patients over 65 years of age and is predicted to be the leading cause of mortality within a decade [1,2]. HFpEF is characterised by reduced exercise capacity and ability to engage in activities of daily living, poor HealthRelated Quality of Life (HRQoL), high rates of hospitalisation, and premature mortality [3]. In sharp contrast to the wealth of proven therapies for Heart Failure with Reduced Ejection Fraction (HFrEF) that have improved mortality and morbidity, there is a distinct lack of treatment options for HFpEF. Drugs or devices which are recommended in current HF treatment guidelines to improve outcomes in HFrEF have not been shown to have similar benefit in HFpEF patients, and to date, phase III randomised controlled trials have not consistently yielded evidence-based therapy for HFpEF [4]. The lack of treatment ...

Diseases, 2021

Coronavirus disease 2019 (COVID-19) has been reported to cause cardiovascular complications such ... more Coronavirus disease 2019 (COVID-19) has been reported to cause cardiovascular complications such as myocardial injury, thromboembolic events, arrhythmia, and heart failure. Multiple mechanisms—some overlapping, notably the role of inflammation and IL-6—potentially underlie these complications. The reported cardiac injury may be a result of direct viral invasion of cardiomyocytes with consequent unopposed effects of angiotensin II, increased metabolic demand, immune activation, or microvascular dysfunction. Thromboembolic events have been widely reported in both the venous and arterial systems that have attracted intense interest in the underlying mechanisms. These could potentially be due to endothelial dysfunction secondary to direct viral invasion or inflammation. Additionally, thromboembolic events may also be a consequence of an attempt by the immune system to contain the infection through immunothrombosis and neutrophil extracellular traps. Cardiac arrhythmias have also been re...

Cardiovascular Research, 2020

Aims Elderly patients with heart failure with reduced ejection fraction (HFrEF) have worse progn... more Aims Elderly patients with heart failure with reduced ejection fraction (HFrEF) have worse prognosis and less often receive guideline-recommended therapies. We aim to better understand the underlying pathophysiological processes associated with ageing in HFrEF potentially leading to targeted therapies in this vulnerable population. Methods and results From a panel of 363 cardiovascular biomarkers available in 1611 patients with HFrEF in the BIOSTAT-CHF index cohort and cross-validated in 823 patients in the BIOSTAT-CHF validation cohort, we tested which biomarkers were dysregulated in patients aged >75 vs. <65 years. Second, pathway overrepresentation analyses were performed to identify biological pathways linked to higher plasma concentrations of biomarkers in elderly vs. younger patients. After adjustment, multiple test correction [false discovery rate (FDR) 1%], and cross-validation, 27/363 biomarkers were associated with older age, 22 positively and 5 negatively. The bio...

Diabetes Care, 2020

OBJECTIVE To determine the effects of dapagliflozin in patients with heart failure (HF) and type ... more OBJECTIVE To determine the effects of dapagliflozin in patients with heart failure (HF) and type 2 diabetes mellitus (T2DM) on left ventricular (LV) remodeling using cardiac MRI. RESEARCH DESIGN AND METHODS We randomized 56 patients with T2DM and HF with LV systolic dysfunction to dapagliflozin 10 mg daily or placebo for 1 year, on top of usual therapy. The primary end point was difference in LV end-systolic volume (LVESV) using cardiac MRI. Key secondary end points included other measures of LV remodeling and clinical and biochemical parameters. RESULTS In our cohort, dapagliflozin had no effect on LVESV or any other parameter of LV remodeling. However, it reduced diastolic blood pressure and loop diuretic requirements while increasing hemoglobin, hematocrit, and ketone bodies. There was a trend toward lower weight. CONCLUSIONS We were unable to determine with certainty whether dapagliflozin in patients with T2DM and HF had any effect on LV remodeling. Whether the benefits of dapag...

European Journal of Heart Failure, 2019

AimsSevere deficiency of the essential trace element selenium can cause myocardial dysfunction al... more AimsSevere deficiency of the essential trace element selenium can cause myocardial dysfunction although the mechanism at cellular level is uncertain. Whether, in clinical practice, moderate selenium deficiency is associated with worse symptoms and outcome in patients with heart failure is unknown.Methods and resultsBIOSTAT‐CHF is a multinational, prospective, observational cohort study that enrolled patients with worsening heart failure. Serum concentrations of selenium were measured by inductively coupled plasma mass spectrometry. Primary endpoint was a composite of all‐cause mortality and hospitalization for heart failure; secondary endpoint was all‐cause mortality. To investigate potential mechanisms by which selenium deficiency might affect prognosis, human cardiomyocytes were cultured in absence of selenium, and mitochondrial function and oxidative stress were assessed. Serum selenium concentration (deficiency) was <70 μg/L in 485 (20.4%) patients, who were older, more often...

European Heart Journal, 2019

Aim We tested the hypothesis that metformin may regress left ventricular hypertrophy (LVH) in pat... more Aim We tested the hypothesis that metformin may regress left ventricular hypertrophy (LVH) in patients who have coronary artery disease (CAD), with insulin resistance (IR) and/or pre-diabetes. Methods and results We randomly assigned 68 patients (mean age 65 ± 8 years) without diabetes who have CAD with IR and/or pre-diabetes to receive either metformin XL (2000 mg daily dose) or placebo for 12 months. Primary endpoint was change in left ventricular mass indexed to height1.7 (LVMI), assessed by magnetic resonance imaging. In the modified intention-to-treat analysis (n = 63), metformin treatment significantly reduced LVMI compared with placebo group (absolute mean difference −1.37 (95% confidence interval: −2.63 to −0.12, P = 0.033). Metformin also significantly reduced other secondary study endpoints such as: LVM (P = 0.032), body weight (P = 0.001), subcutaneous adipose tissue (P = 0.024), office systolic blood pressure (BP, P = 0.022) and concentration of thiobarbituric acid react...

$Research paper thumbnail of Prognostic significance of changes in heart rate following uptitration of beta-blockers in patients with sub-optimally treated heart failure with reduced ejection fraction in sinus rhythm versus atrial fibrillation$

Clinical Research in Cardiology, 2019

Background In patients with heart failure with reduced ejection fraction (HFrEF) on sub-optimal d... more Background In patients with heart failure with reduced ejection fraction (HFrEF) on sub-optimal doses of beta-blockers, it is conceivable that changes in heart rate following treatment intensification might be important regardless of underlying heart rhythm. We aimed to compare the prognostic significance of both achieved heart rate and change in heart rate following beta-blocker uptitration in patients with HFrEF either in sinus rhythm (SR) or atrial fibrillation (AF). Methods We performed a post hoc analysis of the BIOSTAT-CHF study. We evaluated 1548 patients with HFrEF (mean age 67 years, 35% AF). Median follow-up was 21 months. Patients were evaluated at baseline and at 9 months. The combined primary outcome was all-cause mortality and heart failure hospitalisation stratified by heart rhythm and heart rate at baseline. Results Despite similar changes in heart rate and beta-blocker dose, a decrease in heart rate at 9 months was associated with reduced incidence of the primary outcome in both SR and AF patients [HR per 10 bpm decrease-SR: 0.83 (0.75-0.91), p < 0.001; AF: 0.89 (0.81-0.98), p = 0.018], whereas the relationship was less strong for achieved heart rate in AF [HR per 10 bpm higher-SR: 1.26 (1.10-1.46), p = 0.001; AF: 1.08 (0.94-1.23), p = 0.18]. Achieved heart rate at 9 months was only prognostically significant in AF patients with high baseline heart rates (p for interaction 0.017 vs. low). Conclusions Following beta-blocker uptitration, both achieved and change in heart rate were prognostically significant regardless of starting heart rate in SR, however, they were only significant in AF patients with high baseline heart rate.

BMJ open, Jan 16, 2017

Type 2 diabetes (T2D) and heart failure (HF) are a frequent combination, where treatment options ... more Type 2 diabetes (T2D) and heart failure (HF) are a frequent combination, where treatment options remain limited. There has been increasing interest around the sodium-glucose cotransporter 2 (SGLT2) inhibitors and their use in patients with HF. Data on the effect of SGLT2 inhibitor use with diuretics are limited. We hypothesise that SGLT2 inhibition may augment the effects of loop diuretics and the benefits of SGLT2 inhibitors may extend beyond those of their metabolic (glycaemic parameters and weight loss) and haemodynamic parameters. The effects of SGLT2 inhibitors as an osmotic diuretic and on natriuresis may underlie the cardiovascular and renal benefits demonstrated in the recent EMPA-REG study. To assess the effect of SGLT2 inhibitors when used in combination with a loop diuretic, the RECEDE-CHF (Renal and Cardiovascular Effects of SGLT2 inhibition in combination with loop Diuretics in diabetic patients with Chronic Heart Failure) trial is a single-centre, randomised, double-bl...

Diseases, 2017

Despite significant improvements in morbidity and mortality with current evidence-based pharmaceu... more Despite significant improvements in morbidity and mortality with current evidence-based pharmaceutical-based treatment of heart failure (HF) over the previous decades, the burden of HF remains high. An alternative approach is currently being developed, which targets myocardial energy efficiency and the dysfunction of the cardiac mitochondria. Emerging evidence suggests that the insufficient availability of ATP to the failing myocardium can be attributed to abnormalities in the myocardial utilisation of its substrates rather than an overall lack of substrate availability. Therefore, the development of potential metabolic therapeutics has commenced including trimetazidine, ranolazine and perhexiline, as well as specific mitochondrial-targeting pharmaceuticals, such as elamipretide. Large randomised controlled trials are required to confirm the role of metabolic-modulating drugs in the treatment of heart failure, but early studies have been promising in their possible efficacy for the management of heart failure in the future.

Heart (British Cardiac Society), Oct 8, 2017

Natriuretic peptides, especially B-type natriuretic peptide (BNP), have primarily been regarded a... more Natriuretic peptides, especially B-type natriuretic peptide (BNP), have primarily been regarded as biomarkers in heart failure (HF). However, they are also possible therapeutic agents due to their potentially beneficial physiological effects. The angiotensin receptor-neprilysin inhibitor, sacubitril/valsartan, simultaneously augments the natriuretic peptide system (NPS) by inhibiting the enzyme neprilysin (NEP) and inhibits the renin-angiotensin-aldosterone system (RAAS) by blocking the angiotensin II receptor. It has been shown to improve mortality and hospitalisation outcomes in patients with HF due to left ventricular systolic dysfunction. The key advantage of sacubitril/valsartan has been perceived to be its ability to augment BNP, while its other effects have largely been overlooked. This review highlights the important effects of sacubitril/valsartan, beyond just the augmentation of BNP. First we discuss how NPS physiology differs between healthy individuals and those with HF ...

$Research paper thumbnail of Mineralocorticoid receptor antagonist pattern of use in heart failure with reduced ejection fraction: findings from BIOSTAT-CHF$

European journal of heart failure, Oct 5, 2017

Mineralocorticoid receptor antagonists (MRAs) are recommended (unless contraindicated) to all pat... more Mineralocorticoid receptor antagonists (MRAs) are recommended (unless contraindicated) to all patients with heart failure with reduced ejection fraction (HFrEF). However, MRAs are still largely underused in routine clinical practice. This study aims to describe the determinants and pattern of use of MRAs in HFrEF. BIOSTAT-CHF is a European multicentre, prospective study which enrolled patients suboptimally treated with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs) and/or beta-blockers, with the aim of optimizing guideline-based use of these agents. From the original 2516 subjects, this retrospective post hoc analysis included the 1325 patients with an indication for MRA therapy (i.e. left ventricular ejection fraction ≤35%, estimated glomerular filtration rate ≥30 mL/min/1.73 m(2) , K(+) ≤5.0 mmol/L). The mean age was 66.1 ± 12.2 years. At baseline an MRA was prescribed to 741 (56%) patients. Patients who were prescribed MRAs at baseline were you...

Pharmacogenomics, 2015

Heart failure is a common disease with high levels of morbidity and mortality. Current treatment ... more Heart failure is a common disease with high levels of morbidity and mortality. Current treatment comprises β-blockers, ACE inhibitors, aldosterone antagonists and diuretics. Variation in clinical response seen in patients begs the question of whether there is a pharmacogenetic component yet to be identified. To date, the genes most studied involve the β-1, β-2, α-2 adrenergic receptors and the renin-angiotensin-aldosterone pathway, mainly focusing on SNPs. However results have been inconsistent. Genome-wide association studies and next-generation sequencing are seen as alternative approaches to discovering genetic variations influencing drug response. Hopefully future research will lay the foundations for genotype-led drug management in these patients with the ultimate aim of improving their clinical outcome.

Vascular Health and Risk Management, 2015

Heart failure remains a major concern across the globe as life expectancies and delivery of healt... more Heart failure remains a major concern across the globe as life expectancies and delivery of health care continue to improve. There has been a dearth of new developments in heart failure therapies in the last decade until last year, with the release of the results from the PARADIGM-HF Trial heralding the arrival of a promising new class of drug, ie, the angiotensin receptor-neprilysin inhibitor. In this review, we discuss the evolution of our incremental understanding of the neurohormonal mechanisms involved in the pathophysiology of heart failure, which has led to our success in modulating its various pathways. We start by examining the renin-angiotensin-aldosterone system, followed by the challenges of modulating the natriuretic peptide system. We then delve deeper into the pharmacology and mechanisms by which angiotensin receptor-neprilysin inhibitors achieve their significant cardiovascular benefits. Finally, we also consider the potential application of this new class of drug in other areas, such as heart failure with preserved ejection fraction, hypertension, patients with renal impairment, and following myocardial infarction.

The Lancet, 2015

To provide insights into pathogenesis of disease progression and potential novel treatment target... more To provide insights into pathogenesis of disease progression and potential novel treatment targets for patients with heart failure by investigation of the plasma proteome using network analysis.

Journal of the Renin-Angiotensin-Aldosterone System, 2003

Conventional diuretic agents are very effective agents in relieving volume overload and congestiv... more Conventional diuretic agents are very effective agents in relieving volume overload and congestive symptoms in chronic heart failure (CHF). However, they are associated with activation of the renin-angiotensin system (RAS) and the sympathetic nervous system and a reduction in glomerular filtration rate, all of which have been associated with adverse outcomes in CHF. Therefore, there is an increasing interest in drugs that target the natriuretic system without neurohormonal activation and deterioration of renal function. In this review, we will discuss the underlying rationale and evidence behind currently pursued strategies that target the natriuretic system. This includes the administration of natriuretic peptides (NPs) and strategies that potentiate the NP system, such as neutral endopeptidase inhibition. We will also highlight some potentially important interactions of these strategies with drugs that target the RAS.

European Journal of Clinical Pharmacology, 1995

This study examined the effects of lisinopril on diastolic function in 12 normotensive patients (... more This study examined the effects of lisinopril on diastolic function in 12 normotensive patients (mean age 72 years) with symptomatic congestive heart failure, intact left ventricular systolic function and abnormal diastolic function secondary to ischaemic heart disease in a placebo-controlled double blind crossover study, with each treatment dosed orally for 5 continuous weeks. Compared to placebo, lisinopril significantly decreased blood pressure, increased plasma renin activity without altering heart rate or plasma norepinephrine. There was no statistically significant improvement with lisinopril in radionuclide derived peak filling rate and time to peak filling rate, in Doppler echocardiographic measurements of the ratio of peak flow velocity in early diastole to the peak flow velocity of atrial contraction (E :A ratio) and in visual analogue scales of symptoms. Thus, although angiotension converting enzyme inhibitors may have an established role in the treatment of heart failure secondary to left ventricular systolic dysfunction, its use in patients with isolated diastolic dysfunction remains unclear.

Diabetes Care, 2006

A table elsewhere in this issue shows conventional and Système International (SI) units and conve... more A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

Current Pharmaceutical Design, 2003

Physiological and pharmacological responses may be influenced by ethnicity as a result of genetic... more Physiological and pharmacological responses may be influenced by ethnicity as a result of genetic factors, environmental factors and/or their interaction. This review is divided into 2 parts. Firstly, there will be overview of ethnicity as a determinant of drug metabolism and response with reference to antihypertensive agents. The concept of ethnicity has been applied extensively to the study of hypertension especially in American blacks in whom the hypertension is more common and more aggressive. Thus, the second part of this review will then focus on examining the black-white differences in physiological responses to pharmacological challenge that may provide a link between these models and known ethnic differences in drug responses. We will discuss the hypertension studies that have examined the relative effectiveness of different classes of antihypertensive agents including several recent cardiovascular outcome trials that either have a high proportion of blacks or were conducted entirely in black subjects.

Clinical Science, 2004

Measurement of endothelial function in patients has emerged as a useful tool for cardiovascular r... more Measurement of endothelial function in patients has emerged as a useful tool for cardiovascular research. Although no gold standard for the measurement of endothelial function exists, the measurement of flow-mediated dilation in the brachial artery, assessed with Doppler ultrasonography, is the most studied method. However, the assumption that endothelial dysfunction detected in brachial arteries is a manifestation of systemic endothelial dysfunction including the coronary circulation may not be entirely valid. Brachial and myocardial circulations differ in terms of the microvascular architecture, the pattern of blood flow and vascular resistance (e.g. shunt vessels occur in the hand but not in the myocardium), their metabolic regulation, type of receptors that contribute to humoral regulation and the pathways that are activated to induce hyperaemia. In this context, measuring coronary vasomotor function may be more useful than brachial artery measures to predict and assess potentia...