Publications by authors named "Chim C Lang"

192 Publications

The genomics of heart failure: design and rationale of the HERMES consortium.

ESC Heart Fail 2021 Sep 3. Epub 2021 Sep 3.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Aims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure.

Methods And Results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 × 10 under an additive genetic model.

Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.
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http://dx.doi.org/10.1002/ehf2.13517DOI Listing
September 2021

Precision Medicine and Adverse Drug Reactions Related to Cardiovascular Drugs.

Diseases 2021 Aug 12;9(3). Epub 2021 Aug 12.

Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee DD1 9SY, UK.

Cardiovascular disease remains the leading global cause of death. Early intervention, with lifestyle advice alongside appropriate medical therapies, is fundamental to reduce patient mortality among high-risk individuals. For those who live with the daily challenges of cardiovascular disease, pharmacological management aims to relieve symptoms and prevent disease progression. Despite best efforts, prescription drugs are not without their adverse effects, which can cause significant patient morbidity and consequential economic burden for healthcare systems. Patients with cardiovascular diseases are often among the most vulnerable to adverse drug reactions due to multiple co-morbidities and advanced age. Examining a patient's genome to assess for variants that may alter drug efficacy and susceptibility to adverse reactions underpins pharmacogenomics. This strategy is increasingly being implemented in clinical cardiology to tailor patient therapies. The identification of specific variants associated with adverse drug effects aims to predict those at greatest risk of harm, allowing alternative therapies to be given. This review will explore current guidance available for pharmacogenomic-based prescribing as well as exploring the potential implementation of genetic risk scores to tailor treatment. The benefits of large databases and electronic health records will be discussed to help facilitate the integration of pharmacogenomics into primary care, the heartland of prescribing.
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http://dx.doi.org/10.3390/diseases9030055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396016PMC
August 2021

Mitogen and Stress-Activated Kinases 1 and 2 Mediate Endothelial Dysfunction.

Int J Mol Sci 2021 Aug 11;22(16). Epub 2021 Aug 11.

The Institute of Cardiovascular Research, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK.

Inflammation promotes endothelial dysfunction, but the underlying mechanisms remain poorly defined in vivo. Using translational vascular function testing in myocardial infarction patients, a situation where inflammation is prevalent, and knock-out (KO) mouse models we demonstrate a role for mitogen-activated-protein-kinases (MAPKs) in endothelial dysfunction. Myocardial infarction significantly lowers mitogen and stress kinase 1/2 (MSK1/2) expression in peripheral blood mononuclear cells and diminished endothelial function. To further understand the role of MSK1/2 in vascular function we developed in vivo animal models to assess vascular responses to vasoactive drugs using laser Doppler imaging. Genetic deficiency of MSK1/2 in mice increased plasma levels of pro-inflammatory cytokines and promoted endothelial dysfunction, through attenuated production of nitric oxide (NO), which were further exacerbated by cholesterol feeding. MSK1/2 are activated by toll-like receptors through MyD88. MyD88 KO mice showed preserved endothelial function and reduced plasma cytokine expression, despite significant hypercholesterolemia. MSK1/2 kinases interact with MAPK-activated proteins 2/3 (MAPKAP2/3), which limit cytokine synthesis. Cholesterol-fed MAPKAP2/3 KO mice showed reduced plasma cytokine expression and preservation of endothelial function. MSK1/2 plays a significant role in the development of endothelial dysfunction and may provide a novel target for intervention to reduce vascular inflammation. Activation of MSK1/2 could reduce pro-inflammatory responses and preserve endothelial vasodilator function before development of significant vascular disease.
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http://dx.doi.org/10.3390/ijms22168655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395442PMC
August 2021

Letter by Singh et al Regarding Article, "Effect of Empagliflozin on Left Ventricular Volumes in Patients With Type 2 Diabetes, or Prediabetes, and Heart Failure With Reduced Ejection Fraction (SUGAR-DM-HF)".

Circulation 2021 Jul 19;144(3):e38-e39. Epub 2021 Jul 19.

Division of Molecular and Clinical Medicine, University of Dundee Medical School, Scotland, United Kingdom.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.053057DOI Listing
July 2021

Effect of hypoglycaemia on measures of myocardial blood flow and myocardial injury in adults with and without type 1 diabetes: A prospective, randomised, open-label, blinded endpoint, cross-over study.

Endocrinol Diabetes Metab 2021 Jul 7;4(3):e00258. Epub 2021 May 7.

Department of Diabetes Royal Infirmary of Edinburgh Edinburgh UK.

Aims: This study examined the effect of experimentally-induced hypoglycaemia on measures of myocardial blood flow and myocardial injury in adults with, and without, type 1 diabetes.

Methods: In a prospective, randomised, open-label, blinded, endpoint cross-over study, 17 young adults with type 1 diabetes with no cardiovascular risk factors, and 10 healthy non-diabetic volunteers, underwent hyperinsulinaemic-euglycaemic (blood glucose 4.5-5.5 mmol/L) and hypoglycaemic (2.2-2.5 mmol/L) clamps. Myocardial blood flow was assessed using transthoracic echocardiography Doppler coronary flow reserve (CFR) and myocardial injury using plasma high-sensitivity cardiac troponin I (hs-cTnI) concentration.

Results: During hypoglycaemia, coronary flow reserve trended non-significantly lower in those with type 1 diabetes than in the non-diabetic participants (3.54 ± 0.47 vs. 3.89 ± 0.89). A generalised linear mixed-model analysis examined diabetes status and euglycaemia or hypoglycaemia as factors affecting CFR. No statistically significant difference in CFR was observed for diabetes status ( = .23) or between euglycaemia and hypoglycaemia ( = .31). No changes in hs-cTnI occurred during hypoglycaemia or in the recovery period ( = .86).

Conclusions: A small change in CFR was not statistically significant in this study, implying hypoglycaemia may require more than coronary vasomotor dysfunction to cause harm. Further larger studies are required to investigate this putative problem.
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http://dx.doi.org/10.1002/edm2.258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279606PMC
July 2021

COVID-19-Associated Cardiovascular Complications.

Diseases 2021 Jun 29;9(3). Epub 2021 Jun 29.

Division of Molecular & Clinical Medicine, School of Medicine, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, UK.

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 reported with a wide range of implicated contributory factors, ranging from direct viral myocardial injury, as well as other factors, including at-risk individuals with underlying inherited arrhythmia syndromes. Heart failure may also occur as a progression from cardiac injury, precipitation secondary to the initiation or withdrawal of certain drugs, or the accumulation of des-Arg-bradykinin (DABK) with excessive induction of pro-inflammatory G protein coupled receptor B (BK1). The presenting cardiovascular symptoms include chest pain, dyspnoea, and palpitations. There is currently intense interest in vaccine-induced thrombosis and in the treatment of Long COVID since many patients who have survived COVID-19 describe persisting health problems. This review will summarise the proposed physiological mechanisms of COVID-19-associated cardiovascular complications.
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http://dx.doi.org/10.3390/diseases9030047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293160PMC
June 2021

Impact of mitral regurgitation in patients with worsening heart failure: insights from BIOSTAT-CHF.

Eur J Heart Fail 2021 Jun 23. Epub 2021 Jun 23.

Institute of Cardiology, ASST Spedali Civili, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy.

Aims: Few data regarding the prevalence and prognostic impact of mitral regurgitation (MR) in patients with worsening chronic or new-onset acute heart failure (HF) are available. We investigated the role of MR in the BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF).

Methods And Results: We performed a retrospective post-hoc analysis including patients from both the index and validation BIOSTAT-CHF cohorts with data regarding MR status. The primary endpoint was a composite of all-cause death or HF hospitalization. Among 4023 patients included, 1653 patients (41.1%) had moderate-severe MR. Compared to others, patients with moderate-severe MR were more likely to have atrial fibrillation and chronic kidney disease and had larger left ventricular (LV) dimensions, lower LV ejection fraction (LVEF), worse quality of life, and higher plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP). A primary outcome event occurred in 697 patients with, compared to 836 patients without, moderate-severe MR [Kaplan-Meier 2-year estimate: 42.2% vs. 35.3%; hazard ratio (HR) 1.28; 95% confidence interval (CI) 1.16-1.41; log-rank P < 0.0001]. The association between MR and the primary endpoint remained significant after adjusting for baseline variables and the previously validated BIOSTAT-CHF risk score (adjusted HR 1.11; 95% CI 1.00-1.23; P = 0.041). Subgroup analyses showed a numerically larger impact of MR on the primary endpoint in patients with lower LVEF, larger LV end-diastolic diameter, and higher plasma NT-proBNP.

Conclusions: Moderate-severe MR is common in patients with worsening chronic or new-onset acute HF and is strongly associated with outcome, independently of other features related to HF severity.
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http://dx.doi.org/10.1002/ejhf.2276DOI Listing
June 2021

Type 2 Diabetes, Metabolic Traits, and Risk of Heart Failure: A Mendelian Randomization Study.

Diabetes Care 2021 Jun 4. Epub 2021 Jun 4.

Medical Research Council Population Health Research Unit, University of Oxford, Oxford, U.K.

Objective: The aim of this study was to use Mendelian randomization (MR) techniques to estimate the causal relationships between genetic liability to type 2 diabetes (T2D), glycemic traits, and risk of heart failure (HF).

Research Design And Methods: Summary-level data were obtained from genome-wide association studies of T2D, insulin resistance (IR), glycated hemoglobin, fasting insulin and glucose, and HF. MR was conducted using the inverse-variance weighted method. Sensitivity analyses included the MR-Egger method, weighted median and mode methods, and multivariable MR conditioning on potential mediators.

Results: Genetic liability to T2D was causally related to higher risk of HF (odds ratio [OR] 1.13 per 1-log unit higher risk of T2D; 95% CI 1.11-1.14; < 0.001); however, sensitivity analysis revealed evidence of directional pleiotropy. The relationship between T2D and HF was attenuated when adjusted for coronary disease, BMI, LDL cholesterol, and blood pressure in multivariable MR. Genetically instrumented higher IR was associated with higher risk of HF (OR 1.19 per 1-log unit higher risk of IR; 95% CI 1.00-1.41; = 0.041). There were no notable associations identified between fasting insulin, glucose, or glycated hemoglobin and risk of HF. Genetic liability to HF was causally linked to higher risk of T2D (OR 1.49; 95% CI 1.01-2.19; = 0.042), although again with evidence of pleiotropy.

Conclusions: These findings suggest a possible causal role of T2D and IR in HF etiology, although the presence of both bidirectional effects and directional pleiotropy highlights potential sources of bias that must be considered.
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http://dx.doi.org/10.2337/dc20-2518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323186PMC
June 2021

Neutrophil-to-lymphocyte ratio and outcomes in patients with new-onset or worsening heart failure with reduced and preserved ejection fraction.

ESC Heart Fail 2021 Aug 16;8(4):3168-3179. Epub 2021 May 16.

Division of Molecular and Clinical Medicine, University of Dundee, Dundee, UK.

Aims: Inflammation is thought to play a role in heart failure (HF) pathophysiology. Neutrophil-to-lymphocyte ratio (NLR) is a simple, routinely available measure of inflammation. Its relationship with other inflammatory biomarkers and its association with clinical outcomes in addition to other risk markers have not been comprehensively evaluated in HF patients.

Methods: We evaluated patients with worsening or new-onset HF from the BIOlogy Study to Tailored Treatment in Chronic Heart Failure (BIOSTAT-CHF) study who had available NLR at baseline. The primary outcome was time to all-cause mortality or HF hospitalization. Outcomes were validated in a separate HF population.

Results: 1622 patients were evaluated (including 523 ventricular ejection fraction [LVEF] < 40% and 662 LVEF ≥ 40%). NLR was significantly correlated with biomarkers related to inflammation as well as NT-proBNP. NLR was significantly associated with the primary outcome in patients irrespective of LVEF (hazard ratio [HR] 1.18 per standard deviation increase; 95% confidence interval [CI] 1.11-1.26, P < 0.001). Patients with NLR in the highest tertile had significantly worse outcome than those in the lowest independent of LVEF (<40%: HR 2.75; 95% CI 1.84-4.09, P < 0.001; LVEF ≥ 40%: HR 1.51; 95% CI 1.05-2.16, P = 0.026). When NLR was added to the BIOSTAT-CHF risk score, there were improvements in integrated discrimination index (IDI) and net reclassification index (NRI) for occurrence of the primary outcome (IDI + 0.009; 95% CI 0.00-0.019, P = 0.030; continuous NRI + 0.112, 95% CI 0.012-0.176, P = 0.040). Elevated NLR was similarly associated with adverse outcome in the validation cohort. Decrease in NLR at 6 months was associated with reduced incidence of the primary outcome (HR 0.75; 95% CI 0.57-0.98, P = 0.036).

Conclusions: Elevated NLR is significantly associated with elevated markers of inflammation in HF patients and is associated with worse outcome. Elevated NLR might potentially be useful in identifying high-risk HF patients and may represent a treatment target.
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http://dx.doi.org/10.1002/ehf2.13424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318449PMC
August 2021

Corrigendum to "Metformin: Still the sweet spot for CV protection in diabetes?" [Curr Opin Pharmacol 54 (2020) 202-208].

Curr Opin Pharmacol 2021 May 10. Epub 2021 May 10.

Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, DD1 9SY, Scotland, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.coph.2021.03.010DOI Listing
May 2021

Perceived risk profile and treatment optimization in heart failure: an analysis from BIOlogy Study to TAilored Treatment in chronic heart failure.

Clin Cardiol 2021 Jun 7;44(6):780-788. Epub 2021 May 7.

Université de Lorraine, INSERM, Centre d'Investigations Cliniques Plurithématique 1433, Inserm U1116, CHRU de Nancy and F-CRIN INI-CRCT, Nancy, France.

Background: Achieving target doses of angiotensin-converting-enzyme inhibitor/angiotensin-receptor blockers (ACEi/ARB) and beta-blockers in heart failure with reduced ejection fraction (HFrEF) is often underperformed. In BIOlogy Study to TAilored Treatment in chronic heart failure (BIOSTAT-CHF) study, many patients were not up-titrated for which no clear reason was reported. Therefore, we hypothesized that perceived-risk profile might influence treatment optimization.

Methods: We studied 2100 patients with HFrEF (LVEF≤40%) to compare the clinical characteristics and adverse events associated with treatment up-titration (after a 3-month titration protocol) between; a) patients not reaching target doses for unclear reason; b) patients not reaching target doses due to symptoms and/or side effects; c) patients reaching target doses.

Results: For ACEi/ARB, (a), (b) and (c) was observed in 51.3%, 25.9% and 22.7% of patients, respectively. For beta-blockers, (a), (b) and (c) was observed in 67.5%, 20.2% and 12.3% of patients, respectively. By multinomial logistic regression analysis for ACEi/ARB, patients in group (a) and (b) had lower blood pressure and poorer renal function, and patients in group (a) were older and had lower ejection fraction. For beta-blockers, patients in group (a) and (b) had more severe congestion and lower heart rate. At 9 months, adverse events (i.e., hypotension, bradycardia, renal impairment, and hyperkalemia) occurred similarly among the three groups.

Conclusions: Patients in whom clinicians did not give a reason why up-titration was missed were older and had more co-morbidities. Patients in whom up-titration was achieved did not have excess adverse events. However, from these observational findings, the pattern of subsequent adverse events among patients in whom up-titration was missed cannot be determined.
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http://dx.doi.org/10.1002/clc.23576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207977PMC
June 2021

Impaired High-Density Lipoprotein Function in Patients With Heart Failure.

J Am Heart Assoc 2021 05 17;10(9):e019123. Epub 2021 Apr 17.

Department of Pediatrics University of Groningen Groningen The Netherlands.

Background We recently showed that, in patients with heart failure, lower high-density lipoprotein (HDL) cholesterol concentration was a strong predictor of death or hospitalization for heart failure. In a follow-up study, we suggested that this association could be partly explained by HDL proteome composition. However, whether the emerging concept of HDL function contributes to the prognosis of patients with heart failure has not been addressed. Methods and Results We measured 3 key protective HDL function metrics, namely, cholesterol efflux, antioxidative capacity, and anti-inflammatory capacity, at baseline and after 9 months in 446 randomly selected patients with heart failure from BIOSTAT-CHF (A Systems Biology Study to Tailored Treatment in Chronic Heart Failure). Additionally, the relationship between HDL functionality and HDL proteome composition was determined in 86 patients with heart failure. From baseline to 9 months, HDL cholesterol concentrations were unchanged, but HDL cholesterol efflux and anti-inflammatory capacity declined (both <0.001). In contrast, antioxidative capacity increased (<0.001). Higher HDL cholesterol efflux was associated with lower mortality after adjusting for BIOSTAT-CHF risk models and log HDL cholesterol (hazard ratio, 0.81; 95% CI, 0.71-0.92; =0.001). Other functionality measures were not associated with outcome. Several HDL proteins correlated with HDL functionality, mainly with cholesterol efflux. Apolipoprotein A1 emerged as the main protein associated with all 3 HDL functionality measures. Conclusions Better HDL cholesterol efflux at baseline was associated with lower mortality during follow-up, independent of HDL cholesterol. HDL cholesterol efflux and anti-inflammatory capacity declined during follow-up in patients with heart failure. Measures of HDL function may provide clinical information in addition to HDL cholesterol concentration in patients with heart failure.
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http://dx.doi.org/10.1161/JAHA.120.019123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200730PMC
May 2021

Telomere length is independently associated with all-cause mortality in chronic heart failure.

Heart 2021 Mar 31. Epub 2021 Mar 31.

Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.

Objective: Patients with heart failure have shorter mean leucocyte telomere length (LTL), a marker of biological age, compared with healthy subjects, but it is unclear whether this is of prognostic significance. We therefore sought to determine whether LTL is associated with outcomes in patients with heart failure.

Methods: We measured LTL in patients with heart failure from the BIOSTAT-CHF Index (n=2260) and BIOSTAT-CHF Tayside (n=1413) cohorts. Cox proportional hazards analyses were performed individually in each cohort and the estimates combined using meta-analysis. Our co-primary endpoints were all-cause mortality and heart failure hospitalisation.

Results: In age-adjusted and sex-adjusted analyses, shorter LTL was associated with higher all-cause mortality in both cohorts individually and when combined (meta-analysis HR (per SD decrease in LTL)=1.16 (95% CI 1.08 to 1.24); p=2.66×10), an effect equivalent to that of being four years older. The association remained significant after adjustment for the BIOSTAT-CHF clinical risk score to account for known prognostic factors (HR=1.12 (95% CI 1.05 to 1.20); p=1.04×10). Shorter LTL was associated with both cardiovascular (HR=1.09 (95% CI 1.00 to 1.19); p=0.047) and non-cardiovascular deaths (HR=1.18 (95% CI 1.05 to 1.32); p=4.80×10). There was no association between LTL and heart failure hospitalisation (HR=0.99 (95% CI 0.92 to 1.07); p=0.855).

Conclusion: In patients with heart failure, shorter mean LTL is independently associated with all-cause mortality.
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http://dx.doi.org/10.1136/heartjnl-2020-318654DOI Listing
March 2021

Nicorandil-induced colovesical fistula in a patient with diverticular disease.

Clin Case Rep 2021 Mar 10;9(3):1737-1741. Epub 2021 Feb 10.

Division of Molecular & Clinical Medicine School of Medicine University of Dundee Dundee UK.

Nicorandil's adverse effects can cause severe patient morbidity and can present to any specialty. Those with underlying diverticular disease are most susceptible. Medication reviews are vital for patients presenting with ulcer or fistula symptoms.
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http://dx.doi.org/10.1002/ccr3.3888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981709PMC
March 2021

Non-adherence to heart failure medications predicts clinical outcomes: assessment in a single spot urine sample by liquid chromatography-tandem mass spectrometry (results of a prospective multicentre study).

Eur J Heart Fail 2021 07 3;23(7):1182-1190. Epub 2021 May 3.

Department of Cardiovascular Science, University of Leicester, NIHR Leicester Biomedical Research Centre, Cardiovascular Unit and University Hospitals of Leicester NHS Trust, Leicester, UK.

Aims: Liquid chromatography-mass spectrometry (LC-MS/MS) is an objective new technique to assess non-adherence to medications. We used this method to study the prevalence, predictors and outcomes of non-adherence in patients with heart failure with reduced left ventricular ejection fraction (HFrEF).

Methods And Results: This study included 1296 patients with HFrEF from BIOSTAT-CHF, a study that aimed to optimise guideline-recommended therapies. Angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists, β-blockers and loop diuretics were measured in a single spot urine sample at 9 months using LC-MS/MS. The relationship between medication non-adherence and the composite endpoint of all-cause death or heart failure hospitalisation, over a median follow-up of 21 months, was evaluated. Non-adherence to at least one prescribed medication was observed in 45.9% of patients. The strongest predictor of non-adherence was non-adherence to any of the other medication classes (P < 0.0005). Regional differences within Europe were observed. On multivariable analyses, non-adherence to ACEi/ARBs and β-blockers was associated with an increased risk of the composite endpoint [hazard ratio (HR) 1.38, 95% confidence interval (CI) 1.09-1.95, P = 0.008 and HR 1.48, 95% CI 1.12-1.96, P = 0.006, respectively). Non-adherence to β-blockers was also associated with an increased risk of death (HR 2.48, 95% CI 1.67-3.68, P < 0.0005). Patients who were non-adherent to loop diuretics were healthier and had a decreased risk of the composite endpoint (HR 0.69, 95% CI 0.51-0.93, P = 0.014). Non-adherence to mineralocorticoid receptor antagonists was not related to any clinical outcome.

Conclusion: Non-adherence to medications, assessed by a single urine test, is common and predicts clinical outcomes in patients with HFrEF.
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http://dx.doi.org/10.1002/ejhf.2160DOI Listing
July 2021

Dipeptidyl peptidase 3, a marker of the antagonist pathway of the renin-angiotensin-aldosterone system in patients with heart failure.

Eur J Heart Fail 2021 06 30;23(6):947-953. Epub 2021 Mar 30.

University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Aims: Recently, dipeptidyl peptidase 3 (DPP3) has been discovered as the peptidase responsible for cleavage of angiotensin (1-7) [Ang (1-7)]. Ang (1-7) is part of the angiotensin-converting enzyme-Ang (1-7)-Mas pathway which is considered to antagonize the renin-angiotensin-aldosterone system (RAAS). Since DPP3 inhibits the counteracting pathway of the RAAS, we hypothesize that DPP3 might be deleterious in the setting of heart failure. However, no data are available on DPP3 in chronic heart failure. We therefore investigated the clinical characteristics and outcome related to elevated DPP3 concentrations in patients with worsening heart failure.

Methods And Results: Dipeptidyl peptidase 3 was measured in 2156 serum samples of patients with worsening heart failure using luminometric immunoassay (DPP3-LIA) by 4TEEN4 Pharmaceuticals GmbH, Hennigsdorf, Germany. Predictors of DPP3 levels were selected using multiple linear regression with stepwise backward selection. Median DPP3 concentration was 11.45 ng/mL with a range from 2.8 to 84.9 ng/mL. Patients with higher DPP3 concentrations had higher renin [78.3 (interquartile range, IQR 26.3-227.7) vs. 120.7 IU/mL (IQR 34.74-338.9), P < 0.001, for Q1-3 vs. Q4] and aldosterone [88 (IQR 44-179) vs. 116 IU/mL (IQR 46-241), P < 0.001, for Q1-3 vs. Q4] concentrations. The strongest independent predictors for higher concentration of DPP3 were log-alanine aminotransferase, log-total bilirubin, the absence of diabetes, higher osteopontin, fibroblast growth factor-23 and N-terminal pro-B-type natriuretic peptide concentrations (all P < 0.001). In univariable survival analysis, DPP3 was associated with mortality and the combined endpoint of death or heart failure hospitalization (P < 0.001 for both). After adjustment for confounders, this association was no longer significant.

Conclusions: In patients with worsening heart failure, DPP3 is a marker of more severe disease with higher RAAS activity. It may be deleterious in heart failure by counteracting the Mas receptor pathway. Procizumab, a specific antibody against DPP3, might be a potential future treatment option for patients with heart failure.
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http://dx.doi.org/10.1002/ejhf.2158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359955PMC
June 2021

The value of spot urinary creatinine as a marker of muscle wasting in patients with new-onset or worsening heart failure.

J Cachexia Sarcopenia Muscle 2021 06 20;12(3):555-567. Epub 2021 Mar 20.

Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background: Muscle wasting and unintentional weight loss (cachexia) have been associated with worse outcomes in heart failure (HF), but timely identification of these adverse phenomena is difficult. Spot urinary creatinine may be an easily accessible marker to assess muscle loss and cachexia. This study investigated the association of urinary creatinine with body composition changes and outcomes in patients with new-onset or worsening HF (WHF).

Methods: In BIOSTAT-CHF, baseline spot urinary creatinine measurements were available in 2315 patients with new-onset or WHF in an international cohort (index cohort) and a validation cohort of 1431 similar patients from Scotland.

Results: Median spot urinary creatinine concentrations were 5.2 [2.7-9.6] mmol/L in the index cohort. Median age was 69 ± 12 years and 73% were men. Lower spot urinary creatinine was associated with older age, lower height and weight, worse renal function, more severe HF, and a higher risk of >5% weight loss from baseline to 9 months (odds ratio = 1.23, 95% CI = 1.09-1.39 per log decrease; P = 0.001). Spot urinary creatinine was associated with Evans criteria of cachexia (OR = 1.26 per log decrease, 95% CI = 1.04-1.49; P = 0.016) and clustered with markers of heart failure severity in hierarchical cluster analyses. Lower urinary creatinine was associated with poorer exercise capacity and quality of life (both P < 0.001) and predicted a higher rate for all-cause mortality [hazard ratio (HR) = 1.27, 95% CI = 1.17-1.38 per log decrease; P < 0.001] and the combined endpoints HF hospitalization or all-cause mortality (HR = 1.23, 95% CI = 1.15-1.31 per log decrease; P < 0.001). Significance was lost after addition of the BIOSTAT risk model. Analyses of the validation cohort yielded similar findings.

Conclusions: Lower spot urinary creatinine is associated with smaller body dimensions, renal dysfunction, and more severe HF in patients with new-onset/WHF. Additionally, lower spot urinary creatinine is associated with an increased risk of weight loss and a poorer exercise capacity/quality of life. Urinary creatinine could therefore be a novel, easily obtainable marker to assess (risk of) muscle wasting in HF patients.
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http://dx.doi.org/10.1002/jcsm.12690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200450PMC
June 2021

Quality of life in men and women with heart failure: association with outcome, and comparison between the Kansas City Cardiomyopathy Questionnaire and the EuroQol 5 dimensions questionnaire.

Eur J Heart Fail 2021 04 4;23(4):567-577. Epub 2021 May 4.

Department of Cardiology, University of Groningen, Groningen, The Netherlands.

Aims: We sought to analyse quality of life (QoL) measures derived from two questionnaires widely used in clinical trials, the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the EuroQoL 5 dimensions (EQ-5D), and to compare their prognostic value in men and women with heart failure and reduced ejection fraction (HFrEF).

Methods And Results: From the BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) we compared KCCQ and EQ-5D at baseline and after 9 months in 1276 men and 373 women with new-onset or worsening symptoms of HFrEF, who were sub-optimally treated and in whom there was an anticipated up-titration of guideline-derived medical therapies. Women had significantly worse baseline QoL (median) as compared with men, both when assessed with KCCQ overall score (KCCQ-OS, 44 vs. 53, P < 0.001) and EQ-5D utility score (0.62 vs. 0.73, P < 0.001). QoL improved equally in women and men at follow-up. All summary measures of QoL were independently associated with all-cause mortality, with KCCQ-OS showing the most remarkable association with mortality up to 1 year compared to the EQ-5D scores (C-statistic 0.650 for KCCQ-OS vs. 0.633 and 0.599 for EQ-5D utility score and EQ-5D visual analogue scale, respectively). QoL was associated with all outcomes analysed, both in men and women (all P for interaction with sex >0.2).

Conclusion: Amongst patients with HFrEF, women reported significantly worse QoL than men. QoL was independently associated with subsequent outcome, similarly in men and women. The KCCQ in general, and the KCCQ-OS in particular, showed the strongest independent association with outcome.
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http://dx.doi.org/10.1002/ejhf.2154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252457PMC
April 2021

A heart failure phenotype stratified model for predicting 1-year mortality in patients admitted with acute heart failure: results from an individual participant data meta-analysis of four prospective European cohorts.

BMC Med 2021 01 27;19(1):21. Epub 2021 Jan 27.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30.001, 9700 RB, Groningen, the Netherlands.

Background: Prognostic models developed in general cohorts with a mixture of heart failure (HF) phenotypes, though more widely applicable, are also likely to yield larger prediction errors in settings where the HF phenotypes have substantially different baseline mortality rates or different predictor-outcome associations. This study sought to use individual participant data meta-analysis to develop an HF phenotype stratified model for predicting 1-year mortality in patients admitted with acute HF.

Methods: Four prospective European cohorts were used to develop an HF phenotype stratified model. Cox model with two rounds of backward elimination was used to derive the prognostic index. Weibull model was used to obtain the baseline hazard functions. The internal-external cross-validation (IECV) approach was used to evaluate the generalizability of the developed model in terms of discrimination and calibration.

Results: 3577 acute HF patients were included, of which 2368 were classified as having HF with reduced ejection fraction (EF) (HFrEF; EF < 40%), 588 as having HF with midrange EF (HFmrEF; EF 40-49%), and 621 as having HF with preserved EF (HFpEF; EF ≥ 50%). A total of 11 readily available variables built up the prognostic index. For four of these predictor variables, namely systolic blood pressure, serum creatinine, myocardial infarction, and diabetes, the effect differed across the three HF phenotypes. With a weighted IECV-adjusted AUC of 0.79 (0.74-0.83) for HFrEF, 0.74 (0.70-0.79) for HFmrEF, and 0.74 (0.71-0.77) for HFpEF, the model showed excellent discrimination. Moreover, there was a good agreement between the average observed and predicted 1-year mortality risks, especially after recalibration of the baseline mortality risks.

Conclusions: Our HF phenotype stratified model showed excellent generalizability across four European cohorts and may provide a useful tool in HF phenotype-specific clinical decision-making.
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http://dx.doi.org/10.1186/s12916-020-01894-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839199PMC
January 2021

Use of Population-Based Health Informatics Research to Improve Care for Patients with Cardiovascular Diseases.

Diseases 2020 Dec 17;8(4). Epub 2020 Dec 17.

Division of Molecular & Clinical Medicine, School of Medicine, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, UK.

There are common clinical scenarios in chronic heart disease where no randomized controlled data exist to guide management, and it is likely that well-designed observational studies will have to be used to inform clinical practice. Showing the clinical applicability of this type of study design, using record linkage of population electronic health records, we have provided key observational evidence that use of renin-angiotensin-system (RAS) blockers is associated with better outcomes in patients with aortic stenosis and that metformin could be used safely as an antiglycemic drug in patients with diabetes and heart failure. Each of these pieces of underpinning research has made a major contribution to relevant international clinical practice guidelines, helped the Food and Drug Administration in their decision making and changed prescribing practice.
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http://dx.doi.org/10.3390/diseases8040047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768487PMC
December 2020

Is acute heart failure a distinctive disorder? An analysis from BIOSTAT-CHF.

Eur J Heart Fail 2021 01 22;23(1):43-57. Epub 2021 Jan 22.

Momentum Research, Inc., Durham, NC, USA.

Aims: This retrospective analysis sought to identify markers that might distinguish between acute heart failure (HF) and worsening HF in chronic outpatients.

Methods And Results: The BIOSTAT-CHF index cohort included 2516 patients with new or worsening HF symptoms: 1694 enrolled as inpatients (acute HF) and 822 as outpatients (worsening HF in chronic outpatients). A validation cohort included 935 inpatients and 803 outpatients. Multivariable models were developed in the index cohort using clinical characteristics, routine laboratory values, and proteomics data to examine which factors predict adverse outcomes in both conditions and to determine which factors differ between acute HF and worsening HF in chronic outpatients, validated in the validation cohort. Patients with acute HF had substantially higher morbidity and mortality (6-month mortality was 12.3% for acute HF and 4.7% for worsening HF in chronic outpatients). Multivariable models predicting 180-day mortality and 180-day HF readmission differed substantially between acute HF and worsening HF in chronic outpatients. Carbohydrate antigen 125 was the strongest single biomarker to distinguish acute HF from worsening HF in chronic outpatients, but only yielded a C-index of 0.71. A model including multiple biomarkers and clinical variables achieved a high degree of discrimination with a C-index of 0.913 in the index cohort and 0.901 in the validation cohort.

Conclusions: This study identifies different characteristics and predictors of outcome in acute HF patients as compared to outpatients with chronic HF developing worsening HF. The markers identified may be useful in better diagnosing acute HF and may become targets for treatment development.
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http://dx.doi.org/10.1002/ejhf.2077DOI Listing
January 2021

Effect of the 2017 European Guidelines on Reclassification of Severe Aortic Stenosis and Its Influence on Management Decisions for Initially Asymptomatic Aortic Stenosis.

Circ Cardiovasc Imaging 2020 12 8;13(12):e011763. Epub 2020 Dec 8.

Department of Cardiovascular Sciences, University of Leicester and Cardiovascular Theme, NIHR Leicester Biomedical Research Centre, Glenfield Hospital, United Kingdom (D.C.S.C., A.S., L.L.N., G.P.M.).

Background: The 2017 European Society of Cardiology guidelines for valvular heart disease included changes in the definition of severe aortic stenosis (AS). We wanted to evaluate its influence on management decisions in asymptomatic patients with moderate-severe AS.

Methods: We reclassified the AS severity of the participants of the PRIMID-AS study (Prognostic Importance of Microvascular Dysfunction in Asymptomatic Patients With AS), using the 2017 guidelines, determined their risk of reaching a clinical end point (valve replacement for symptoms, hospitalization, or cardiovascular death) and evaluated the prognostic value of aortic valve calcium score and biomarkers. Patients underwent echocardiography, cardiac magnetic resonance imaging, exercise tolerance testing, and biomarker assessment.

Results: Of the 174 participants, 45% (56/124) classified as severe AS were reclassified as moderate AS. This reclassified group was similar to the original moderate group in clinical characteristics, gradients, calcium scores, and remodeling parameters. There were 47 primary end points (41 valve replacement, 1 death, and 5 hospitalizations-1 chest pain, 2 dyspnea, 1 heart failure, and 1 syncope) over 368±156 days follow-up. The severe and reclassified groups had a higher risk compared with moderate group (adjusted hazard ratio 4.95 [2.02-12.13] and 2.78 [1.07-7.22], respectively), with the reclassified group demonstrating an intermediate risk. A mean pressure gradient ≥31 mm Hg had a 7× higher risk of the primary end point in the reclassified group. Aortic valve calcium score was more prognostic in females and low valve area but not after adjusting for gradients. NT-proBNP (N-terminal pro-brain-type natriuretic peptide) and myocardial perfusion reserve were associated with the primary end point but not after adjusting for positive exercise tolerance testing. Troponin was associated with cardiovascular death or unplanned hospitalizations.

Conclusions: Reclassification of asymptomatic severe AS into moderate AS was common using the European Society of Cardiology 2017 guidelines. This group had an intermediate risk of reaching the primary end point. Exercise testing, multimodality imaging, and lower mean pressure gradient threshold of 31 mm Hg may improve risk stratification. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01658345.
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http://dx.doi.org/10.1161/CIRCIMAGING.120.011763DOI Listing
December 2020

Metformin: still the sweet spot for CV protection in diabetes?

Curr Opin Pharmacol 2020 10 30;54:202-208. Epub 2020 Nov 30.

Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, DD1 9SY, Scotland, United Kingdom. Electronic address:

Metformin remains the first-line drug treatment for type 2 diabetes (T2D) in most guidelines not only because it achieves significant reduction in HbA1c but also because of a wealth of clinical experience regarding its safety and observational data that has shown that metformin use is associated with lower mortality rates when compared to sulphonylureas or insulin. Recently other diabetes drugs, particularly SGLT2 inhibitors (SGLT2i) and GLP1 receptor agonists (GLP1RA), have attracted considerable attention for their cardioprotective benefits reported in cardiovascular outcome trials (CVOTs). Randomised control trials on these newer drugs are on a larger scale but have shorter follow-up than UKPDS, the main study supporting metformin use. In a recent change to the European Society of Cardiology guidelines, metformin was replaced by SGLT2i and GLP1RA as first-line for T2D with atherosclerotic cardiovascular disease, whereas American Diabetes Association and UK-wide guidelines maintain metformin as first choice drug pharmacotherapy for all T2D. A definitive evidence-base for prioritisation of these drugs is currently missing because there are no head-to-head clinical trial data. Without such trials being forthcoming, innovative, pragmatic and low-cost 'real-world' trial approaches based on electronic health records may need to be harnessed to determine the correct priority, combinations of drugs and/or identify-specific patient populations most likely to benefit from each one.
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http://dx.doi.org/10.1016/j.coph.2020.10.018DOI Listing
October 2020

Genetic and pharmacological relationship between P-glycoprotein and increased cardiovascular risk associated with clarithromycin prescription: An epidemiological and genomic population-based cohort study in Scotland, UK.

PLoS Med 2020 11 23;17(11):e1003372. Epub 2020 Nov 23.

Division of Molecular and Clinical Medicine, University of Dundee, Dundee, United Kingdom.

Background: There are conflicting reports regarding the association of the macrolide antibiotic clarithromycin with cardiovascular (CV) events. A possible explanation may be that this risk is partly mediated through drug-drug interactions and only evident in at-risk populations. To the best of our knowledge, no studies have examined whether this association might be mediated via P-glycoprotein (P-gp), a major pathway for clarithromycin metabolism. The aim of this study was to examine CV risk following prescription of clarithromycin versus amoxicillin and in particular, the association with P-gp, a major pathway for clarithromycin metabolism.

Methods And Findings: We conducted an observational cohort study of patients prescribed clarithromycin or amoxicillin in the community in Tayside, Scotland (population approximately 400,000) between 1 January 2004 and 31 December 2014 and a genomic observational cohort study evaluating genotyped patients from the Genetics of Diabetes Audit and Research Tayside Scotland (GoDARTS) study, a longitudinal cohort study of 18,306 individuals with and without type 2 diabetes recruited between 1 December 1988 and 31 December 2015. Two single-nucleotide polymorphisms associated with P-gp activity were evaluated (rs1045642 and rs1128503 -AA genotype associated with lowest P-gp activity). The primary outcome for both analyses was CV hospitalization following prescription of clarithromycin versus amoxicillin at 0-14 days, 15-30 days, and 30 days to 1 year. In the observational cohort study, we calculated hazard ratios (HRs) adjusted for likelihood of receiving clarithromycin using inverse proportion of treatment weighting as a covariate, whereas in the pharmacogenomic study, HRs were adjusted for age, sex, history of myocardial infarction, and history of chronic obstructive pulmonary disease. The observational cohort study included 48,026 individuals with 205,227 discrete antibiotic prescribing episodes (34,074 clarithromycin, mean age 73 years, 42% male; 171,153 amoxicillin, mean age 74 years, 45% male). Clarithromycin use was significantly associated with increased risk of CV hospitalization compared with amoxicillin at both 0-14 days (HR 1.31; 95% CI 1.17-1.46, p < 0.001) and 30 days to 1 year (HR 1.13; 95% CI 1.06-1.19, p < 0.001), with the association at 0-14 days modified by use of P-gp inhibitors or substrates (interaction p-value: 0.029). In the pharmacogenomic study (13,544 individuals with 44,618 discrete prescribing episodes [37,497 amoxicillin, mean age 63 years, 56% male; 7,121 clarithromycin, mean age 66 years, 47% male]), when prescribed clarithromycin, individuals with genetically determined lower P-gp activity had a significantly increased risk of CV hospitalization at 30 days to 1 year compared with heterozygotes or those homozygous for the non-P-gp-lowering allele (rs1045642 AA: HR 1.39, 95% CI 1.20-1.60, p < 0.001, GG/GA: HR 0.99, 95% CI 0.89-1.10, p = 0.85, interaction p-value < 0.001 and rs1128503 AA 1.41, 95% CI 1.18-1.70, p < 0.001, GG/GA: HR 1.04, 95% CI 0.95-1.14, p = 0.43, interaction p-value < 0.001). The main limitation of our study is its observational nature, meaning that we are unable to definitively determine causality.

Conclusions: In this study, we observed that the increased risk of CV events with clarithromycin compared with amoxicillin was associated with an interaction with P-glycoprotein.
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http://dx.doi.org/10.1371/journal.pmed.1003372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682888PMC
November 2020

Differences in biomarkers and molecular pathways according to age for patients with HFrEF.

Cardiovasc Res 2021 Aug;117(10):2228-2236

Université de Lorraine, Inserm, Centre d'Investigation Clinique - Plurithématique 14-33, Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), 4 rue du Morvan, Nancy 54500, France.

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 biomarkers that were positively associated with older age were associated with tumour cell regulation, extra-cellular matrix organization, and inflammatory processes, whereas biomarkers negatively associated with older age were associated with pathways that may point to cell proliferation and tumourigenesis. Among the 27 biomarkers, WFDC2 (WAP four-disulphide core domain protein 2)-that broadly functions as a protease inhibitor-was associated with older age and had the strongest association with all outcomes. No protein-by-sex interaction was observed.

Conclusions : In elderly HFrEF patients, pathways associated with extra-cellular matrix organization, inflammatory processes, and tumour cell regulation were activated, while pathways associated with tumour proliferation functions were down-regulated. These findings may help in a better understanding of the ageing processes in HFrEF and identify potential therapeutic targets.
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http://dx.doi.org/10.1093/cvr/cvaa279DOI Listing
August 2021

Renal and Cardiovascular Effects of SGLT2 Inhibition in Combination With Loop Diuretics in Patients With Type 2 Diabetes and Chronic Heart Failure: The RECEDE-CHF Trial.

Circulation 2020 11 29;142(18):1713-1724. Epub 2020 Aug 29.

Division of Molecular and Clinical Medicine, University of Dundee, Scotland, United Kingdom (N.A.M., I.R.M., R.J.M., A.D.S., C.C.L.).

Background: SGLT2 (sodium-glucose cotransporter-2) inhibitors improve heart failure-associated outcomes in patients with type 2 diabetes. In patients with heart failure, SGLT2 inhibitors will likely be coprescribed with a loop diuretic, but this combined effect is not well-defined. Our aim was to assess the diuretic and natriuretic effect of empagliflozin in combination with loop diuretics.

Methods: The RECEDE-CHF trial (SGLT2 Inhibition in Combination With Diuretics in Heart Failure) was a randomized, double-blind, placebo-controlled, crossover trial of patients with type 2 diabetes and heart failure with reduced ejection fraction taking regular loop diuretic who were randomized to empagliflozin 25 mg once daily or placebo for 6 weeks with a 2-week washout period. The primary outcome was change in 24-hour urinary volume from baseline to week 6.

Results: Twenty-three participants (mean age, 69.8 years; 73.9% male; mean furosemide dose, 49.6±31.3 mg/d; mean HbA1c, 7.9±3.8%) were recruited. Compared with placebo, empagliflozin caused a significant increase in 24-hour urinary volume at both day 3 (mean difference, 535 mL [95% CI, 133-936]; =0.005) and week 6 (mean difference, 545 mL [95% CI, 136-954]; =0.005) after adjustment for treatment order, baseline 24-hour urine volume, and percentage change in loop diuretic dose. At 6 weeks, empagliflozin did not cause a significant change in 24-hour urinary sodium (mean difference, -7.85 mmol/L [95% CI, -2.43 to 6.73]; =0.57). Empagliflozin caused a nonsignificant increase in fractional excretion of sodium at day 3, which was absent at week 6 (mean difference day 3, 0.30% [95% CI, -0.03 to 0.63]; =0.09; week 6, 0.11% [95% CI, -0.22 to 0.44]; >0.99), and a significant increase in electrolyte-free water clearance at week 6 (mean difference, 312 mL [95% CI, 26-598]; =0.026) compared with placebo. Empagliflozin also caused significant reductions in body weight and serum urate at week 6.

Conclusions: Empagliflozin caused a significant increase in 24-hour urine volume without an increase in urinary sodium when used in combination with loop diuretic. Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT03226457.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.048739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594536PMC
November 2020

Genetic Associations With Plasma Angiotensin Converting Enzyme 2 Concentration: Potential Relevance to COVID-19 Risk.

Circulation 2020 09 7;142(11):1117-1119. Epub 2020 Jul 7.

Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, United Kingdom (C.P.N., V.C., T.R.W., S.Y., L.L.N., N.J.S.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.049007DOI Listing
September 2020
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