Publications by authors named "Patrick Rossignol"

373 Publications

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

Clin Cardiol 2021 May 7. 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
May 2021

Diuretic therapy as prognostic enrichment factor for clinical trials in patients with heart failure with reduced ejection fraction.

Clin Res Cardiol 2021 May 6. Epub 2021 May 6.

Université de Lorraine, Centre D'Investigations Cliniques-INSERM CHRU de Nancy, Institut Lorrain du Coeur Et Des Vaisseaux Louis Mathieu, 4 rue du Morvan, 54500, Vandoeuvre lès Nancy, France.

Background: Loop diuretics are the mainstay of congestion treatment in patients with heart failure (HF). We assessed the association between baseline loop diuretic use and outcome. We also compared the increment in risk related to diuretic dose with conventional prognostic enrichment criteria used in the EMPHASIS-HF trial, which included patients with systolic HF and mild symptoms, such as prior hospitalization and elevated natriuretic peptides.

Methods: Individual analyses were performed according to baseline loop diuretic usage (furosemide-equivalent dose > 40 mg, 1-40 mg, and no furosemide), and according to enrichment criteria adopted in the trial [i.e. recent hospitalization (< 30 days or 30 to 180 days prior to randomization) due to HF or other cardiovascular cause, or elevated natriuretic peptides]. The primary endpoint was a composite of cardiovascular death or HF hospitalization.

Results: Loop diuretic usage at baseline (HR for > 40 mg furosemide-equivalent dose = 3.16, 95% CI 2.43-4.11; HR for 1-40 mg = 2.06, 95% CI 1.60-2.65) was significantly associated with a higher risk for the primary endpoint in a stepwise manner when compared to no baseline loop diuretic usage. In contrast, the differences in outcome rates were more modest when using history of hospitalization and/or BNP: all HR ranged from 1 (reference, non-HF related CV hospitalization > 30 days) to 2.04 (HF hospitalization < 30 days). The effect of eplerenone on the primary endpoint was consistent across subgroups in both analyses (P for interaction ≥ 0.2 for all).

Conclusions: Loop diuretic usage (especially at doses > 40 mg) identified patients at higher risk than history of HF hospitalization and/or high BNP blood concentrations.
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http://dx.doi.org/10.1007/s00392-021-01851-wDOI Listing
May 2021

Mineralocorticoid receptor antagonists for nephroprotection and cardioprotection in patients with diabetes mellitus and chronic kidney disease.

Nephrol Dial Transplant 2021 May 4. Epub 2021 May 4.

Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Diabetic kidney disease develops in about 40% of patients with diabetes and is the commonest cause of chronic kidney disease worldwide. Patients with chronic kidney disease, especially those with diabetes mellitus, are at high risk of both developing kidney failure and cardiovascular death. The use of renin-angiotensin system blockers to reduce the incidence of kidney failure in patients with diabetic kidney disease dates back to studies that are now 20 or more years old. During the last few years sodium-glucose co-transporter-2 inhibitors have shown beneficial renal effects in randomized trials. However, even in response to combined treatment with renin-angiotensin system blockers and sodium-glucose co-transporter-2 inhibitors, the renal residual risk remains high with kidney failure only deferred, but not avoided. The risk of cardiovascular death also remains high even with optimal current treatment. Steroidal mineralocorticoid receptor antagonists reduce albuminuria and surrogate markers of cardiovascular disease in patients already on optimal therapy. However, their use has been curtailed by the significant risk of hyperkalaemia. In The FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease (FIDELIO-DKD) study comparing the actions of the non-steroidal mineralocorticoid receptor antagonist finerenone with placebo, finerenone reduced the progression of diabetic kidney disease and the incidence of cardiovascular events with a relatively safe adverse event profile. This document presents in detail the available evidence on the cardioprotective and nephroprotective effects of mineralocorticoid receptor antagonists, analyses the potential mechanisms involved and discusses their potential future place in the treatment of patients with diabetic chronic kidney disease.
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http://dx.doi.org/10.1093/ndt/gfab167DOI Listing
May 2021

Serum sodium and eplerenone use in patients with a myocardial infarction and left ventricular dysfunction or heart failure: insights from the EPHESUS trial.

Clin Res Cardiol 2021 Apr 23. Epub 2021 Apr 23.

Centre d'Investigation Clinique 1433 module Plurithematique, Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu, F-CRIN INI-CRCT Network, Universite de Lorraine, Inserm U1116, 4 rue du Morvan, 54500, Vandoeuvre les Nancy, France.

Background: Sodium changes are common in myocardial infarction (MI) complicated with left ventricular systolic dysfunction (LVSD) and/or heart failure (HF). Sodium handling is fine-tuned in the distal nephron, were eplerenone exhibits some of its pleotropic effects. Little is known about the effect of eplerenone on serum sodium and the prognostic relevance of sodium alterations in patients with MI complicated with LVSD and/or HF.

Methods: The EPHESUS trial randomized 6632 patients to either eplerenone or placebo. Hyponatremia and hypernatremia were defined as sodium < 135 mmol/L or > 145 mmol/L, respectively. Linear mixed models and time updated Cox regression analysis were used to determine the effect of eplerenone on sodium changes and the prognostic importance of sodium changes, respectively. The primary outcomes were all-cause mortality and a composite of cardiovascular (CV) mortality and CV-hospitalization.

Results: A total of 6221 patients had a post-baseline sodium measurement, 797 patients developed hyponatremia (mean of 0.2 events/per patient) and 1476 developed hypernatremia (mean of 0.4 events/per patient). Patients assigned to eplerenone had a lower mean serum sodium over the follow-up (140 vs 141 mmol/L; p < 0.0001) and more often developed hyponatremia episodes (15 vs 11% p = 0.0001) and less often hypernatremia episodes (22 vs. 26% p = 0.0003). Hyponatremia, but not hypernatremia was associated with adverse outcome for all outcome endpoints in the placebo group but not in the eplerenone group (interaction p value < 0.05 for all). Baseline sodium values did not influence the treatment effect of eplerenone in reducing the various endpoints (interaction p value > 0.05 for all). Development of new-onset hyponatremia following eplerenone initiation did not diminish the beneficial eplerenone treatment effect.

Conclusion: Eplerenone induces minor reductions in serum sodium. The beneficial effect of eplerenone was maintained regardless of the baseline serum sodium or the development of hyponatremia. Sodium alterations should not refrain clinicians from prescribing eplerenone to patients who had an MI complicated with LVSD and/or HF.

Trail Registry: ClinicalTrials.gov identifier: NCT00232180. Serum sodium and eplerenone use in patients with a myocardial infarction and left ventricular dysfunction or heart failure: insights from the EPHESUS trial.
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http://dx.doi.org/10.1007/s00392-021-01853-8DOI Listing
April 2021

Understanding and Overcoming the Challenges Related to Cardiovascular Trials Involving Patients with Kidney Disease.

Clin J Am Soc Nephrol 2021 Apr 23. Epub 2021 Apr 23.

Department of Medicine, Division of Cardiology, Hennepin Healthcare, University of Minnesota, Minneapolis, Minnesota

Cardiovascular disease is a prevalent and prognostically important comorbidity among patients with kidney disease, and individuals with kidney disease make up a sizeable proportion (30%-60%) of patients with cardiovascular disease. However, several systematic reviews of cardiovascular trials have observed that patients with kidney disease, particularly those with advanced kidney disease, are often excluded from trial participation. Thus, currently available trial data for cardiovascular interventions in patients with kidney disease may be insufficient to make recommendations on the optimal approach for many therapies. The Kidney Health Initiative, a public-private partnership between the American Society of Nephrology and the US Food and Drug Administration, convened a multidisciplinary, international work group and hosted a stakeholder workshop intended to understand and develop strategies for overcoming the challenges with involving patients with kidney disease in cardiovascular clinical trials, with a particular focus on those with advanced disease. These efforts considered perspectives from stakeholders, including academia, industry, contract research organizations, regulatory agencies, patients, and care partners. This article outlines the key challenges and potential solutions discussed during the workshop centered on the following areas for improvement: building the business case, re-examining study design and implementation, and changing the clinical trial culture in nephrology. Regulatory and financial incentives could serve to mitigate financial concerns with involving patients with kidney disease in cardiovascular trials. Concerns that their inclusion could affect efficacy or safety results could be addressed through thoughtful approaches to study design and risk mitigation strategies. Finally, there is a need for closer collaboration between nephrologists and cardiologists and systemic change within the nephrology community such that participation of patients with kidney disease in clinical trials is prioritized. Ultimately, greater participation of patients with kidney disease in cardiovascular trials will help build the evidence base to guide optimal management of cardiovascular disease for this population.
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http://dx.doi.org/10.2215/CJN.17561120DOI Listing
April 2021

Urinary peptides in heart failure: a link to molecular pathophysiology.

Eur J Heart Fail 2021 Apr 21. Epub 2021 Apr 21.

Non-Profit Research Institution Alliance for the Promotion of Preventive Medicine, Mechelen, Belgium.

Aims: Heart failure (HF) is a major public health concern worldwide. The diversity of HF makes it challenging to decipher the underlying complex pathological processes using single biomarkers. We examined the association between urinary peptides and HF with reduced (HFrEF), mid-range (HFmrEF) and preserved (HFpEF) ejection fraction, defined based on the European Society of Cardiology guidelines, and the links between these peptide biomarkers and molecular pathophysiology.

Methods And Results: Analysable data from 5608 participants were available in the Human Urinary Proteome database. The urinary peptide profiles from participants diagnosed with HFrEF, HFmrEF, HFpEF and controls matched for sex, age, estimated glomerular filtration rate, systolic and diastolic blood pressure, diabetes and hypertension were compared applying the Mann-Whitney test, followed by correction for multiple testing. Unsupervised learning algorithms were applied to investigate groups of similar urinary profiles. A total of 577 urinary peptides significantly associated with HF were sequenced, 447 of which (77%) were collagen fragments. In silico analysis suggested that urinary biomarker abnormalities in HF principally reflect changes in collagen turnover and immune response, both associated with fibrosis. Unsupervised clustering separated study participants into two clusters, with 83% of non-HF controls allocated to cluster 1, while 65% of patients with HF were allocated to cluster 2 (P < 0.0001). No separation based on HF subtype was detectable.

Conclusions: Heart failure, irrespective of ejection fraction subtype, was associated with differences in abundance of urinary peptides reflecting collagen turnover and inflammation. These peptides should be studied as tools in early detection, prognostication, and prediction of therapeutic response.
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http://dx.doi.org/10.1002/ejhf.2195DOI Listing
April 2021

Chronic use of Renin-Angiotensin-Aldosterone-System blockers and mortality in COVID-19: a multicenter prospective cohort and literature review.

Fundam Clin Pharmacol 2021 Apr 20. Epub 2021 Apr 20.

AP-HP, Hôpital Bichat, Service de Physiologie rénale, F-75018, Paris, France.

Aims: The role of renin-angiotensin-aldosterone system (RAAS) blockers on the course of coronavirus disease 2019 (COVID-19) is debated. We assessed the association between chronic use of RAAS blockers and mortality among inpatients with COVID-19, and explored reasons for discrepancies in the literature.

Methods And Results: We included adult hypertensive patients from a prospective nationwide cohort of 3512 inpatients with COVID-19 up to June 30, 2020. Cox proportional hazard models with various adjustment or propensity weighting methods were used to estimate the Hazard Ratios (HR) of 30-day mortality for chronic users versus non-users of RAAS blockers. We analyzed data of 1160 hypertensive patients; 719 (62%) were male, 777 (67%) were older than 65 years. The main comorbidities were diabetes (n=416, 36%), chronic cardiac disease (n=401, 35%) and obesity (n=340, 29%); 705 (61%) received oxygen therapy. We recorded 135 (11.6%) deaths within 30 days of diagnosis. We found no association between chronic use of RAAS blockers and mortality (unadjusted HR=1.13, 95% CI [0.8-1.6]; propensity inverse probability treatment weighted HR=1.09 [0.86-1.39]; propensity standardized mortality ratio weighted HR=1.08 [0.79-1.47]). Our comprehensive review of previous studies highlighted that significant associations were mostly found in unrestricted populations with inappropriate adjustment, or with biased in-hospital exposure measurement.

Conclusion: Our results do not support previous concerns regarding these drugs, nor a potential protective effect as reported in previous poorly designed studies and metanalyses. RAAS blockers should not be discontinued during the pandemic, while in-hospital management of these drugs will be clarified by randomized trials. NCT04262921.
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http://dx.doi.org/10.1111/fcp.12683DOI Listing
April 2021

Blood pressure reduction and anti-hypertensive treatment choice: A post-hoc analysis of the SPRINT trial.

Clin Cardiol 2021 Apr 6. Epub 2021 Apr 6.

Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK.

Background: Uncontrolled blood pressure (BP) increases the risk of major adverse cardiovascular events. In SPRINT an intensive versus standard BP lowering strategy resulted in a lower rate of cardiovascular events and death. Whether BP reduction only or also the choice of anti-hypertensive drugs is associated with outcomes remains to be elucidated.

Aims: We aim to study the association of BP and different anti-hypertensive drugs with several cardiovascular outcomes.

Methods: Time-updated Cox and mixed-effects models. The primary outcome was a composite of first myocardial infarction, acute coronary syndrome, stroke, heart failure, or cardiovascular death.

Results: A total of 9361 patients were included. The anti-hypertensive agents most frequently used were ACEi/ARBs, with an almost 20% higher prescription rate in the intensive arm (80% vs. 61%), followed by thiazide-type diuretics (65% vs. 42%), calcium-channel blockers (57% vs. 39%), and beta-blockers (52% vs. 26%). Mineralocorticoid receptor antagonists were rarely used (≤7% of the observations). In multivariate analysis, the use of ACEi/ARBs, especially in combination with thiazides, were independently associated with a lower primary outcome event-rate (HR [95%CI] 0.75 [0.61-0.92], p = .006), whereas a DBP <60 mmHg was independently associated with a higher event-rate (HR [95%CI] 1.36 [1.07-1.71], p = .011). SBP <120 mmHg was associated with lower rate of cardiovascular and all-cause death on intensive treatment but not on the standard arm (interaction p < .05 for both).

Conclusions: In SPRINT, an intensive therapy strategy achieving SBP <120 mmHg with a DBP ≥60 mmHg, and using ACEi/ARBs plus thiazides was associated with a lower event-rate.
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http://dx.doi.org/10.1002/clc.23591DOI Listing
April 2021

Spironolactone effect on the blood pressure of patients at risk of developing heart failure: an analysis from the HOMAGE trial.

Eur Heart J Cardiovasc Pharmacother 2021 Apr 2. Epub 2021 Apr 2.

Université de Lorraine, Inserm, Centre d'Investigation Clinique Plurithématique, CHRU de Nancy, F-CRIN INI-CRCT, Nancy, 1433, U1116, France.

Background: Uncontrolled blood pressure (BP) increases the risk of developing heart failure (HF). The effect of spironolactone on BP of patients at risk of developing HF is yet to be determined.

Aims: To evaluate the effect of spironolactone on the BP of patients at risk for HF and whether renin can predict spironolactone`s effect.

Methods: HOMAGE (Heart OMics in Aging) was a prospective multicenter randomized open-label blinded Endpoint (PROBE) trial including 527 patients at risk for developing HF randomly assigned to either spironolactone (25-50mg/day) or usual care alone for a maximum of 9 months. Sitting BP was assessed at baseline, month 1 and 9 (or last visit). Analysis of covariance (ANCOVA), mixed effects models, and structural modelling equations were used.

Results: The median (percentile25-75) age was 73 (69-79) years, 26% were female, and >75% had history of hypertension. Overall, the baseline BP was 142/78 mmHg. Patients with higher BP were older, more likely to have diabetes and less likely to have coronary artery disease, had greater left ventricular mass (LVM), and left atrial volume (LAV). Compared with usual care, by last visit, spironolactone changed SBP by -10.3 (-13.0 to -7.5)mmHg and DBP by -3.2 (-4.8 to -1.7)mmHg (p < 0.001 for both). A higher proportion of patients on spironolactone had controlled BP < 130/80 mmHg (36 vs. 26%; p = 0.014). Lower baseline renin levels predicted a greater response to spironolactone (interactionp=0.041).

Conclusion: Spironolactone had a clinically important BP-lowering effect. Spironolactone should be considered for lowering blood pressure in patients who are at risk of developing HF.
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http://dx.doi.org/10.1093/ehjcvp/pvab031DOI Listing
April 2021

Blood pressure monitoring in kidney transplantation: a systematic review on hypertension and target organ damage.

Nephrol Dial Transplant 2021 Mar 25. Epub 2021 Mar 25.

CNR-Institute of Clinical Physiology; Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, Reggio Calabria, Italy.

Background: Sparse studies show that ambulatory blood pressure monitoring (ABPM) is superior to office BP (oBP) measurements to predict target organ damage and cardiovascular (CV) events in kidney transplant recipients (KTRs). We performed a systematic review aimed at determining the potential associations between BP recordings by different methods and renal and CV outcomes in this population.

Methods: Major medical databases were searched for studies enrolling adult KTRs undergoing 24h ABPM compared to office or home BP measurements. Main outcomes were: associations between different BP recordings and renal and CV outcomes. Additionally, any association between the circadian BP pattern (dipping/non-dipping status) and outcomes was assessed.

Results: Twenty-two studies (2078 participants) were reviewed. Amongst 12 studies collecting data on renal endpoints, ten studies found that BP assessed by ABPM was a stronger predictor of renal function decline, assessed by serum creatinine (SCr) and/or creatinine clearance (CrCl) or estimated glomerular filtration rate (eGFR), than traditional office measurements. Twelve studies analyzed the relation between different BP recordings and CV target organ damages and reported robust correlations between echocardiographic abnormalities [i.e. left ventricular mass index (LVM/LVMI)] and 24h ABPM, but not with office BPs. Furthermore, 24h ABPM correlated better than oBP with markers of vascular damage, such as carotid intima-media thickness (IMT), diffuse thickening, and endothelial dysfunction. Additionally, abnormal circadian BP pattern (non-dippers and reverse dippers) identified a group of kidney recipients at risk for kidney function loss and CV abnormalities.

Conclusions: In our systematic review, ABPM reflected target organ damage more closely than oBP in KTRs. Furthermore, altered circadian BP profile associated with renal and CV target organ damages.
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http://dx.doi.org/10.1093/ndt/gfab076DOI Listing
March 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 Mar 20. 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
March 2021

Mineralocorticoid Receptor Antagonists and SGLT2 Inhibitor Therapy: The Best of Both Worlds in HFrEF.

JACC Heart Fail 2021 Apr 10;9(4):265-267. Epub 2021 Mar 10.

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

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http://dx.doi.org/10.1016/j.jchf.2020.12.009DOI Listing
April 2021

Should renin angiotensin aldosterone system inhibition enablement be a therapeutic target in CKD patients?

Nephrol Dial Transplant 2021 Mar 2. Epub 2021 Mar 2.

Department of Medicine, Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, USA.

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http://dx.doi.org/10.1093/ndt/gfab061DOI Listing
March 2021

Serum microRNAs and antifibrotic response to eplerenone in acute myocardial infarction complicated by systolic dysfunction.

Int J Cardiol 2021 Jun 5;332:35-37. Epub 2021 Mar 5.

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

Background: After myocardial infarction (MI) complicated by heart failure (HF), eplerenone reduced serum concentrations of amino-terminal propeptide of type III collagen (PIIINP) and carboxy-terminal propeptide of type I collagen (PICP). Determining a subgroup who are more prone to decrease their collagen content and to respond better to the antifibrotic effects of mineralocorticoid receptor antagonists (MRA) may be relevant for a personalized treatment approach. Whether circulating microRNAs may identify a subgroup that have experienced a more pronounced antifibrotic effect of eplerenone as measured by a PICP and PIIINP decrease is unclear.

Methods: A set of circulating microRNAs linked to cardiac fibrosis (mir-1, mir-21, mir-29a, mir-29b, mir-101, mir-122, mir-133a) were measured at baseline in 198 patients in the biomarker substudy of Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Associations between baseline microRNA levels and changes in both PIIINP and PICP from baseline to month 9 were studied using multivariable analysis of covariance, adjusting for age, sex, history of hypertension and diabetes mellitus, prescription of ACE-inhibitors or angiotensin receptor blockers, baseline PIIINP or PICP, and eplerenone treatment. Furthermore, a treatment-by-microRNA interaction was studied.

Results: From the selected microRNAs, only mir-133a was associated with a PICP decrease (ß-6.43, 95%CI-12.71 to -0.15,p = 0.045). None of the microRNAs was associated with a PIIINP change. The microRNAs did not predict an effect of eplerenone on PICP and PIIINP changes.

Conclusion: Although serum mir-133a was associated with PICP change, none of the microRNAs previously linked to cardiac fibrosis predicted an antifibrotic response to eplerenone. Further study is needed to identify other suitable targets for a personalized treatment approach.
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http://dx.doi.org/10.1016/j.ijcard.2021.02.088DOI Listing
June 2021

Risk stratification with echocardiographic biomarkers in heart failure with preserved ejection fraction: the media echo score.

ESC Heart Fail 2021 Mar 3. Epub 2021 Mar 3.

Inserm, Centre d'Investigations Cliniques-Plurithématique 1433, Inserm U1116, CHRU Nancy, Université de Lorraine, and F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France.

Aims: Echocardiographic predictors of outcomes in heart failure with preserved ejection fraction (HFpEF) have not been systematically or independently validated. We aimed at identifying echocardiographic predictors of cardiovascular events in a large cohort of patients with HFpEF and to validate these in an independent large cohort.

Methods And Results: We assessed the association between echocardiographic parameters and cardiovascular outcomes in 515 patients with heart failure with preserved left ventricular (LV) ejection fraction (>50%) in the MEtabolic Road to DIAstolic Heart Failure (MEDIA) multicentre study. We validated out findings in 286 patients from the Karolinska-Rennes Prospective Study of HFpEF (KaRen). After multiple adjustments including N-terminal pro-brain natriuretic peptide (NT-proBNP), the significant predictors of death or cardiovascular hospitalization were pulmonary arterial systolic pressure > 40 mmHg, respiratory variation in inferior vena cava diameter > 0.5, E/e' > 9, and lateral mitral annular s' < 7 cm/s. The combination of these four variables differentiated patients with <10% vs. >35% 1 year risk. Adding these four echocardiographic variables on top of clinical variables and NT-proBNP yielded significant net reclassification improvement (33.8%, P < 0.0001) and increase in C-index (5.3%, a change from 72.2% to 77.5%, P = 0.015) of similar magnitude as the addition of NT-proBNP on top of clinical variables alone. In the KaRen cohort, these four variables yielded a similar improvement in net reclassification improvement (22.3%, P = 0.014) and C-index (4.0%, P = 0.029).

Conclusions: Use of four simple echocardiographic parameters (within the MEDIA echo score), indicative of pulmonary hypertension, elevated central venous pressure, LV diastolic dysfunction, and LV long-axis systolic dysfunction, independently predicted prognosis and improved risk stratification additionally to clinical variables and NT-proBNP in HFpEF. This finding was validated in an independent cohort.
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http://dx.doi.org/10.1002/ehf2.13251DOI Listing
March 2021

Non-fatal cardiovascular events preceding sudden cardiac death in patients with an acute myocardial infarction complicated by heart failure: insights from the high-risk myocardial infarction database.

Eur Heart J Acute Cardiovasc Care 2021 Apr;10(2):127-131

National Institute of Health and Medical Research Center for Clinical Multidisciplinary Research, INSERM U1116, Université de Lorraine, Inserm, Centre d'Investigations cliniques-plurithématique 1433, Inserm U1116; CHRU Nancy; F-CRIN INI-CRCT network, Nancy, France.

Aims: Among patients with acute myocardial infarction (AMI) complicated by heart failure [HF; clinical HF or left ventricular (LV) systolic dysfunction], we explored the probability of subsequent non-fatal cardiovascular (CV) events and sudden cardiac death (SCD).

Methods And Results: The high-risk myocardial infarction (HRMI) database contains 28 771 patients with signs of HF or reduced LV ejection fraction (<40%) after AMI. We evaluated the temporal association between SCD with preceding non-fatal CV event [HF hospitalization, recurrent myocardial infarction (MI), or stroke]. Median follow-up was 1.9 years. Mean age was 65.0 ± 11.5 years and 70% were male. The incidence of CV death was 7.9 per 100 patient-years and for SCD was 3.1 per patient-years (40% of CV deaths). The incidence of SCD preceded by HF hospitalization was greater than SCD without preceding HF hospitalization (P < 0.05). However, overall, SCD was less likely to be preceded by a non-fatal CV event compared to other causes of death: 9.6% of SCD events were preceded by an MI (vs. 46.6% for non-sudden CV death); 17.0% of SCD events were preceded with an HF hospitalization (vs. 25.4% for non-sudden CV death); and 2.7% of SCD events were preceded by stroke (vs.12.9% for non-sudden CV death).

Conclusion: Among patients with AMI complicated by HF, SCD, compared with other causes of death, was less likely to be preceded by a non-fatal CV event. As patients are less likely to have preceding non-fatal CV events to alert the healthcare team of a possible impending SCD event, additional strategies for risk stratification for SCD are needed.
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http://dx.doi.org/10.1093/ehjacc/zuaa012DOI Listing
April 2021

Head-to-head comparison of clustering methods for heterogeneous data: a simulation-driven benchmark.

Sci Rep 2021 Feb 18;11(1):4202. Epub 2021 Feb 18.

Centre d'Investigations Cliniques Plurithématique 1433, INSERM 1116, CHRU de Nancy, Université de Lorraine, Nancy, France.

The choice of the most appropriate unsupervised machine-learning method for "heterogeneous" or "mixed" data, i.e. with both continuous and categorical variables, can be challenging. Our aim was to examine the performance of various clustering strategies for mixed data using both simulated and real-life data. We conducted a benchmark analysis of "ready-to-use" tools in R comparing 4 model-based (Kamila algorithm, Latent Class Analysis, Latent Class Model [LCM] and Clustering by Mixture Modeling) and 5 distance/dissimilarity-based (Gower distance or Unsupervised Extra Trees dissimilarity followed by hierarchical clustering or Partitioning Around Medoids, K-prototypes) clustering methods. Clustering performances were assessed by Adjusted Rand Index (ARI) on 1000 generated virtual populations consisting of mixed variables using 7 scenarios with varying population sizes, number of clusters, number of continuous and categorical variables, proportions of relevant (non-noisy) variables and degree of variable relevance (low, mild, high). Clustering methods were then applied on the EPHESUS randomized clinical trial data (a heart failure trial evaluating the effect of eplerenone) allowing to illustrate the differences between different clustering techniques. The simulations revealed the dominance of K-prototypes, Kamila and LCM models over all other methods. Overall, methods using dissimilarity matrices in classical algorithms such as Partitioning Around Medoids and Hierarchical Clustering had a lower ARI compared to model-based methods in all scenarios. When applying clustering methods to a real-life clinical dataset, LCM showed promising results with regard to differences in (1) clinical profiles across clusters, (2) prognostic performance (highest C-index) and (3) identification of patient subgroups with substantial treatment benefit. The present findings suggest key differences in clustering performance between the tested algorithms (limited to tools readily available in R). In most of the tested scenarios, model-based methods (in particular the Kamila and LCM packages) and K-prototypes typically performed best in the setting of heterogeneous data.
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http://dx.doi.org/10.1038/s41598-021-83340-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892576PMC
February 2021

Circulating multimarker approach to identify patients with preclinical left ventricular remodelling and/or diastolic dysfunction.

ESC Heart Fail 2021 Apr 12;8(2):1700-1705. Epub 2021 Feb 12.

Université de Lorraine, Centre d'Investigations Cliniques-Plurithématique, Inserm1433, CHRU Nancy, Inserm DCAC, and F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), INSERM CHU de Nancy, Institut Lorrain du Cœur et des Vaisseaux Louis Mathieu, 4 Rue du Morvan, 54500 Vandoeuvre lès, Nancy, France.

Aims: Biomarkers reflecting myocardial fibrosis and inflammation have been individually associated with left ventricular hypertrophy (LVH) and diastolic dysfunction (DD). However, the added value of a fibrosis-inflammation multimarker approach in a populational setting is yet to be studied. We evaluated the value of a multimarker approach to detect LVH and DD in a large population-based cohort.

Methods And Results: In a prespecified analysis (BioSe-PreIC study) of the 4th visit of the STANISLAS cohort (1705 subjects, 47 ± 14 years, 47.4% men), we evaluated the ability of brain natriuretic peptide (BNP), Galectin-3 (GAL3), N-terminal propeptide of procollagen type III (P3NP), and soluble ST2 to predict LVH (LV mass > 116/100 g/m for men/women) and DD using discrimination (C-index) and reclassification analysis (NRI). Participants with LVH and/or DD had significantly higher levels of BNP, GAL3, and ST2. Overall, the predictive value of clinical variables for LVH and/or DD was good (C-index ranging from 0.76 to 0.82) and the addition of BNP, Gal3, P3NP, and ST2 moderately but significantly improved predictive value (delta C-index = 0.03, P = 0.03 for LVH and 0.01, P = 0.01 for DD) and reclassification (NRI = 25.3, P = 0.02 for LVH and NRI = 32.7 for DD, P < 0.0001). Gal3, P3NP, and ST2 significantly improved predictive value (delta C-index = 0.01, P = 0.01) and reclassification (NRI = 31.3, P < 0.0001) for DD of top of clinical variables and BNP.

Conclusions: As the measurement of Gal3, P3NP, and ST2 results in marginal (even if significant) increase in the prediction of DD/LVH on top of routine evaluation, their systematic use should not be promoted in unselected healthy individuals to screen for preclinical DD. Further research is needed to determine whether a more personalized medicine approach combing proteomic and clinical scoring can amplify the added value of biomarkers to identify preclinical DD.
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http://dx.doi.org/10.1002/ehf2.13203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006620PMC
April 2021

Impact of anti-hypertensive therapy in the sexual health of men and women: an analysis from the SPRINT trial.

Am J Hypertens 2021 Feb 11. Epub 2021 Feb 11.

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

Background: Pharmacologic anti-hypertensive (HT) treatment reduces cardiovascular risk. However, many patients are non-adherent due to perceived or real concern about sexual-related side-effects.

Objectives: In a subset of the SPRINT (a randomized trial of intensive versus standard blood-pressure control) trial, we sought to investigate the impact of anti-HT treatment on sexual activities of men and women over time, and whether this impact varied with a more or less intensive anti-HT therapy.

Methods: Random-effects models for panel/longitudinal data.

Results: Among the 1268 men and 613 women included in this sub-study, 862 (68%) men and 178 (29%) women declared to be engaged in sexual activity of any kind. Compared with women and men not engaged in sexual activity, those engaged were younger (64 vs. 69yr for women and 65 vs. 75yr for men). Women had an overall low satisfaction with their sexual life but their sexual health was not affected by anti-HT therapy over time nor modified by an intensive treatment. Men's erections were slightly deteriorated over time (-0.1 to -0.2 points on a scale of 1 (worse) to 5 (best); p<0.05), but were not aggravated by intensive anti-HT therapy (p>0.05 for all).

Conclusions: Self-declared women`s sexual health was not affected by an intensive anti-HT therapy. Men, reported a slight deterioration in the quality of their erections, irrespective of standard or intensive therapy. These findings may help reassuring patients about the sexual safety of intensive anti-HT therapy, therefore, potentially improving adherence to intensive therapy strategy.
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http://dx.doi.org/10.1093/ajh/hpab035DOI Listing
February 2021

Impact of Geographic Region on the COMMANDER-HF Trial.

JACC Heart Fail 2021 Mar 3;9(3):201-211. Epub 2021 Feb 3.

Centre d'Investigations Cliniques Plurithématique, Université de Lorraine, Inserm 1433, Nancy, France, Centre Hospitalier Régional Universitaire (CHRU) de Nancy, Inserm U1116, Nancy, France, French Clinical Research Infrastructure Network Investigation Network Initiative - Cardiovascular and Renal Clinical Trialists, Nancy, France.

Objectives: This study sought to compare patient characteristics, outcomes, and treatment effects among regions in the COMMANDER-HF trial.

Background: Globalization of cardiovascular trials increases generalizability. However, regional differences may also introduce heterogeneity in results.

Methods: Incidence rates and interactions with treatment were recorded in pre-specified regions: Eastern Europe, Western Europe and South Africa, North America, Asia-Pacific, and Latin America.

Results: Most patients (n = 3,224; 64.2%) were from Eastern Europe; 458 (9.1%) were from Western Europe and South Africa; 149 (3.0%) were from North America; 733 (14.6%) were from Asia-Pacific; and 458 (9.1%) were from Latin America. Compared with patients from Eastern Europe, patients from Western Europe and South Africa, North America, and Asia-Pacific were older and more likely to have coronary interventions and cardiac devices. Patients from Eastern Europe had the lowest event rates. For the primary outcome of myocardial infarction (MI), stroke, or all-cause death, event rates (100/year) were 11.6 in Eastern Europe (10.8 to 12.5); 19.5 (16.5 to 23.0) in Western Europe and South Africa; 14.2 (10.5 to 19.2) in North America; 17.7 (15.4 to 20.3) in Asia-Pacific; and 18.6 (15.6 to 22.1) in Latin America. There was a lower incidence of bleeding in Eastern Europe. Blood concentrations of rivaroxaban (Xarelto, Titusville, New Jersey) at 4 weeks were undetectable in 21% patients from Eastern Europe (n = 128) compared to 5% in other regions (n = 42). There was no evidence of treatment-by-region heterogeneity for the primary outcome (interaction = 0.14), but a favorable effect on the secondary outcome of MI, stroke, or cardiovascular death was observed in Western Europe and South Africa, North America, and Latin America but not in Eastern Europe and Asia-Pacific (interaction = 0.017).

Conclusions: In the COMMANDER-HF study, patients from Eastern Europe had a lower risk profile and fewer cardiovascular and bleeding events, possibly related to lower treatment adherence. Those differences might have influenced the effect of rivaroxaban therapy. (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction or Stroke in Participants With Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure [COMMANDER HF]; NCT01877915).
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http://dx.doi.org/10.1016/j.jchf.2020.11.007DOI Listing
March 2021

Proteomic and Mechanistic Analysis of Spironolactone in Patients at Risk for HF.

JACC Heart Fail 2021 Apr 3;9(4):268-277. Epub 2021 Feb 3.

Université de Lorraine, Inserm, Centre d'Investigation Clinique Plurithématique 1433, CHRU de Nancy, F-CRIN INI-CRCT, Nancy, France. Electronic address:

Objectives: This study sought to further understand the mechanisms underlying effect of spironolactone and assessed its impact on multiple plasma protein biomarkers and their respective underlying biologic pathways.

Background: In addition to their beneficial effects in established heart failure (HF), mineralocorticoid receptor antagonists may act upstream on mechanisms, preventing incident HF. In people at risk for developing HF, the HOMAGE (Heart OMics in AGEing) trial showed that spironolactone treatment could provide antifibrotic and antiremodeling effects, potentially slowing the progression to HF.

Methods: Baseline, 1-month, and 9-month (or last visit) plasma samples of HOMAGE participants were measured for protein biomarkers (n = 276) by using Olink Proseek-Multiplex cardiovascular and inflammation panels (Olink, Uppsala, Sweden). The effect of spironolactone on biomarkers was assessed by analysis of covariance and explored by knowledge-based network analysis.

Results: A total of 527 participants were enrolled; 265 were randomized to spironolactone (25 to 50 mg/day) and 262 to standard care ("control"). The median (interquartile range) age was 73 years (69 to 79 years), and 26% were female. Spironolactone reduced biomarkers of collagen metabolism (e.g., COL1A1, MMP-2); brain natriuretic peptide; and biomarkers related to metabolic processes (e.g., PAPPA), inflammation, and thrombosis (e.g., IL17A, VEGF, and urokinase). Spironolactone increased biomarkers that reflect the blockade of the mineralocorticoid receptor (e.g., renin) and increased the levels of adipokines involved in the anti-inflammatory response (e.g., RARRES2) and biomarkers of hemostasis maintenance (e.g., tPA, UPAR), myelosuppressive activity (e.g., CCL16), insulin suppression (e.g., RETN), and inflammatory regulation (e.g., IL-12B).

Conclusions: Proteomic analyses suggest that spironolactone exerts pleiotropic effects including reduction in fibrosis, inflammation, thrombosis, congestion, and vascular function improvement, all of which may mediate cardiovascular protective effects, potentially slowing progression toward heart failure. (HOMAGE [Bioprofiling Response to Mineralocorticoid Receptor Antagonists for the Prevention of Heart Failure]; NCT02556450).
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http://dx.doi.org/10.1016/j.jchf.2020.11.010DOI Listing
April 2021

Antifibrotic effect of novel neutrophil gelatinase-associated lipocalin inhibitors in cardiac and renal disease models.

Sci Rep 2021 Jan 28;11(1):2591. Epub 2021 Jan 28.

INSERM, UMRS 1138, Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, 15 rue de l'Ecole de Médecine, 75006, Paris, France.

Neutrophil gelatinase-associated lipocalin (NGAL) is involved in cardiovascular and renal diseases. Gene inactivation of NGAL blunts the pathophysiological consequences of cardiovascular and renal damage. We aimed to design chemical NGAL inhibitors and investigate its effects in experimental models of myocardial infarction (MI) and chronic kidney disease induced by 5/6 nephrectomy (CKD) on respectively 8-12 weeks old C57Bl6/j and FVB/N male mice. Among the 32 NGAL inhibitors tested, GPZ614741 and GPZ058225 fully blocked NGAL-induced inflammatory and profibrotic markers in human cardiac fibroblasts and primary mouse kidney fibroblasts. The administration of GPZ614741 (100 mg/kg/day) for three months, was able to improve cardiac function in MI mice and reduced myocardial fibrosis and inflammation. The administration of GPZ614741 (100 mg/kg/day) for two months resulting to no renal function improvement but prevented the increase in blood pressure, renal tubulointerstitial fibrosis and profibrotic marker expression in CKD mice. In conclusion, we have identified new compounds with potent inhibitory activity on NGAL-profibrotic and pro-inflammatory effects. GPZ614741 prevented interstitial fibrosis and dysfunction associated with MI, as well as tubulointerstitial fibrosis in a CKD model. These inhibitors could be used for other diseases that involve NGAL, such as cancer or metabolic diseases, creating new therapeutic options.
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http://dx.doi.org/10.1038/s41598-021-82279-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844219PMC
January 2021

Sarcopenia in patients after an episode of acute decompensated heart failure: An underdiagnosed problem with serious impact.

Clin Nutr 2021 Jan 9. Epub 2021 Jan 9.

Cardiology Department, CHU Clermont-Ferrand, Clermont-Ferrand, France and Université Clermont Auvergne, CHU Clermont-Ferrand, CNRS, SIGMA Clermont, Institut Pascal, F-63000, Clermont-Ferrand, France; F-CRIN, INI-CRCT, Nancy, France.

Background & Aims: Sarcopenia is a multifactorial syndrome resulting in a decrease in both muscle mass and function. Little is known about the prevalence and prognostic impact of sarcopenia in patients with acutely decompensated chronic heart failure (ADHF). We aimed to evaluate the prevalence (main endpoint) and impact of sarcopenia on ADHF patients.

Methods: 140 ADHF patients were enrolled between November 2014 and September 2018 in a multicenter prospective longitudinal study. A similar, independent multi-departmental cross-sectional study in 165 ADHF patients was used for external validation of prevalence data. All subjects were assessed on the European Working Group on Sarcopenia criteria.

Results: Ninety-one patients (65%) had sarcopenia (vs. 53.6% in the external replication regional cohort). Patients with sarcopenia were older and more likely to have eGFR <60 ml/min/1.73 m (p < 0.001 and p = 0.002). Sarcopenia was associated with impaired functional status [lower 6 min walking test (220 ± 108 vs. 279 ± 170, p = 0.03) and 4 m gait speed (0.56 ± 0.24 vs. 0.80 ± 0.37, p < 0.001)] and autonomy [Instrumental activities of daily living: 6.7 ± 1.4 vs. 7.3 ± 1.2, p = 0.005]. Over up to 4 years' follow-up, 30 cardiovascular (CV) deaths and 42 non-CV deaths occurred. In a multivariable analysis, sarcopenia was associated with time to first non-CV hospitalization (hazard ratio 1.93; 95% confidence interval 1.14-3.24; p = 0.014) but not with any other hospitalization, any mortality endpoint, or a composite endpoint of CV death and HF hospitalization.

Conclusions: The prevalence of sarcopenia in ADHF patients is high and associated with greater risk of non-CV hospitalizations, highlighting the importance of identifying and managing the condition in a multidisciplinary approach.

Clinical Trial Registration: NCT03153774.
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http://dx.doi.org/10.1016/j.clnu.2020.12.033DOI Listing
January 2021

Intravenous Mineralocorticoid Receptor Antagonist Use in Acutely Decompensated Heart Failure with Diuretic Resistance.

Int Heart J 2021 Jan 16;62(1):193-196. Epub 2021 Jan 16.

Université de Lorraine, INSERM, Centre d'Investigations Cliniques 1433, CHRU de Nancy, Inserm 1116 and INI-CRCT (Cardiovascular and Renal Clinical Trialists) F-CRIN Network.

Intravenous mineralocorticoid receptor antagonists (MRAs) have been used in some centers for decades to reduce the risk of hypokalemia and boost diuresis in acutely decompensated heart failure (ADHF). We report the well-tolerated use of intravenous MRAs as a rescue procedure in 3 patients admitted for ADHF with important diuretic resistance. Undertaking trials evaluating the effect of this therapeutic strategy in ADHF could represent a promising avenue.
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http://dx.doi.org/10.1536/ihj.20-442DOI Listing
January 2021

Estimated plasma volume status in heart failure: clinical implications and future directions.

Clin Res Cardiol 2021 Jan 6. Epub 2021 Jan 6.

Centre d'Investigations Cliniques Plurithématique, INSERM 1433, CHRU de Nancy, Inserm 1116 and INI-CRCT (Cardiovascular and Renal Clinical Trialists) F-CRIN Network, Université de Lorraine, Nancy, France.

Congestion is one of the main predictors of poor outcome in patients with heart failure (HF). Assessing and monitoring congestion is essential for optimizing HF therapy. Among the various available methods, serial measurements of estimated plasma volume (ePVS) using routine blood count and/or body weight (e.g., the Strauss, Duarte, Hakim formulas) may be useful in HF management. Further prospective study is warranted to determine whether ePVS can help optimize decongestion therapy (loop diuretics, mineralocorticoid receptor antagonists, SGLT2i) in various HF settings. This narrative review summarizes the recent evidence supporting the association of ePVS with clinical congestion and outcome(s) and discusses future directions for monitoring ePVS in HF.
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http://dx.doi.org/10.1007/s00392-020-01794-8DOI Listing
January 2021

Challenges of Cardio-Kidney Composite Outcomes in Large-Scale Clinical Trials.

Circulation 2021 Mar 7;143(9):949-958. Epub 2021 Jan 7.

Université de Lorraine, INSERM, Centre d'Investigations Cliniques, INI CRCT, and INSERM U1116, CHRU Nancy, France (J.P.F., P.R., F.Z.).

Patients with chronic cardiovascular or metabolic diseases, including diabetes, hypertension, obesity, and heart failure, often have comorbid kidney disease. Long-term outcomes are worse in the setting of both cardiac and kidney disease compared with either disease in isolation. In addition, the clinical presentations of certain acute cardiovascular events (such as heart failure) and worsening kidney function overlap and may be challenging to distinguish. Recently, certain novel treatments have demonstrated beneficial effects on both cardiac and kidney outcomes. Sodium-glucose cotransporter-2 inhibitors have exhibited concordant risk reduction and clinically important benefits in chronic kidney disease with and without diabetes, diabetes and established cardiovascular disease or multiple atherosclerotic vascular disease risk factors, and heart failure with reduced ejection fraction with and without diabetes. Primary trial results have revealed that sacubitril-valsartan therapy improves cardiovascular outcomes in patients with chronic heart failure with reduced ejection fraction and post hoc analyses suggest favorable kidney effects. A concordant pattern of kidney benefit with sacubitril-valsartan has also been observed in chronic heart failure with preserved ejection fraction. Given the complex interplay between cardiac and kidney disease and the possibility that treatments may show concordant cardio-kidney benefits, there has been recent interest in formally acknowledging, defining, and using composite cardio-kidney outcomes in future cardiovascular trials. This review describes potential challenges in use of such outcomes that should be considered and addressed before their incorporation into such trials.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.049514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920916PMC
March 2021

Relationship between measured and prescribed dialysate sodium in haemodialysis: a systematic review and meta-analysis.

Nephrol Dial Transplant 2021 Mar;36(4):695-703

The George Institute for Global Health, UNSW Sydney, Sydney, Australia.

Background: Dialysate sodium (DNa) prescription policy differs between haemodialysis (HD) units, and the optimal DNa remains uncertain. We sought to summarize the evidence on the agreement between prescribed and delivered DNa, and whether the relationship varied according to prescribed DNa.

Methods: We searched MEDLINE and PubMed from inception to 26 February 2020 for studies reporting measured and prescribed DNa. We analysed results reported in aggregate with random-effects meta-analysis. We analysed results reported by individual sample, using mixed-effects Bland-Altman analysis and linear regression. Pre-specified subgroup analyses included method of sodium measurement, dialysis machine manufacturer and proportioning method.

Results: Seven studies, representing 908 dialysate samples from 10 HD facilities (range 16-133 samples), were identified. All but one were single-centre studies. Studies were of low to moderate quality. Overall, there was no statistically significant difference between measured and prescribed DNa {mean difference = 0.73 mmol/L [95% confidence interval (CI) -1.12 to 2.58; P = 0.44]} but variability across studies was substantial (I2 = 99.3%). Among individually reported samples (n = 295), measured DNa was higher than prescribed DNa by 1.96 mmol/L (95% CI 0.23-3.69) and the 95% limits of agreement ranged from -3.97 to 7.88 mmol/L. Regression analysis confirmed a strong relationship between prescribed and measured DNa, with a slope close to 1:1 (β = 1.16, 95% CI 1.06-1.27; P < 0.0001).

Conclusions: A limited number of studies suggest that, on average, prescribed and measured DNa are similar. However, between- and within-study differences were large. Further consideration of the precision of delivered DNa is required to inform rational prescribing.
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http://dx.doi.org/10.1093/ndt/gfaa287DOI Listing
March 2021

The effect of spironolactone on cardiovascular function and markers of fibrosis in people at increased risk of developing heart failure: the heart 'OMics' in AGEing (HOMAGE) randomized clinical trial.

Eur Heart J 2021 Feb;42(6):684-696

Université de Lorraine, Inserm, Centre d'Investigation Clinique Plurithématique 1433, CHRU de Nancy, F-CRIN INI-CRCT, Nancy, U1116, France.

Aims : To investigate the effects of spironolactone on fibrosis and cardiac function in people at increased risk of developing heart failure.

Methods And Results : Randomized, open-label, blinded-endpoint trial comparing spironolactone (50 mg/day) or control for up to 9 months in people with, or at high risk of, coronary disease and raised plasma B-type natriuretic peptides. The primary endpoint was the interaction between baseline serum galectin-3 and changes in serum procollagen type-III N-terminal pro-peptide (PIIINP) in participants assigned to spironolactone or control. Procollagen type-I C-terminal pro-peptide (PICP) and collagen type-1 C-terminal telopeptide (CITP), reflecting synthesis and degradation of type-I collagen, were also measured. In 527 participants (median age 73 years, 26% women), changes in PIIINP were similar for spironolactone and control [mean difference (mdiff): -0.15; 95% confidence interval (CI) -0.44 to 0.15 μg/L; P = 0.32] but those receiving spironolactone had greater reductions in PICP (mdiff: -8.1; 95% CI -11.9 to -4.3 μg/L; P < 0.0001) and PICP/CITP ratio (mdiff: -2.9; 95% CI -4.3 to -1.5; <0.0001). No interactions with serum galectin were observed. Systolic blood pressure (mdiff: -10; 95% CI -13 to -7 mmHg; P < 0.0001), left atrial volume (mdiff: -1; 95% CI -2 to 0 mL/m2; P = 0.010), and NT-proBNP (mdiff: -57; 95% CI -81 to -33 ng/L; P < 0.0001) were reduced in those assigned spironolactone.

Conclusions : Galectin-3 did not identify greater reductions in serum concentrations of collagen biomarkers in response to spironolactone. However, spironolactone may influence type-I collagen metabolism. Whether spironolactone can delay or prevent progression to symptomatic heart failure should be investigated.
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http://dx.doi.org/10.1093/eurheartj/ehaa758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878013PMC
February 2021

Diagnostic performance of congestion score index evaluated from chest radiography for acute heart failure in the emergency department: A retrospective analysis from the PARADISE cohort.

PLoS Med 2020 11 11;17(11):e1003419. Epub 2020 Nov 11.

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

Background: Congestion score index (CSI), a semiquantitative evaluation of congestion on chest radiography (CXR), is associated with outcome in patients with heart failure (HF). However, its diagnostic value in patients admitted for acute dyspnea has yet to be evaluated.

Methods And Findings: The diagnostic value of CSI for acute HF (AHF; adjudicated from patients' discharge files) was studied in the Pathway of dyspneic patients in Emergency (PARADISE) cohort, including patients aged 18 years or older admitted for acute dyspnea in the emergency department (ED) of the Nancy University Hospital (France) between January 1, 2015 and December 31, 2015. CSI (ranging from 0 to 3) was evaluated using a semiquantitative method on CXR in consecutive patients admitted for acute dyspnea in the ED. Results were validated in independent cohorts (N = 224). Of 1,333 patients, mean (standard deviation [SD]) age was 72.0 (18.5) years, 686 (51.5%) were men, and mean (SD) CSI was 1.42 (0.79). Patients with higher CSI had more cardiovascular comorbidities, more severe congestion, higher b-type natriuretic peptide (BNP), poorer renal function, and more respiratory acidosis. AHF was diagnosed in 289 (21.7%) patients. CSI was significantly associated with AHF diagnosis (adjusted odds ratio [OR] for 0.1 unit CSI increase 1.19, 95% CI 1.16-1.22, p < 0.001) after adjustment for clinical-based diagnostic score including age, comorbidity burden, dyspnea, and clinical congestion. The diagnostic accuracy of CSI for AHF was >0.80, whether alone (area under the receiver operating characteristic curve [AUROC] 0.84, 95% CI 0.82-0.86) or in addition to the clinical model (AUROC 0.87, 95% CI 0.85-0.90). CSI improved diagnostic accuracy on top of clinical variables (net reclassification improvement [NRI] = 94.9%) and clinical variables plus BNP (NRI = 55.0%). Similar diagnostic accuracy was observed in the validation cohorts (AUROC 0.75, 95% CI 0.68-0.82). The key limitation of our derivation cohort was its single-center and retrospective nature, which was counterbalanced by the validation in the independent cohorts.

Conclusions: In this study, we observed that a systematic semiquantified assessment of radiographic pulmonary congestion showed high diagnostic value for AHF in dyspneic patients. Better use of CXR may provide an inexpensive, widely, and readily available method for AHF triage in the ED.
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http://dx.doi.org/10.1371/journal.pmed.1003419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657510PMC
November 2020