Long-Term Trajectories of Biomarkers, Functional, and Echocardiographic Parameters in Patients with Chronic Heart Failure from Dilated or Ischaemic Cardiomyopathy.

INTRODUCTION: The long-term evolution of clinical, echocardiographic, and laboratory parameters of cardiac function in patients with chronic heart failure (HF) with either reduced (HFrEF) or mildly reduced (HFmrEF) left ventricular ejection fraction (LVEF) is incompletely characterised. METHODS: We identified patients with chronic stable HF who presented at least twice to a university HF outpatient clinic between 1995 and 2021. Trajectories of NYHA functional class, LVEF, left ventricular internal end-diastolic diameter (LVIDD), NT-proBNP concentrations, and HF treatment over 10 years of follow-up were analysed using fractional polynomials. Analyses were repeated after stratifying patients according to aetiology (ischaemic vs. dilated) or HF category (HFrEF vs. HFmrEF). RESULTS: A total of 2,132 patients were included, of whom 51% had ischaemic and 49% had dilated HF. Eighty six percent and 14% were classified as HFrEF and HFmrEF, respectively. Mean LVEF was 28 ± 10%, and median NT-proBNP and estimated glomerular filtration rate values were 1,170 (385-3,176) pmol/L and 81 (62-100) mL/min/1.73 m2, respectively. Median follow-up was 5.2 (2.6-9.2) years. Overall, NYHA functional class and LVIDD trajectories were U-shaped, whereas LVEF and NT-proBNP concentrations markedly improved during the first year and remained stable thereafter. However, the evolution of HF parameters significantly differed with respect to HF category and aetiology, with greater improvements seen in patients with HFrEF of non-ischaemic origin. Improvements in HF variables were associated with optimization of HF therapy, notably with initiation and up-titration of renin-angiotensin-system blockers. CONCLUSION: This study provides insights into the natural history of HF in a large cohort of well-treated chronic HF outpatients with respect to subgroups of HF and different aetiologists.

Prognostic relevance of gradual weight changes on long-term mortality in chronic heart failure.

BACKGROUND AND AIMS: While obesity has been linked to better ouctomes (the obesity paradox), cachexia is associated with higher mortality in patients with heart failure with reduced ejection fraction (HFrEF). As opposed to overt cachexia, little is known about the prognostic impact of gradual, long-term weight changes in stable HFrEF. METHODS AND RESULTS: We included ambulatory patients with clinically stable chronic HFrEF on individually optimized treatment. Next to other clinical and functional parameters, changes in body weight over the past one (n = 733, group 1) or two (n = 636, group 2) years were recorded. Four-year mortality was analysed with respect to baseline BMI and changes in body weight or BMI using fractional polynomials. In addition, outcome was stratified by BMI categories (18.5-25 kg/m2: normal weight, >25-30 kg/m2: overweight, >30 kg/m2: obesity). An obesity paradox was present in both groups, with overweight and obese patients having the best prognosis. In both groups, a gradual weight gain of 5% was associated with the lowest mortality, whereas mortality steadily increases with increasing weight loss. Excessive weight gain >10% was also related to higher mortality. Stratification by baseline BMI categories revealed that weight loss was most detrimental in normal weight patients, whereas the prognostic impact of weight change was weaker in obese patients. CONCLUSION: In patients with chronic HFrEF, gradual weight loss is associated with steadily increasing mortality, whereas a weight gain of 5% is related to the best prognosis. Prevention of any inappropriate weight loss might be a therapeutic goal in HFrEF patient care.

The Obesity Paradox in Heart Failure: Is It Still Valid in Light of New Therapies?

BACKGROUND: Obesity increases the risk of cardiovascular disease and heart failure (HF). However, in patients with established HF, many studies observed greater survival with increasing adiposity. This counterintuitive observation has been termed the "obesity paradox." In recent years, new HF therapies have emerged that improve prognosis in patients with HF. Some of these, such as sodium-glucose cotransporter 2 inhibitors (SGLT2i), cause weight loss and may therefore interfere with the obesity paradox. SUMMARY: This article is a narrative review on the relationship between body weight and outcomes in patients with HF with special focus on new HF treatments. PubMed was searched for studies reporting the prognostic impact of obesity in HF from 2002 to February 22, 2022. More than 400 records were examined, with 150 being included in the present review. Literature provides evidence for an obesity paradox in a broad range of HF patients, including acute and chronic HF across the spectrum of left ventricular ejection fraction. It has been verified in HF patients treated with SGLT2i but not in those using sacubitril/valsartan. Cardiorespiratory fitness and the severity of HF seem to be important confounders of the obesity paradox in HF. While unintentional weight loss is associated with a poor prognosis in HF, weight loss associated with SGLT2i treatment appears safe. KEY MESSAGES: Consensus has yet to emerge as to whether the obesity paradox is a true phenomenon in HF. As cardiorespiratory fitness is strongly associated with prognosis and significantly modifies the relationship between adiposity and survival in HF, regular physical activity is recommended irrespective of the body weight. In HF patients with severe obesity, a modest weight reduction of 5-10% may be reasonable to improve HF symptoms and quality of life.

Comparative efficacy of sodium-glucose cotransporter-2 inhibitors (SGLT2i) for cardiovascular outcomes in type 2 diabetes: a systematic review and network meta-analysis of randomised controlled trials.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) improve cardiovascular outcomes in patients with type 2 diabetes mellitus (T2D). The comparative efficacy of individual SGLT2i remains unclear. We searched PubMed, www.clinicaltrials.gov and the Cochrane Central Register of Controlled Trials for randomised controlled trials exploring the use of canagliflozin, dapagliflozin, empagliflozin or ertugliflozin in patients with T2D. Comparators included placebo or any other active treatment. The primary endpoint was all-cause mortality. Secondary endpoints were cardiovascular mortality and worsening heart failure (HF). Evidence was synthesised using network meta-analysis (NMA). Sixty-four trials reporting on 74,874 patients were included. The overall quality of evidence was high. When compared with placebo, empagliflozin and canagliflozin improved all three endpoints, whereas dapagliflozin improved worsening HF. When compared with other SGLT2i, empagliflozin was superior for all-cause and cardiovascular mortality reduction. Empagliflozin, canagliflozin and dapagliflozin had similar effects on improving worsening HF. Ertugliflozin had no effect on any of the three endpoints investigated. Sensitivity analyses including extension periods of trials or excluding studies with a treatment duration of < 52 weeks confirmed the main results. Similar results were obtained when restricting mortality analyses to patients included in cardiovascular outcome trials (n = 38,719). Empagliflozin and canagliflozin improved survival with empagliflozin being superior to the other SGLT2i. Empagliflozin, canagliflozin and dapagliflozin had similar effects on improving worsening HF. Prospective head-to-head comparisons would be needed to confirm these results.

Relative Efficacy of Spironolactone, Eplerenone, and cAnRenone in patients with Chronic Heart failure (RESEARCH): a systematic review and network meta-analysis of randomized controlled trials.

This study aims to assess the comparative benefit and risk profile of treatment with mineralocorticoid receptor antagonists (MRAs) with regard to all-cause mortality (primary endpoint), cardiovascular mortality, or heart failure (HF)-related hospitalization (secondary endpoints) and the safety endpoints hyperkalemia, acute renal failure, and gynecomastia in patients with chronic HF. We conducted a systematic review and network meta-analysis following PRISMA-P and PRISMA-NMA guidelines. From 16 different sources, 14 randomized controlled trials totaling 12,213 patients testing an active treatment of either spironolactone, eplerenone, or canrenone/potassium-canreonate in adults with symptomatic HF due to systolic dysfunction reporting any of the above endpoints were retained. Efficacy in comparison to placebo/standard medical care with respect to all-cause mortality was confirmed for spironolactone and eplerenone while no conclusion could be drawn for canrenone (HR 0.69 (0.62; 0.77), 0.82 (0.75; 0.91), and 0.50 (0.17; 1.45), respectively). Indirect comparisons hint a potential (non-significant) preference of spironolactone over eplerenone (HR 0.84 (0.68; 1.03)). The overall risk of bias was low to intermediate. Results for secondary endpoints as well as sensitivity analyses essentially mirrored these findings. The beta-blocker adjusted meta-analysis for the primary endpoint showed the same tendency as the unadjusted one (HR 0.39 (0.07; 2.03)). Results need to be interpreted with caution, though, as the resultant mix of patient- and study-level covariates produced unstable statistical modeling. We found no significant and systematic superiority of either MRA regarding efficacy toward all endpoints considered in both direct and indirect comparisons.

READY: relative efficacy of loop diuretics in patients with chronic systolic heart failure-a systematic review and network meta-analysis of randomised trials.

The majority of patients with chronic heart failure (HF) receive long-term treatment with loop diuretics. The comparative effectiveness of different loop diuretics is unknown. We searched PubMed, clinicaltrials.gov , the Cochrane Central Register of Controlled Trials and the European Union Clinical Trials Register for randomised clinical trials exploring the efficacy of the loop diuretics azosemide, bumetanide, furosemide or torasemide in patients with HF. Comparators included placebo, standard medical care or any other active treatment. The primary endpoint was all-cause mortality. Secondary endpoints included cardiovascular mortality, HF-related hospitalisation and any combined endpoint thereof. Hypokalaemia and acute renal failure were defined as additional safety endpoints. Evidence was synthesised using network meta-analysis (NMA). Thirty-four trials reporting on 2647 patients were included. The overall quality of evidence was rated as moderate. NMA demonstrated no significant differences between loop diuretics with respect to all-cause mortality, cardiovascular mortality or hypokalaemia. In contrast, torasemide ranked best in terms of HF hospitalisation, and there was a trend towards benefits with torasemide with regard to occurrence of acute renal failure. Sensitivity analyses excluding trials with a follow-up < 6 months, trials with a cross-over design and those including < 25 patients confirmed the main results. We found no significant superiority of either loop diuretic with respect to mortality and safety endpoints. However, clinicians may prefer torasemide, as it was associated with fewer HF-related hospitalisations.

Hemodynamic Determinants of the Biologic Variation of N-Terminal Pro-B-Type Natriuretic Peptide in Patients With Stable Systolic Chronic Heart Failure.

BACKGROUND CONTEXT: Biologic variation of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in chronic heart failure (CHF) may affect blood levels and risk stratification. The sources of NT-proBNP variation are unknown. METHODS AND RESULTS: We performed NT-proBNP measurements and clinical and hemodynamic assessments in 50 patients with heart failure with reduced ejection fraction (HFrEF) who met criteria for clinical stability over 2 time intervals. Hemodynamic variables were measured with the use of inert gas rebreathing and impedance cardiography. Heart rhythm was monitored with the use of external electrocardiographic event recorders throughout the study. Determinants of NT-proBNP-levels and both absolute (ΔNT-proBNPabs) and relative (ΔNT-proBNP%) changes at 1-week and 2-week intervals were identified with the use of univariable and multivariable linear mixed-effects models and linear regression analyses, respectively. Clinical and hemodynamic variables did not significantly change between study visits. The individual variation of NT-proBNP at 2 weeks was 9.2% (range 3.9%-18.6%). Weight and glomerular filtration rate were independently associated with baseline NT-proBNP concentrations (P = .01 and P = .005, respectively). There was no relationship between absolute and relative changes of NT-proBNP at 1-week intervals and changes in clinical and hemodynamic variables. Absolute change of NT-proBNP at 2-week intervals was associated with absolute change in left cardiac work index (P = .008), and relative change in NT-proBNP at 2-week intervals was determined by relative change of thoracic fluid content index (P = .008) and diastolic blood pressure (P = .01). The coefficients of determination (R2) for the multivariable models with Δ1wkNT-proBNPabs, Δ2-weeksNT-proBNPabs, Δ1wkNT-proBNP%, and Δ2wksNT-proBNP% as dependent variables were 0.21, 0.19, 0.10, and 0.32, respectively. CONCLUSIONS: In patients with stable HFrEF, changes in clinical and hemodynamic variables only marginally contribute to the variation of NT-proBNP.

Preexisting Heart Disease Underlies Newly Diagnosed Atrial Fibrillation After Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Whether newly diagnosed atrial fibrillation (nAF) after stroke reflects underlying heart disease and represents an increased risk of cardioembolic stroke, or whether it is triggered by neurogenic mechanisms remains uncertain. We investigated, whether cardiovascular risk factors and echocardiographic parameters in patients with nAF are similar to patients with known AF (kAF) and differ from patients without AF. METHODS: Consecutive acute ischemic stroke patients were enrolled into a prospective stroke database. All patients with echocardiography were included and univariable and multivariable testing was applied to compare clinical characteristics and echocardiographic findings among patients with nAF, kAF, and no AF. RESULTS: A total of 1397 patients were included (male, 62.3%; median age, 71 years). AF was present in 320 (22.9%) patients. Of those, nAF was present in 36.2% (116/320) and kAF in 63.8% (204/320). No clinical or echocardiographic factor was independently associated with detection of nAF compared with kAF but a trend toward larger left atrial diameters in patients with kAF was observed (P=0.070). In contrast, patients with nAF were more often female (P<0.001), older (P<0.001) and had a larger left atrial diameters (P<0.001) compared with patients without AF. While stroke severity in patients with nAF and kAF was similar, patients without AF had less severe strokes. CONCLUSIONS: Stroke patients with nAF and with kAF share common cardiovascular risk factors, have similar echocardiographic findings and suffer equally severe strokes. We conclude that preexisting heart disease is the major cause of AF that is first diagnosed after stroke.

Long-term changes of renal function in relation to ace inhibitor/angiotensin receptor blocker dosing in patients with heart failure and chronic kidney disease.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have become cornerstones of therapy for chronic heart failure (CHF). Guidelines advise high target doses for ACEIs/ARBs, but fear of worsening renal function may limit dose titration in patients with concomitant chronic kidney disease (CKD). METHODS: In this retrospective observational study, we identified 722 consecutive patients with systolic CHF, stable CKD stage III/IV (estimated glomerular filtration rate [eGFR] 15-60 mL min(-1) 1.73 m(-2)) and chronic ACEI/ARB treatment from the outpatient heart failure clinics at the Universities of Hull, UK, and Heidelberg, Germany. Change of renal function, worsening CHF, and hyperkalemia at 12-month follow-up were analyzed as a function of both baseline ACEI/ARB dose and dose change from baseline. RESULTS: ΔeGFR was not related to baseline dose of ACEI/ARB (P = .58), or to relative (P = .18) or absolute change of ACEI/ARB dose (P = .21) during follow-up. Expressing change of renal function as a categorical variable (improved/stable/decreased) as well as subgroup analyses with respect to age, sex, New York Heart Association functional class, left ventricular ejection fraction, diabetes, concomitant aldosterone antagonists, CKD stage, hypertension, ACEI vs ARB, and congestion status yielded similar results. There was no association of dose/dose change with incidence of either worsening CHF or hyperkalemia. CONCLUSIONS: In patients with systolic CHF and stable CKD stage III/IV, neither continuation of high doses of ACEI/ARB nor up-titration was related to adverse changes in longer-term renal function. Conversely, down-titration was not associated with improvement in eGFR. Use of high doses of ACEI/ARB and their up-titration in patients with CHF and CKD III/IV may be appropriate provided that the patient is adequately monitored.

Interpretation of elevated baseline concentrations and serial changes of high-sensitivity cardiac troponin T in confirmed muscular dystrophies.

AIMS: Concentrations of high-sensitivity cardiac troponin T (hs-cTnT) are frequently elevated in stable patients with confirmed muscle dystrophies. However, sparse information is available on the interpretation of serial concentration changes. METHODS: Hs-cTnT was collected in 35 stable outpatients with confirmed skeletal muscle dystrophies at 0 and 1 h and after 6-12 months during scheduled outpatient visits. We simulated the effectiveness of the European Society of Cardiology (ESC) 0/1 h algorithm and assessed biological variation at 6-12 months using two established methods: reference change value (RCV) and minimal important difference (MID). RESULTS: Median baseline hs-cTnT concentrations were 34.4 ng/L [inter-quartile range (IQR): 17.5-46.2], and values > 99th percentile upper limit of normal were present in 34 of 35 patients. All patients were stable without cardiovascular adverse events during a follow-up of 6.6 months (IQR: 6-7). Median concentration change was 1.9 ng/L (IQR: 0.7-3.2) and 0.8 ng/L (IQR: 0-7.0) at 60 min and 6-9 months, respectively. Applying the criteria of the ESC 0/1 h algorithm for triage of suspected acute coronary syndrome (ACS) showed poor overall effectiveness of baseline hs-cTnT values. No patient would qualify for rule-out based on hs-cTnT less than the limit of detection, whereas five cases would qualify for rule-in based on hs-cTnT ≥ 52 ng/L. Biological variabilities at 6-12 months per MID and RCV were 1.2 ng/L [95% confidence interval (CI): 0.7-2.1] and 28.6% (95% CI: 27.9-29.6), respectively. A total of 8 (22.9%) and 25 (71.4%) cases exceeded the biological variation range, suggesting some additional myocardial damage. CONCLUSIONS: The high prevalence of elevated hs-cTnT could negatively impact the effectiveness of rule-out and rule-in strategies based on a single hs-cTnT value. Knowledge of the physiological and biological variation of hs-cTnT after 6-12 months is helpful to detect the progression of cardiac involvement or to search for cardiac complications including but not limited to arrhythmias that may trigger acute or chronic myocardial damage.

Glycaemic control and insulin therapy are significant confounders of the obesity paradox in patients with heart failure and diabetes mellitus.

BACKGROUND: A high body mass index (BMI) confers a paradoxical survival benefit in patients with heart failure (HF) or diabetes mellitus (DM). There is, however, controversy whether an obesity paradox is also present in patients with HF and concomitant DM. In addition, the influence of glycaemic control and diabetes treatment on the presence or absence of the obesity paradox in patients with HF and DM is unknown. METHODS: We identified 2936 patients with HF with reduced ejection fraction (HFrEF) in the HF registries of the universities of Heidelberg, Germany, and Hull, UK (general sample). Of these, 598 (20%) were treated for concomitant DM (DM subgroup). The relationship between BMI and all-cause mortality was analysed in both the general sample and the DM subgroup. Patients with concomitant DM were stratified according to HbA1c levels or type of diabetes treatment and analyses were repeated. RESULTS: We found an inverse BMI-mortality relationship in both the general sample and the DM subgroup. However, the obesity paradox was less pronounced in patients with diabetes treated with insulin and it disappeared in those with poor glycaemic control as defined by HbA1c levels > 7.5%. CONCLUSION: In patients with HFrEF, a higher BMI is associated with better survival irrespective of concomitant DM. However, insulin treatment and poor glycaemic control make the relationship much weaker.

Haemodynamic Effects of Sacubitril/Valsartan Initiation in Outpatients with Chronic Heart Failure.

BACKGROUND: Sacubitril/valsartan (S/V) improves outcomes in patients with heart failure with reduced ejection fraction (HFrEF). Data about the immediate, short-, and intermediate-term hemodynamic effects of S/V are limited. METHODS: In this prospective observational study, 37 outpatients with chronic HFrEF were treated with S/V according to current guideline recommendations. Next to clinical, laboratory and echocardiographic parameters, haemodynamic variables were assessed non-invasively by use of inert gas rebreathing and bioimpedance cardiography at baseline and at 2-week, 3-month and 6-month follow-up. The course of variables throughout the study and the relationship between variables were analysed using fractional polynomials. RESULTS: S/V treatment resulted in short- and intermediate-term improvements in NYHA functional class (2.3 ± 0.6 at baseline vs. 1.9 ± 0.5 at 6-month follow-up, p = 0.14), 6-min walk test (453 ± 110 vs. 528 ± 98 m, p = 0.02), ejection fraction (31 ± 9 vs. 36 ± 12%, p = 0.13), pulmonary artery pressure (39 ± 10 vs. 31 ± 10 mmHg, p = 0.02), and NT-proBNP values (1702 (782-2897 vs. 1004 (599-1627) ng/L, p = 0.03). In addition, S/V caused immediate decreases in systemic vascular resistance index (SVRI) and systolic blood pressure (SBP), which were associated with a simultaneous drop in stroke volume (SV) and cardiac index (CI). However, while SVRI and SBP remained at low levels during further treatment, SV and CI restored rapidly and increased to slightly higher levels thereafter. CONCLUSION: The vasodilative effects of S/V result in immediate reductions in SVRI, SBP, SV and CI. However, S/V induces reverse cardiac remodelling, which is apparent shortly after treatment initiation and leads to improvements of clinical, functional, echocardiographic, laboratory and haemodynamic variables.

Influence of receptor selectivity on benefits from SGLT2 inhibitors in patients with heart failure: a systematic review and head-to-head comparative efficacy network meta-analysis.

BACKGROUND: Receptor selectivity of sodium-glucose cotransporter-2 inhibitors (SGLT2i) varies greatly between agents. The overall improvement of cardiovascular (CV) outcomes in heart failure (HF) patients varies between trials. We, therefore, evaluated the comparative efficacy of individual SGLT2i and the influence of their respective receptor selectivity thereon. METHODS: We identified randomized controlled trials investigating the use of SGLT2i in patients with HF-either as the target cohort or as a subgroup of it. Comparators included placebo or any other active treatment. The primary endpoint was the composite of hospitalization for HF or CV death. Secondary outcomes included all-cause mortality, CV mortality, hospitalization for HF, worsening renal function (RF), and the composite of worsening RF or CV death. Evidence was synthesized using network meta-analysis. In addition, the impact of receptor selectivity on outcomes was analysed using meta-regression. RESULTS: We identified 18,265 patients included in 22 trials. Compared to placebo, selective and non-selective SGLT2i improved fatal and non-fatal HF events. Head-to-head comparisons suggest superior efficacy with sotagliflozin as compared to dapagliflozin, empagliflozin or ertugliflozin. No significant difference was found between canagliflozin and sotagliflozin. Meta-regression analyses show a decreasing benefit on HF events with increasing receptor selectivity of SGLT2i. In contrast, receptor selectivity did not affect mortality and renal endpoints and no significant difference between individual SGLT2i was noted. CONCLUSION: Our data point towards a class-effect of SGLT2i on mortality and renal outcomes. However, non-selective SGLT2i such as sotagliflozin may be superior to highly selective SGLT2i in terms of HF outcomes.

Impact of Percutaneous Mitral Valve Repair Using the MitraClipTM System on Ventricular Arrhythmias and ICD Therapies.

Transcatheter edge-to-edge repair (TEER) using the MitraClip™ device has been established as a suitable alternative to mitral valve surgery in patients with severe mitral regurgitation (MR) and high or prohibitive surgical risk. Only limited information regarding the impact of TEER on ventricular arrhythmias (VA) has been reported. The aim of the present study was to assess the impact of TEER using the MitraClipTM device on the burden of VA and ICD (Implantable Cardioverter Defibrillator) therapies. Among 600 MitraClipTM implantations performed in our clinic between September 2009 and October 2018, we identified 86 patients with successful TEER and an active implantable cardiac device (pacemaker, ICD, CRT-P/D (Cardiac Resynchronization Therapy-Pacemaker/Defibrillator)) eligible for retrospective VA analyses. These patients presented with mainly functional MR (81.4%) and severely reduced left ventricular ejection fraction (mean LVEF 22.1% ± 10.3%). The observation period comprised 456 ± 313 days before and 424 ± 287 days after TEER. The burden of ventricular arrhythmias (sustained ventricular tachycardia (sVT) and ventricular fibrillation (VF)) was significantly reduced after TEER (0.85 ± 3.47 vs. 0.43 ± 2.03 events per patient per month, p = 0.01). Furthermore, the rate of ICD therapies (anti-tachycardia pacing (ATP) and ICD shock) decreased significantly after MitraClipTM implantation (1.0 ± 3.87 vs. 0.32 ± 1.41, p = 0.014). However, reduction of VA burden did not result in improved two-year survival in this patient cohort with severely reduced LVEF. Mitral valve TEER using the MitraClip™ device was associated with a significant reduction of ventricular arrhythmias and ICD therapies.

Prognostic value of changes in high-sensitivity cardiac troponin T beyond biological variation in stable outpatients with cardiovascular disease: a validation study.

OBJECTIVE: To evaluate the prognostic implications of longitudinal long-term changes beyond the biological variation of high-sensitivity cardiac troponin T (hs-cTnT) in outpatients with stable or asymptomatic cardiovascular disease (CV) and to assess possible differences in the prognostic value while using reference change value (RCV) and minimal important differences (MID) as metric for biological variation. METHODS: Hs-cTnT was measured at index visit and after 12 months in outpatients presenting for routine follow-up. The prognostic relevance of a concentration change of hs-cTnT values exceeding the biological variation defined by RCV and MID of a healthy population within the next 12 months following the stable initial period was determined regarding three endpoints: all-cause mortality (EP1), a composite of all-cause mortality, non-fatal myocardial infarction and stroke (EP2), and a composite of all-cause mortality, non-fatal myocardial infarction, stroke, hospitalization for acute coronary syndrome (ACS) or decompensated heart failure, and planned and unplanned percutaneous coronary interventions (PCI, EP3). RESULTS: Change in hs-cTnT values exceeding the biovariability defined by MID but not by RCV discriminated a group with a higher cardiovascular risk profile. Changes within MID were associated with uneventful course (NPV 91.6-99.7%) while changes exceeding MID were associated with a higher occurrence of all endpoints within the next 365 days indicating a 5.5-fold increased risk for EP 1 (p = 0.041) a 2.4-fold increased risk for EP 2 (p = 0.049) and a 1.9-fold increased risk for EP 3 (p < 0.0001). CONCLUSIONS: In stable outpatients MID calculated from hs-cTnT changes measured 365 ± 120 days apart are helpful to predict an uneventful clinical course. CLINICAL TRIALS IDENTIFIER: NCT01954303.

Impact of the introduction of percutaneous edge-to-edge mitral valve reconstruction on clinical practice in Germany compared to surgical valve repair.

BACKGROUND: The introduction of percutaneous mitral valve (MV) repair had an effect on clinical practice in comparison with surgical MV repair. Complete nationwide data are useful in examining how the introduction of a new technique influences clinical practice. METHODS: We analyzed procedural numbers, patient characteristics, and in-hospital outcomes for all percutaneous edge-to-edge and surgical MV reconstruction procedures performed in Germany between 2009 and 2015. RESULTS: 12,664 percutaneous edge-to-edge and 22,825 surgical MV reconstructions were recorded. Numbers increased steadily, albeit more rapidly in the percutaneous edge-to-edge group (108-4079 vs. 2923-3603 with surgical MV reconstruction). Patients with percutaneous edge-to-edge MV reconstruction were older (75.6 ± 8.8 vs 61.6 ± 13.4 years, P < 0.001) and at higher operative risk (estimated logistic EuroSCORE 13.2% vs. 4.7%, P < 0.001) compared to those undergoing surgery. However, in-hospital mortality did not differ (2.9% vs. 2.8%; P = 0.395). This was also true for the subset of 2103 patients at intermediate operative risk as defined by a logistic EuroSCORE ≥ 4% and ≤ 9%. Of note, complication rates (except acute kidney injury) were more favorable in patients undergoing percutaneous edge-to-edge reconstruction. CONCLUSIONS: Percutaneous edge-to-edge MV reconstruction has markedly changed clinical practice of MR therapy in Germany. Annual overall procedural numbers more than doubled, with a massive increase in percutaneous edge-to-edge procedures. Our data demonstrate its use mainly in high-risk patients and prove the favorable safety profile of this novel technique, with low in-hospital mortality and complication rates.

N-terminal pro brain natriuretic peptide eliminates the prognostic effect of atrial fibrillation in patients with chronic heart failure.

AIMS: Co-morbid atrial fibrillation (AF) increases both mortality and N-terminal pro brain natriuretic peptide (NT-proBNP) concentrations in patients with chronic heart failure (CHF). It is unclear whether AF worsens prognosis independently from NT-proBNP concentrations. If AF was an independent risk factor, NT-proBNP levels for outcome prediction would need to be adjusted in patients with AF. We aimed to analyse the influence of AF on the prognostic value of NT-proBNP in patients with CHF. METHODS AND RESULTS: A total of 2541 consecutive CHF patients with sinus rhythm (SR) or AF were identified in the outpatients' CHF registry of the University of Heidelberg, Germany. Of these, 250 patients with SR were individually matched to 250 patients with AF with respect to NT-proBNP, New York Heart Association functional class, sex, age, and aetiology of CHF. In the general sample, both AF and NT-proBNP were associated with all-cause mortality [hazard ratio (HR) = 1.96, 95% confidence interval (CI) 1.61-2.39, P < 0.001; and HR = 1.03 per 1000 ng/L increase, 95% CI 1.02 to 1.04, P < 0.001, respectively]. After matching, NT-proBNP retained its prognostic power (HR = 1.13 per 1000 ng/L increase, 95% CI 1.10 to 1.16, P < 0.001), but AF did not (HR = 0.91, 95% CI 0.66 to 1.25, P = 0.56). Despite similar prognosis, matched patients with SR were in more advanced CHF than were AF patients as indicated by a lower left ventricular ejection fraction (30 ± 13% vs. 34 ± 14%, P < 0.001). CONCLUSIONS: The prognostic value of NT-proBNP in CHF is not influenced by concomitant AF. AF, in return, might be a surrogate of a worse cardiac condition rather than an independent risk factor.

Long-term biological variation of high-sensitivity cardiac troponin T using minimal important differences and reference change values in stable outpatients with cardiovascular disease.

OBJECTIVE: To evaluate the long term biological variation of high-sensitivity cardiac troponin T (hs-cTnT) in stable outpatients with cardiovascular disease (CVD). METHODS: After applying 8 exclusion criteria to 965 patients, hs-cTnT was measured at index visit and at a 12-month interval in 169 stable outpatients presenting for routine follow-up visits for any CVD. Stability was defined as absence of any endpoint within the follow-up period. Reference change values (RCVs) and minimal important differences (MIDs) were determined to assess biological variation of hs-cTnT. RESULTS: MID and RCV for the 12 months interval in patients were 3.8 ng/L or 44.2%, respectively. MID and transformed MID values were lower than the corresponding RCV with a value of 5.1 ng/L for the transformed RCV and 28.1% for the transformed MID. Similar patterns were shown in different subgroups as sex, age, and renal function. We observed a baseline hs-cTnT value dependent change of MID and RCV with increasing values for MID and decreasing values for RCV which converge to stable values between a baseline hs-cTNT value of 11 to 25 ng/L. CONCLUSIONS: Biological variation of hs-cTnT over 12 months in stable outpatients depends on the concentration at index visit, and is consistent among important prespecified subgroups. MID shows a low biovariability over 12 months. Clinical Trials Identifier:NCT01954303.

Epidemiology and long-term outcome in outpatients with chronic heart failure in Northwestern Europe.

OBJECTIVE: To describe the epidemiology, long-term outcomes and temporal trends in mortality in ambulatory patients with chronic heart failure (HF) with reduced (HFrEF), mid-range (HFmrEF) or preserved ejection fraction (HFpEF) from three European countries. METHODS: We identified 10 312 patients from the Norwegian HF Registry and the HF registries of the universities of Heidelberg, Germany, and Hull, UK. Patients were classified according to baseline left ventricular ejection fraction (LVEF) and time of enrolment (period 1: 1995-2005 vs period 2: 2006-2015). Predictors of mortality were analysed by use of univariable and multivariable Cox regression analyses. RESULTS: Among 10 312 patients with stable HF, 7080 (68.7%), 2086 (20.2%) and 1146 (11.1%) were classified as having HFrEF, HFmrEF or HFpEF, respectively. A total of 4617 (44.8%) patients were included in period 1, and 5695 (55.2%) patients were included in period 2. Baseline characteristics significantly differed with respect to type of HF and time of enrolment. During a median follow-up of 66 (33-105) months, 5297 patients (51.4%) died. In multivariable analyses, survival was independent of LVEF category (p>0.05), while mortality was lower in period 2 as compared with period 1 (HR 0.81, 95% CI 0.72 to 0.91, p<0.001). Significant predictors of all-cause mortality regardless of HF category were increasing age, New York Heart Association functional class, N-terminal pro-brain natriuretic peptide and use of loop diuretics. CONCLUSION: Ambulatory patients with HF stratified by LVEF represent different phenotypes. However, after adjusting for a wide range of covariates, long-term survival is independent of LVEF category. Outcome significantly improved during the last two decades irrespective from type of HF.

Comparative effectiveness of loop diuretics on mortality in the treatment of patients with chronic heart failure - A multicenter propensity score matched analysis.

BACKGROUND: Loop diuretics are given to the majority of patients with chronic heart failure (HF). Whether the different pharmacological properties of the three guideline-recommended loop diuretics result in differential effects on survival is unknown. METHODS: 6293 patients with chronic HF using either bumetanide, furosemide or torasemide were identified in three European HF registries. Patients were individually matched on both the respective propensity scores for receipt of the individual drug and dose-equivalents thereof. RESULTS: During a follow-up of 35,038 patient-years, 652 (53.7%), 2179 (51.9%), and 268 (30.4%) patients died amongst those prescribed bumetanide, furosemide, and torasemide, respectively. In univariable analyses of the general sample, bumetanide and furosemide were both associated with higher mortality as compared with torasemide treatment (HR 1.50, 95% CI 1.31-1.73, p < 0.001, and HR 1.34, CI 1.18-1.52, p < 0.001, respectively). Mortality was higher in bumetanide users when compared to furosemide users (HR 1.11, 95% CI 1.02-1.20, p = 0.01). However, there was no significant association between loop diuretic choice and all-cause mortality in any of the matched samples (bumetanide vs. furosemide, HR 1.03, 95% CI 0.93-1.14, p = 0.53; bumetanide vs. torasemide, HR 0.98, 95% CI 0.78-1.24, p = 0.89; furosemide vs. torasemide, HR 1.02, 95% CI 0.84-1.24, p = 0.82). The results were confirmed in subgroup analyses with respect to age, sex, left ventricular ejection fraction, NYHA functional class, cause of HF, rhythm, and systolic blood pressure. CONCLUSIONS: In patients with HF, mortality is not affected by the choice of individual loop diuretics.