bluuebunny/crossref_metadata_2025 huggingface dataset:
Incidence and mortality of women diagnosed with peripartum cardiomyopathy from 1997 to 2019 in Sweden, national registry-based study
Authors: Basic C , Schaufelberger M , Svanvik T , Thunstrom E
Published: October 2022

Background

Data from previous studies indicate on increase in incidence of cardiomyopathies in Sweden. Another study confirmed high validity of diagnosis cardiomyopathy in western Sweden suggesting that a real increase in cardiomyopathy diagnosis might have occurred. Peripartum cardiomyopathy is a potentially dangerous condition that occurs few months before or up to five months after delivery.

Purpose

To assess incidence and mortality rates of women diagnosed with PPCM over last two decades in Sweden.

Methods

All women 18 to 50 years of age registered in the National Patient Register (NPR) in the period 1st January 1997 to 31st December 2019 were included. With the use of personal identification number (PIN), the data was than linked to other registers. Data on pregnancies were obtained from the Swedish Medical Birth Register (MBR) and data on the time of death and causes of death were gained from the Cause of Death Register. Women with PPCM were identified in the NPR using the international classification code for disease ICD-10 codes 090.3 as well as other coexisting conditions. The observation time was divided into fallowing periods: 1997–2001, 2002–2004, 2005–2007, 2008–2010, 2011–2013, 2014–2016 and 2017–2019.

Results

In total, over the period of 23 years we identified 2376988 deliveries. There were 23 women diagnosed with PPCM. The prevalence of women who received the diagnostic code for PPCM increased over time from 0.003% in the first time period to 0.012% in the last time period (Figure 1). In total 4.5% of women diagnosed with PPCM died during the observation time.

Conclusion

In this national, register-based study 187 women had diagnose PPCM. Total mortality over twenty years of time was low. Worryingly, we observed a four-fold increase in the use of diagnostic code for PPCM, suggesting an increse in incidence of PPCM over the last twenty-three years. More research is needed to investigate reasons for that.

Funding Acknowledgement

Type of funding sources: None.
A comprehensive study of the incremental prognostic value of novel biomarkers in PARADIGM-HF (Bio-PREDICT-HF)
Authors: McDowell K , Simpson J , Jhund P S , Abraham W T , Claggett B , Cunningham J , Desai A S , Kober L , Prescott M , Rouleau J L , Swedberg K , Zile M R , Solomon S D , Packer M , McMurray J J V
Published: October 2022

Background

Although multiple novel biomarkers have individually been shown to predict outcomes in patients with HFrEF, the value of these over and above conventional clinical and laboratory variables, plus natriuretic peptides, is uncertain.

Purpose

To test the incremental predictive value of 11 novel biomarkers added to a recent prognostic model 1 (PREDICT-HF) derived in PARADIGM-HF and validated in ATMOSPHERE and the Swedish heart failure registry. The PREDICT-HF model includes clinical variables, standard laboratory variables, and BNP or NT-proBNP.

Methods

1559 participants enrolled in PARADIGM-HF had all 11 biomarkers of interest measured. These reflected different pathophysiological pathways: (i) myocyte injury (high sensitivity cardiac troponin T), (ii) cardiac remodelling and inflammation (growth stimulation expressed gene 2, growth differentiation factor-15 and galectin-3), (iii) extracellular matrix remodelling (matrix metalloproteinase-2, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1), (iv) neurohormonal pathways (aldosterone) and (v) renal dysfunction and injury (cystatin C, kidney injury molecule-1 and urinary albumin to creatinine ratio). The incremental prognostic value of these biomarkers was evaluated using Harrell's C statistic.

Results

The mean age of participants studied was 67.3 (SD 9.9) years, 1254 (80%) were men and 1103 (71%) were in NYHA class II. During a median follow-up of 31 months, 197 patients died and 300 experienced the primary composite outcome (cardiovascular death or heart failure hospitalization).

When each candidate biomarker (log unit) was added individually to the PREDICT-HF base model, GDF-15, ST2, TIMP1, cystatin C, hsTnT and UACR were independent predictors of all-cause mortality (Table 1). GDF-15, TIMP1, hs-TnT and cystatin C consistently increased the risk of both all-cause mortality and the primary outcome. Individuals who had all 4 biomarkers elevated (compared to none elevated) had the highest risk: HR for all-cause mortality 3.65 (2.01–6.64), p<0.0001. Adding these 4 biomarkers to the baseline PREDICT HF model improved the C statistic for all-cause mortality from 0.726 to 0.745.

Conclusion

Several novel biomarkers provide meaningful additional prognostic information in patients with HFrEF. A multimarker approach incorporating biomarkers reflecting different pathophysiological pathways added most information. This approach may be useful in refining risk and targeting treatment.

Funding Acknowledgement

Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): The PARADIGM-HF trial was funded by Novartis.J.J.V.M is supported by a British Heart Foundation Centre of Excellence Grant
Fibroblast growth factor-23 is an independent predictor of hospitalization for heart failure and major cardiovascular adverse events in patients undergoing cardiac surgery
Authors: Hofer F , Hammer A , Kazem N , Koller L , Steinacher E , Steinlechner B , Laufer G , Niessner A , Sulzgruber P
Published: October 2022

Background

Fibroblast growth factor 23 (FGF-23) plays a crucial role in regulating phosphate and vitamin D metabolism and was proved to be associated with an increased risk for fatal events in individuals suffering from cardiovascular diseases. Since data on the prognostic potential of FGF-23 in individuals undergoing cardiac valve and/or coronary artery bypass graft (CABG) surgery are scarce, the specific objective of this study was to investigate the impact of FGF-23 on postoperative complications, particularly postoperative atrial fibrillation (POAF), hospitalization for heart failure (HHF) and cardiovascular (CV) death in an unselected patient population after cardiac surgery.

Methods

Within the present investigation, patients undergoing elective cardiac valve and/or CABG surgery were prospectively enrolled at the Department of Cardiac Surgery of a medical university. Blood samples were taken prior to surgery and FGF-23 concentrations were subsequently assessed. Patients were followed prospectively until the primary study endpoint (CV death) was reached.

Results

In total, 462 patients were included in the present analysis and followed over a median of 3.9 years. During follow-up 67 (14.5%) patients died. The patients' median age was 70 years (interquartile range [IQR] 60 to 75) and 133 (28.8%) were female. The median FGF-23 level in the entire study population was 1.9 pmol/L (IQR 1.2 to 3.5). Notably, individuals with POAF showed significantly higher FGF-23 levels than patients without (p<0.001). After stratification into tertiles (T) of FGF-23 patients in the highest FGF-23 tertile showed greater rates of HHF, all-cause and CV death. Furthermore, FGF-23 was consistently associated with POAF development showing an adjusted OR for a 1-unit increase in standardized log-transformed biomarker of 1.28 (95% CI: 1.01 to 1.63), along with an adjusted OR of 2.04 (95% CI 1.33 to 3.13, p=0.001) for the pre-defined high risk cut-off value. A steady risk increase for HHF and CV death among ascending FGF-23 tertiles has been noted. Moreover FGF-23 showed strong discriminatory performance (area under the curve [AUC] 0.69, 95% CI 0.61–0.77). Reclassification analysis indicated that the addition of FGF-23 to NT-proBNP provides a significant improvement in risk discrimination (NRI at the event rate: 0.58, 95% CI 0.34–0.81, p-value <0.001; IDI: 0.03, 95% CI 0.01–0.05, p-value= 0.001).

Conclusion

FGF-23 proved to be a strong and independent predictor for POAF, HHF and CV death in individuals undergoing cardiac surgery. Considering an individualized risk assessment, routine preoperative FGF-23 evaluation may improve detection of patients at risk, who require in-depth clinical attention throughout the peri- and postoperative phase after cardiac surgery.

Funding Acknowledgement

Type of funding sources: None.
Prognostic value of brain natriuretic peptide in COVID-19 with or without acute heart failure
Authors: Bergami M , Manfrini O , Cenko E , Dorobantu M , Demiri I , Fronea O , Kedev S , Mjehovic P , Pasalic M , Poposka L , Stefanovic M , Vavlukis M , Milicic D , Zdravkovic M , Bugiardini R
Published: October 2022

Background

Although Brain Natriuretic Peptide (BNP) provides strong prognostic information of an unfavorable outcome in patients with acute heart failure (AHF), there is little information of its relevance as a biomarker for outcomes in COVID-19 and its complications

Purpose

To evaluate the association of increased BNP levels with complications and in-hospital mortality in a cohort of hospitalized COVID-19 patients.

Methods

The study included COVID-19 patients with data on BNP levels included in the ISACS COVID-19 registry. The population was categorized according to the presence of peak BNP levels ≥100 pg/mL during hospitalization. Primary outcomes included in-hospital mortality, AHF or acute respiratory failure (ARF, defined as PiO2/FiO2<300 mmHg or need for mechanical ventilation). Calculations were conducted using age and sex-adjusted multivariable logistic regression analyses. Results were also stratified according to presence or absence of cardiovascular disease (CVD) history. Differences between subgroups were verified for statistical significance using test for interaction.

Results

Of the 1152 patients included in the study, 615 (53.4%) had elevated BNP levels. These subjects were older (69.9±13.8 vs 59.1±16.8, p-value<0.001), had higher rates of cardiovascular risk factors (82.9% vs 57.7%, p-value<0.001) and presented more frequently with a prior history of CVD (either ischemic heart disease, cerebrovascular disease, venous thromboembolism, atrial fibrillation or a history of revascularization) (50.1% vs 27.5%, p-value<0.001). No sex differences were observed. When considering outcomes, BNP levels ≥100 pg/mL were associated with increased rates of in-hospital mortality (32.9% vs 4.9%, p-value<0.001), even after adjustment for demographic characteristics (OR: 7.35; 95% CI: 4.75–11.40; p-value<0.001). High BNP levels were also strongly associated with an increased risk of AHF (OR 19.9; 95% CI 8.6–45.9; p-value<0.001), a correlation that persisted both in patients with and without a prior CVD history (p for interaction=0.29). Of note, patients with elevated BNP also had a higher likelihood of developing ARF (OR 2.7; 95% CI 2.1–3.6; p-value<0.001), even in absence of AHF (OR 3.00; 95% CI 2.20–4.1; p-value<0.001).

Conclusions

In COVID-19, blood BNP level not only appears to be predictor of in-hospital mortality and AHF but was also independently associated with an increased risk of ARF. This finding supports the routine use of BNP in all patients admitted to hospital for COVID-19, regardless of a prior history of CVD.

Funding Acknowledgement

Type of funding sources: None.
Echocardiographic diversity associated with exercise capacity in heart failure precursor stage B: the Project Baseline Health Study
Authors: Cauwenberghs N , Daubert M A , Salerno M , Haddad F , Kuznetsova T , Douglas P S
Published: October 2022

Background

The current paradigm to stage heart failure (HF) defines precursor stage B (or “pre-HF”) as having any subclinical change in cardiac structure or function. Yet, HF risk factors and type of cardiac abnormality may induce clinically relevant heterogeneity in HF stage B. Therefore, we assessed clinical and echocardiographic heterogeneity within stage B HF and its association with exercise capacity in a large community-based sample.

Methods

2071 participants to the Baseline Health Study (50.4±17.0 years, 56.2% women, 37.8% hypertensive) underwent echocardiography and physical performance testing including 6-minute walk (6MWT) and treadmill exercise test. We defined echocardiographic profiles of left and right heart remodeling and dysfunction using sex-specific internal reference values. We assessed HF stages (0-A-B-C-D) following HF societies recommendations. stage B participants were stratified according to presence/absence of HF risk factors and to the most severe echocardiographic abnormality present (reduced ejection fraction (EF), left ventricular (LV) hypertrophy/diastolic dysfunction or other abnormalities). We reported associations between physical performance metrics and HF (sub)stages.

Results

Stage B HF was present in 516 participants (24.9%). Within stage B HF, we observed a large diversity in echocardiographic profiles. Yet, stage B participants without HF risk factors (n=96, 18.6% of stage B) predominantly presented echo abnormalities other than LV diastolic dysfunction, hypertrophy and reduced EF, while their physical performance profile resembled that of people with normal echocardiography without HF risk factors. In contrast, stage B participants with HF risk factors (n=420) were characterized by LV diastolic dysfunction, hypertrophy or reduced EF, three phenotypes associated with lower 6MWT distance and lower exercise capacity. Concomitant presence of HF risk factors and LV dysfunction/hypertrophy was associated with worst physical performance.

Conclusions

We observed a wide clinical and echocardiographic diversity affecting physical performance in HF precursor stage B when defined by the current staging paradigm. Concomitant presence of HF risk factors and LV dysfunction/hypertrophy may mark individuals at highest risk for progression towards overt HF.

Funding Acknowledgement

Type of funding sources: Other. Main funding source(s): This research was made supported by an institutional research grant from Verily Inc. (CA, USA) and by the Research Foundation Flanders (Belgium).
Prognostic relevance of left ventricular global longitudinal strain in patients with heart failure and reduced ejection fraction
Authors: Chimed S , Stassen J , Galloo X , Meucci M C , Van Der Bijl P , Marsan N A , Delgado V , Bax J J
Published: October 2022

Background

Patients with heart failure (HF) and reduced ejection fraction (HFrEF) are complex patients who often have a high prevalence of comorbidities and cardiovascular risk factors. However, risk stratification and treatment decision in these patients mainly depend on simple measurements of left ventricular (LV) ejection fraction (EF). In the present study, we investigated the prognostic significance of LV global longitudinal strain (GLS) along with important clinical and echocardiographic risk factors in patients with HFrEF.

Methods

Patients who had a first echocardiographic diagnosis of LV systolic dysfunction, defined as LVEF ≤45%, were identified. LV GLS was measured with speckle-tracking echocardiography and represented by a positive value. To divide the study population into 2 groups, spline curve analysis was used to derive the optimal threshold value of LV GLS (i.e. where the predicted hazard ratio for the endpoint was ≥1) (Figure 1). Patients were followed up for worsening HF, as well as the composite endpoint of worsening HF and all-cause mortality.

Results

A total of 2394 patients (mean age 63±12 years, 75% men) were analyzed. During a median follow-up of 60 months (interquartile range [IQR] 31–60 months), 306 patients (13%) experienced worsening HF and the composite endpoint of worsening HF and all-cause mortality occurred in 673 patients (28%). The 5-year event-free survival rates for the primary and secondary endpoint were significantly lower in the patients who had LV GLS ≤10% compared to the patients who had LV GLS >10% (Figure 2A for worsening HF and Figure 2B for the composite endpoint of worsening HF and all-cause mortality). After adjustment for important clinical and echocardiographic risk factors, including HF treatments and baseline LVEF, baseline LV GLS remained independently associated with a higher risk of worsening HF (HR=0.95, 95% CI 0.90–0.99, p=0.029) and the composite of worsening HF and all-cause mortality (HR=0.94, 95% CI 0.90–0.97, p=0.001).

Conclusions

Baseline LV GLS is associated with long-term prognosis in patients with HFrEF, independently from various clinical and echocardiographic risk factors.

Funding Acknowledgement

Type of funding sources: None.
The prognostic significance of the echocardiographic evaluation of left ventricular myocardial deformation indices at peak cardiopulmonary exercise in patients with severe dilated cardiomyopathy
Authors: Triantafyllidi H , Birmpa D , Fambri A , Benas D , Ikonomidis I , Iliodromitis E K
Published: October 2022

Background

Cardiopulmonary exercise testing (CPET) integrally estimates exercise capacity (peak VO2) and cardiovascular (CV) prognosis (VE/VCO2 slope) in patients with dilated cardiomyopathy (DCM). Myocardial deformation indices (MDI), measured by speckle tracking imaging (STI), allow reliable measurements of left ventricular (LV) function. Little is known about the exercise-induced changes of the multidimensional mechanical properties of the heart and their impact in patient's survival. We aimed to investigate the predictive role regarding 3-year survival of LV MDI (at rest and peak exercise) as well as the main CPET parameters (peak VO2, VE/VCO2 slope) in DCM patients with reduced ejection fraction (EF) using as primary combined end-point the heart transplantation and all cause death.

Patients and methods

We evaluated LV function using STI at rest and at peak exercise during the same CPET session in 53 DCM patients (54±12 years, 76% males, ejection fraction 33±9%).We measured global longitudinal strain (GLS), longitudinal strain rate at systole (LSRS) and diastole (LSRD) at baseline and at peak CPET along with CPET parameters. After a period of 38±15 months, all DCM patients were evaluated by a telephone interview.

Results

From the whole population, totally 7 patients (13%) reached the primary end-point (Group A) as 2 patients were submitted to heart transplantation and 5 patients died (60±13 years, 86% males, EF = 28±9%) while 46 patients remained alive at 3-year follow-up (Group B, 53±12 years, 74% males, EF = 33±9%). We found that Group A patients had similar age, sex and EF but reduced peak VO2 (p=0.04) and increased VE/VCO2 slope (p=0.004), impaired GLS at baseline and peak exercise (p=0.02 and p=0.04, respectively) as well as LSRS at peak exercise (p=0.05) compared to Group B patients.

Conclusions

The evaluation of GLS (rest and peak exercise) and LSRS (peak exercise) as systolic indices of LV myocardial deformation adds valuable information regarding CV prognosis in patients with severe idiopathic DCM. A combined baseline work-up protocol consisted of MDI evaluation at rest and exercise plus the CPET indices may characterize the true severity of heart failure in a DCM population.

Funding Acknowledgement

Type of funding sources: None.
Inferior vena cava diameter adds information to pulmonary artery systolic pressure in outpatients with heart failure
Authors: Iaconelli A , Pellicori P , Maffia P , Clark A L , Cleland J G F
Published: October 2022

Background

Evaluation of pulmonary arterial pressure (PAP) is recommended by guidelines to diagnose and monitor congestion in patients with heart failure (HF). However, the high compliance of the venous system might buffer the effects of a large increase in intravascular volume and delay an elevation in PAP. Therefore, measuring inferior vena cava (IVC) diameter by ultrasounds might add important information in patients with HF, regardless of PAP.

Aim

To evaluate the relationship between the IVC diameter and systolic PAP (PAsP) assessed by echocardiography with mortality in outpatients with HF.

Methods

We enrolled consenting out-patients attending a community HF clinic for initial diagnosis or follow-up in Kingston upon Hull, UK between 2009–2012. HF was defined as the presence of relevant symptoms and signs and objective evidence of cardiac dysfunction: either a left ventricular systolic function (LVEF) <50% or elevated amino-terminal pro-brain natriuretic peptide (NT-proBNP) ≥125 pg/ml. IVC was considered dilated when >2.0 cm, PAsP elevated when >35 mmHg.

Results

Amongst the 874 patients enrolled, median age was 75 years, 68% were men, median LVEF was 44% and median NT-proBNP was 1125 pg/ml. 468 patients (54%) had normal IVC and PAsP, 117 (13%) had normal IVC but elevated PAsP, 75 (8%) had dilated IVC but normal PAsP and 214 (25%) had both dilated IVC and elevated PAsP. Compared to those with normal IVC and PAsP, those with elevated PAsP but normal IVC were older, more likely to be women, and had higher LVEF and NT-proBNP, whilst those with dilated IVC but normal PAsP had similar age and LVEF, but more signs of congestion and higher NT-proBNP. Compared to those with both normal IVC and PAsP (reference), those with dilated IVC but normal PAsP (HR: 1.83; CI: 1.04–3.25; P=0.037) or elevated PAsP but normal IVC (HR: 1.88; CI: 1.25–2.85; P=0.003) had a similarly increased risk of death but those with a dilated IVC and elevated PAsP had the greatest risk (HR: 4.16; CI: 3.10–5.57; P<0.001).

Conclusion

A dilated IVC is associated with mortality even when PAsP is not elevated. Tailoring treatments to reduce IVC diameter is a strategy worth exploring to improve outcomes in outpatients with heart failure.

Funding Acknowledgement

Type of funding sources: None.
Which parameter of right ventricular function predicts outcome in acute heart failure
Authors: Berrill M , Ashcroft E , Baltabaeva A
Published: October 2022

Aims

RV systolic dysfunction is being recognised as significant prognostic marker of poor outcome in acute heart failure. We aimed to characterise the predictive capacity of RV systolic function on long term outcomes in those hospitalised in AHF.

Methods

418 consecutive AHF patients presenting over 12 months were prospectively recruited and underwent bed-side echocardiography within 24 hours of recruitment. 8 parameters of RV systolic function were assessed in predicting 2-year mortality by identifying the sensitivity and specificity associated with the maximum Youden Index. These cut-offs were used as binary determinants of outcome in unadjusted Kaplan-Meier analysis.

Results

7/8 binary assessments of RV systolic dysfunction were significantly predictive of 2 year outcome, including the tricuspid annulus systolic plane excursion (TAPSE) ≤1.6cm, RV fractional area change (RVFAC) ≤38.2%, peak systolic and end systolic RV inferior wall global longitudinal strain of >−18.6% and >−18%, inferior free wall average strain rate >−1.8 s–1, a 2D ellipsoid model of RVEF <46.9% and the ratio of the TAPSE to systolic pulmonary artery pressure <0.0268 cm/mmHg (all p<0.02). Crude hazard ratios ranged from 1.50–2.13. Only the RV tissue doppler imaging S wave velocity ≤0.09m/s could not delineate those at risk of poor outcome (p=0.17).

Discussion

A constellation of RV systolic assessment could effectively delineate those at risk of poor outcome following hospitalisation for AHF. The cut-offs identified were broadly similar to those from the ESC guidelines on RV chamber assessment. Only the S wave velocity from tissue doppler imaging was not predictive. This may be due to more angle dependency in measurements alongside the impact of loading conditions in acute heart failure. RV dysfunction should remain a serious focus of attention from acute physicians and echosonographers.

Funding Acknowledgement

Type of funding sources: Private company. Main funding source(s): Abbott
Prognostic impact of echocardiographic derived precapillary wedge pressure and pulmonary vascular resistances in patients with heart failure
Authors: Giannoni A , Gentile F , Buoncristiani F , Chubuchny V , Sciarrone P , Panichella G , Bazan L , Gasperini S , Fabiani I , Taddei C , Poggianti E , Petersen C , Pasanisi E , Passino C , Emdin M
Published: October 2022

Background

A reliable echocardiographic algorithm for the estimation of precapillary wedge pressure (PCWP) and pulmonary vascular resistances (PVR) has been recently validated by our group in a large cohort of patients undergoing right heart catheterization (RHC) (1). Those metrics may add relevant clinical and prognostic information in patients with heart failure (HF).

Objective

To assess the clinical/prognostic significance of echocardiographic derived PCWP and PVR in a large cohort of chronic HF patients on modern treatments.

Methods

Outpatients with chronic HF with either reduced (≤40%) or mildly reduced LVEF (41–49%) underwent a thorough clinical multiparametric assessment and were followed-up for a composite endpoint of cardiac death, appropriate ICD shock, or first HF hospitalization.

Results

Out of 1,483 patients prospectively enrolled (70±12 years, 73% males, 42% ischemic etiology, LVEF 35±8%), PCWP (16.4±5.8 mmHg) was elevated (>15 mmHg) in 53% of cases, while PVR (1.7±0.7) was elevated (>3 WU) in 6% of cases. Of the latter group, most (92%) had also elevated PCWP. Patients with increased PCWP were older, had a higher heart rate and lower cardiac output, showed a higher degree of left and right chamber remodeling, had a higher neurohormonal activation, worse renal function, worse functional capacity and ventilatory efficiency on effort (all p<0.001). Those patients with high PCWP and PVR showed higher heart rate and pulmonary pressures, lower cardiac output, and right ventricular function, higher neurohormonal activation, lower functional capacity and ventilatory efficiency on effort compared to patients with high PCWP but normal PVR (all p<0.01). The optimal prognostic cut-point was identified for both PCWP (16.2 mmHg) and PVR (2 WU) by log-rank maximal likelihood ratio. Over a median follow-up of 22 (8–37) months, both measures significantly stratified patients for the risk of the primary endpoint at Kaplan-Meier analysis (log-rank 92.9, p<0.001 for PCWP; log-rank 17.3, p<0.001 for PVR). At multivariable Cox regression analysis (adjusted for age, sex, ischemic HF etiology, renal function, LVEF, and NT-proBNP), PCWP (hazard ratio, HR 1.77 [95% CI 1.30–2.40], p<0.001) but not PVR (HR 1.15 [95% CI 0.88–1.51], p=0.31) remained an independent predictor of the primary outcome.

Conclusion

The estimation of PCWP and PVR by echocardiography add relevant clinical and prognostic information and may help in the decision making in patients with HF.

Funding Acknowledgement

Type of funding sources: None.
ARNI effects in HFrEF. Risk reduction beyond LVEF
Authors: Boehmer A A , Schubert T , Zezyk C , Kaess B , Ehrlich J R
Published: October 2022

Background

The imbalance of cardiac autonomic nervous system function plays an important role in heart failure associated mortality. ARNI has demonstrated a paramount effect in reducing risk of death and hospitalization for worsening of heart failure. However, its exact mechanism of action remains only partly understood. We sought to prospectively compare heart rate variability as a noninvasive measure of cardiac autonomic nervous system function.

Methods

The study design was prospective sequential observational. Patients served as their own internal control. Patients with heart failure with reduced ejection fraction (HFrEF) receiving optimal medical therapy who were scheduled for a switch to ARNI therapy underwent echocardiography and a standardized 30-minute 12-lead Holter ECG recording before starting ARNI therapy. A monitoring of the parameters was performed 3 months after the start of therapy. Physicians were instructed to increase ARNI dose to the highest tolerated or maximum dose. Besides left ventricular ejection fraction (LVEF) we assessed heart rate (HR), standard deviation of normal-to-normal intervals (SDNN) and mean square of differences between consecutive R-R intervals (RMSSD).

Results

We recruited 55 patients and baseline characteristics were as follows: age 65±12 years, male sex 78%, NT-proBNP 4989±809 pg/ml, LVEF 28±6%, HR 75±9 bpm, SDNN 43±2 ms, RMSSD 19±2 ms. All patients received beta-blocker therapy and the dosage was similar at baseline and follow-up. After 3 months of ARNI therapy, heart rate showed a significant reduction of 7% (74±14 bpm vs. 69±11 min, P=0.005). SDNN increased by 49% (43±2 ms vs. 64±4 ms, P<0.001) and RMSSD by 42% (19±2 ms vs. 27±3 ms, P=0.01). These results were accompanied by increased LVEF (28±6% vs. 38±10%, P<0.001) and reduced plasma NT-proBNP levels (4989±809 pg/ml vs. 2602±87 pg/ml, P<0.04). NYHA Class of affected patients changed from III to II.

Conclusion

After changing from ACE/AT1-I to ARNI, significant improvement of autonomic cardiac nervous system function could be observed. ARNI apparently activates the parasympathetic nervous system as suggested by decreased HR and increased SDNN and RMSSD. Therefore, part of its cardioprotective and beneficial effects may relate to the restoration of autonomic cardiac nervous system function. Potential beneficial effects regarding incidence of sudden cardiac arrest may relate to these observations.

Funding Acknowledgement

Type of funding sources: None.
Heart failure therapy in new onset heart failure versus chronic heart failure: an analysis of 90,383 patients from the Swedish Heart Failure Registry (SwedeHF)
Authors: Shahim A , Savarese G , Dahlstrom U , Lund L H , Linde C , Hage C
Published: October 2022

Background

The period after newly diagnosed heart failure (HF) presents challenges in HF management. Although recent HF guidelines recommend immediate initiation of HF therapies, little is known about real life HF therapy.

Purpose

We analyzed differences in treatment management in patients with new onset and chronic HF across the ejection fraction (EF) spectrum in the large nationwide Swedish HF registry.

Methods

In patients enrolled 2000–2018 in the Swedish HF registry, clinical characteristics, co-morbidities, laboratory values and use of therapy were analyzed in all HF patients with new onset HF (HF duration <3 months from diagnosis) and chronic HF (HF duration ≥3 months from diagnosis). Additionally, therapy use was studied separately for patients with HFrEF (defined as EF <40%).

Results

Of 90,383 patients, 40% had new onset and 60% had chronic HF. Patients with new onset HF were more likely females (42 vs. 37%) compared to chronic HF. They had lower NYHA class, with higher EF, less often had atrial fibrillation (46 vs. 60%) and left bundle branch block (14 vs. 21%). They more often had hypertension (31 vs. 24%), and less often ischemic heart disease (34 vs. 44%), dilated cardiomyopathy (4.1 vs. 8.1%) and known alcoholic cardiomyopathy (0.6 vs. 0.8) as cause of HF. Chronic HF was associated with worse renal function (eGFR 58 [41, 77] vs. 69 [51, 87] mL/min/1.73 m2) and higher co-morbidity burden. Overall, new onset HF were less often on beta-blockers (85 vs. 88%) and MRAs (26 vs. 40%), whereas patients with chronic HF more often received HF medication and HF related device therapy. Patients with new onset HFrEF and thus with an indication for guidelines directed medical therapies were more often treated with beta-blockers (93 vs. 92%), ACE/ARB (91 vs. 83%), but less often ARNi (2.5 vs. 16%) and device therapy.

Conclusions

In this large HF population, patients with new onset HF were more often females, with less severe HF symptoms, and with fewer co-morbidities; New onset HF was associated with less MRA use. Our findings implies that faster and concomitant HF therapy initiation as recommended in 2021 ESC HF/HFA guidelines should occur in new onset HF patients.

Funding Acknowledgement

Type of funding sources: None.
Cerebral saturation is associated with physical activity and post-discharge mortality in heart failure patients
Authors: Zaghi A , Holm H , Korduner J , Bachus E , Molvin J , Jujic A , Nezami Z , Dieden A , Magnusson M
Published: October 2022

Background

The cross-sectional relationship between heart failure (HF) and cerebral oxygenation has been studied in the past but the prognostic significance of this relationship has been limited. Here, we aimed to assess the role of cerebral tissue oxygen saturation (SctO2) as a risk factor for HF mortality and rehospitalization as well as evaluate the association between SctO2 with physical activity in a Swedish prospective HF cohort.

Methods

Ninety-five patients hospitalized for HF (mean age 70 years; 21% women) were examined with near-infrared spectroscopy (NIRS) and screened for physical activity derived from questionnaires in the Swedish national public health survey. The median follow-up time to death and re-hospitalization was 1377 (interquartile range, 245–2392) and 293 (14–2363) days, respectively. Associations between SctO2 at rest, post-discharge mortality and re-hospitalization were analyzed using multivariable Cox regression analysis adjusted for age, sex, body-mass index, smoking, prevalence of atrial fibrillation, prevalence of diabetes and systolic blood pressure. The associations between SctO2 and self-reported physical activity were explored by using logistic regression analysis adjusted for the aforementioned risk factors.

Results

A total of 25 patients (26%) reported to be engaged in physical activity less than one hour throughout the week. In the fully adjusted Cox regression model, low SctO2 at rest was associated with post-discharge mortality (HR, 0.77; CI, 0.66–0.91; p=0.002). However, low SctO2 was not associated with post-discharge rehospitalization risk (HR, 0.94; CI, 0.88–1.01; p=0.092). In the fully adjusted logistic regression models, low SctO2 at rest was associated with decreased physical activity (<1h per week), (OR 1.22; CI, 1.05–1.42; p=0.01).

Conclusion

We have demonstrated that low cerebral tissue oxygen saturation at rest is associated with post-discharge mortality in patients hospitalized for HF, independently of traditional risk factors. In addition, low cerebral tissue oxygen saturation at rest is associated with low physical activity. These findings highlight the role of cerebral saturation as a risk factor for cardiovascular prognosis, as well as underline the potential importance of taking cerebral perfusion into account when treating for heart failure.

Funding Acknowledgement

Type of funding sources: None.
Treatment with activin type ii receptor antibody improves cardiac function in mice after myocardial infarction
Authors: Bao W B , Haskins N H , Gonzalez C G , Ryden-Markinhutha K R , Gill B G , Guo L G , Jennbacken K J , Wang Q W , Hagvall S H
Published: October 2022

Background

Activin type ii receptor (ActRII) binding to its natural ligands including myostatin, activin, and growth development factor 11 negatively regulates muscle growth. Blockade of the ligands/ActRII signaling with human ActRII monoclonal antibody has been shown to increase body lean mass and reduce fat mass in patients with type 2 diabetes. However, the blockade effect on the ligands/ActRII signaling in heart failure with or without cardiac cachexia remains controversial. We hypothesized that the blockade effect on the ligands/ActRII signaling with a murine ActRII monoclonal antibody would improve cardiac function in a mouse model of heart failure.

Methods

Under anesthesia with isoflurane in oxygen, C57BL/6 mice were subjected to sham surgery or myocardial infarction (MI) by ligation of left anterior descending coronary artery to induce heart failure. Mice were randomized into treatment groups based on ejection fraction measured by Vevo 3100 Imaging System two weeks after MI. MI mice were treated weekly with vehicle (n=11), 10 mg/kg (n=12), or 20 mg/kg (n=12) ActRII antibody by subcutaneous injection for 8 weeks. Cardiac function was determined by Vevo 3100 Imaging system at 4, 8 weeks post-treatment, respectively. Body lean and fat mass were determined by Bruker's Whole Body Composition Analyzer. Myocardial infarct size was determined by Masson's trichrome staining on heart sections.

Results

Myocardial infarction markedly impaired cardiac function in mice. Ejection fraction reduced to 21.3±1.9% in MI mice compared to 56.3±1.2% in sham-operated mice (p<0.0001). Weekly treatment with 10 mg/kg or 20 mg/kg antibody significantly improved ejection fraction to 32.1±2.8%, and 35.9±2.9%, respectively (p<0.01 and p<0.001). Antibody treatment in MI mice also reduced MI-induced lung congestion by 5% and 8% (p<0.01), respectively. However, heart weight and myocardial infarct size in antibody treated mice were comparable to those in vehicle-treated mice. Moreover, antibody treatment dose-dependently increased body weight, which is further confirmed by increases in muscle mass and body lean mass measured by gravimetric analysis and body composition analyzer.

Conclusion

ActRII antibody dose-dependently improved cardiac function independent of myocardial infarct size post-MI. Although antibody significantly increased body weight and lean mass, it did not significantly increase heart weight, indicating that antibody treatment did not cause adverse remodeling post-MI while it remarkably improved cardiac function. Our data suggest that ActRII antibody could be a novel treatment for heart failure with reduced ejection fraction and may be particularly beneficial in patients with cachexia.

Funding Acknowledgement

Type of funding sources: None.
Efficacy and safety of sacubitril valsartan in heart failure compared to renin angiotensin aldosterone system inhibitors: a systematic review and meta analysis of randomised controlled trials
Authors: Hernandez A V , Pasupuleti V , Scarpelli N , Malespini J , Banach M , Bielecka-Dabrowa A M
Published: October 2022

Background

Benefits and harms of the use of LCZ696 (sacubitril/valsartan, S/V), a combination of a neprilysin inhibitor and an angiotensin receptor blocker (ARB), in heart failure (HF) are unknown.

Purpose

To systematically assess benefits and harms of S/V as compared to angiotensin converting enzyme inhibitors (ACEI) or ARB in patients with HF.

Methods

We searched for randomised controlled trials (RCTs) evaluating S/V vs. ACEI or ARB in acute or chronic HF adult patients. Primary outcomes were HF hospitalisation and cardiovascular [CV] mortality; secondary outcomes were all-cause mortality, decline in renal function, myocardial dysfunction, quality of life (QoL), systolic blood pressure (SBP), diastolic blood [DBP], and adverse events (AEs) including worsening renal function (SCr≥2 mg/dL), hyperkalaemia (K+≥5.5 mmol/L), symptomatic hypotension (SBP<100 mmHg), and angio-oedema. Inverse variance random-effects meta-analyses were conducted and effects expressed as hazard ratios (HR), relative risks (RR) or mean difference (MD) and their 95% confidence intervals (CI). GRADE methodology was used to assess the certainty of evidence (CoE).

Results

We selected 11 RCTs (n=18766). Follow-up times ranged between 2 and 48 months; the average age of participants was 61 to 73 years-old. Five RCTs had ACEIs as control, five RCTs had ARBs as control, and one RCT had both ACEI and ARB as control. Six RCTs had low risk of bias; five RCTs had unclear risk of bias. S/V reduced the hazard of HF hospitalisations by 20% (HR 0.80, 95% CI 0.68–0.94; 3 RCTs; I2=65%; high CoE), CV mortality by 14% (HR 0.86, 95% CI 0.73 to 1.01; 2 RCTs; I2=57%; high CoE) and all-cause mortality by 11% (HR 0.89, 95% CI 0.78–1.00; 3 RCTs; I2=36%; high CoE) compared to ACEI or ARB control (Figure 1). S/V slightly improved KCCQ-QoL scores (MD 1.36 points, 95% CI 0.49 to 2.24; 6 RCTs; I2=54%). S/V did not affect LVEF and E/E' but reduced NTproBNP (SMD −0.34, 95% CI −0.52 to −0.16; 3 RCTs; I2=62%), and hs-TNT (Ratio of differences 0.84, 95% CI 0.79–0.88; 2 RCTs; I2=0%). SBP and DBP were reduced by 4 mmHg and 3 mmHg, respectively, and hypotension was increased (RR 1.69, 95% CI 1.33–2.15; 9 RCTs; I2=65%; high CoE) with S/V. Also, S/V reduced the hazard of decline in renal function by 33% (HR 0.67, 95% CI 0.39–1.14; 2RCTs; I2=78%; high CoE); hyperkalaemia and angioedema events were similar between S/V and controls.

Conclusions

Sacubitril/valsartan had better clinical and intermediate outcomes in HF in comparison to ACEI or ARB. Decline of renal function was less frequent with S/V in comparison to controls, and there was no difference in decline of renal function or angioedema and hyperkalaemia events. However, sacubitril/valsartan was associated with more symptomatic hypotension events vs. controls.

Funding Acknowledgement

Type of funding sources: None.
First-in-man trial of b3-adrenoreceptor agonist treatment in chronic heart failure – impact on diastolic function
Authors: Bahrami H , Hasselbalch R , Soeholm H , Thomsen J , Soegaard M , Kofoed K , Valeur N , Boesgaard S , Fry N , Moeller J , Raja A , Koeber L , Iversen K , Rasmussen H , Bundgaard H
Published: October 2022

Background

Diastolic dysfunction (DD) in heart failure (HF) is associated with increased myocardial cytosolic calcium, and calcium-efflux via the sodium-calcium-exchanger depends on the sodium gradient. Beta-3-adrenoceptor (β3-AR)-agonist lowers cytosolic sodium and has been shown to reverse organ congestion.

Purpose

To assess whether β3-AR-agonist treatment improves DD.

Methods

In a first-in-man randomized controlled, double-blind trial, we assigned 70 patients with HF with reduced ejection fraction (HFrEF) (NYHA II–III) and LVEF <40% to receive mirabegron (300 mg/day) or placebo for 6 months, in addition to recommended HF-therapy. Patients were assessed with echocardiography and cardiac computed tomography (CCT) at baseline and follow-up. DD was graded according to the current American/European guidelines.

Results

Baseline and follow-up echocardiographic data were available in 57 patients (59±11 years, 88% male, 49% ischemic heart disease). Baseline LVEF was 34%±8%. No significant change in DD grade was found between the groups at follow-up, p=0.72. Neither was there any clinical differences in any singular diastolic parameters within or between groups by echocardiography (E/e' placebo: 13.3±6.9 to 12.6±5.1, p=0.19 vs. mirabegron: 12.0±5.7 to 12.8±7.9, p=0.67, mean difference 1.12 [95% CI −1.68 to 4.3], p=0.37), or CCT (left atrial max volume index: between group mean difference 0.2 [95% CI −6.2 to 5.6] ml/m2, p=0.91).

Conclusions

In patients with HFrEF, no improvement nor worsening in DD gradings or singular diastolic parameters after β3-AR stimulation compared to placebo were identified. The findings add to previous literature questioning the role of impaired Na+-Ca2+ mediated Ca2+ export as a major culprit in DD.

Funding Acknowledgement

Type of funding sources: Foundation. Main funding source(s): The Heart Centre Research Foundation, RigshospitaletThe Novo Nordic Foundation
Adherence and discontinuation of optimal heart failure therapies according to age
Authors: Garred C H , Zahir D , Butt J H , Ravn P B , Bruhn J , Gislason G , Fosboel E L , Torp-Pedersen C , Petrie M C , McMurray J J V , Koeber L , Schou M
Published: October 2022

Background

Guideline-recommended disease-modifying pharmacological therapies for heart failure (HF) with reduced ejection fraction are underutilized, particularly among elderly patients.

Purpose

We examined adherence with and discontinuation of evidence-based HF pharmacotherapy, comprising of angiotensin-converting enzyme inhibitors (ACEi)/angiotensin-II receptor blockers (ARB), beta-blockers (BB) and mineralocorticoid receptor antagonists (MRA), according to age.

Methods

Using Danish nationwide registries, we included patients with a first HF diagnosis between 2011 and 2018. Patients were stratified into three age groups, <65 years (reference group), 65–79 years, and ≥80 years. The average daily drug dose was calculated as median proportions of target doses one year after inclusion. Adherence was estimated by the proportion of days covered (PDC), i.e., the total number of days with the drug available for a patient alive for the whole first year of the follow-up period. Discontinuation was defined as a break of >90 days, and the 5-year risk of discontinuation according to age groups was estimated with the Aalen-Johansen estimator. Multivariable Cox regression models were used to evaluate the treatment discontinuation rate according to age groups.

Results

We included a total of 29,482 patients (<65 9,449 (25.4% female), 65–79 13,746 (33.1%), ≥80 6,287 (46.3%)). Advancing age was associated with lower median proportions of daily target doses (ACEi 100%, 88%, 63%; ARB 75%, 67%, 50%; BB 75%, 56%, 44%), and lower adherence (ACEi/ARB 79.1%, 77.5%, 69.4%; BB 79.1%, 78.6%, 73.8%), in the <65, 65–79 and ≥80 age groups respectively, one year after inclusion. Age ≥80 was associated with a higher 5-year risk of discontinuation; cumulative incidence, ACEi/ARB 41%, 44%, 51%; BB 38%, 35%, 39%, in the same age group order as above (adjusted hazard ratio: ACEi/ARB 1.60 [95% CI, 1.51–1.69]; BB 1.33 [95% CI, 1.25–1.41]). Conversely, the risk of discontinuation of MRAs differed little with age (<65 50%, 65–79 54%, ≥80 56%), although MRA initiation in the most elderly was less frequent (<65 33%, 65–79 33%, ≥80 22%).

Conclusion

Among a nationwide cohort of HF patients, advanced age was associated with lower proportions of daily target doses, lower adherence, and a higher rate of discontinuation of ACEi/ARB and BBs. Focus on treatment adherence and optimal dosages among elderly HF patients could improve outcomes.

Funding Acknowledgement

Type of funding sources: None.
Real-world eligibility and cost-effectiveness analysis for empagliflozin in patients with heart failure
Authors: Kim E S , Park S K , Youn J C
Published: October 2022

Background/Introduction

Empagliflozin was approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for reducing cardiovascular mortality and heart failure (HF) hospitalization in both patients with HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF).

Purpose

Limited data are available on the generalizability of empagliflozin to clinical practice. Therefore, we evaluated real-world eligibility and cost-effectiveness based on a nationwide prospective HF registry.

Methods

For the study, 3108 HFrEF and 2070 HFpEF patients from the Korean Acute Heart Failure (KorAHF) registry were analysed. Eligibility was estimated by FDA and EMA label criteria and by inclusion and exclusion criteria of EMPEROR-Reduced and EMPEROR-Preserved trials. The cost-effectiveness analysis was performed using the decision tree model, where effectiveness was the avoidance of the first hospitalization.

Results

Among the KorAHF patients, 91.4% met FDA & EMA label criteria, while 44.7% met the clinical trial criteria. The main factor for exclusion in the clinical trial-based empagliflozin eligibility was low systolic blood pressure, including 18.7% of HFrEF and 11.0% of HFpEF patients. Other factors were acute (<4 weeks) myocardial infarction and impaired renal function (eGFR <20 mL/min/1.73 m2 or requiring dialysis). The overall expected hospitalization rate and cost reduction were 3.6 and US$ 14,885 per 100 eligible HF patients per year. In HFrEF patients, hospitalization rate and cost reduction were 4.8 and US$ 28,442. However, in HFpEF, the cost was increased by US$ 7,576, while hospitalization reduction was 1.7.

Conclusion(s)

There is a large discrepancy of real-world eligibility for empagliflozin between FDA & EMA labels and clinical trial criteria. The cost-effectiveness benefit was more evident in patients with HFrEF than HFpEF. The efficacy and safety of empagliflozin in real-world patients should be further investigated for a broader range of clinical applications.

Funding Acknowledgement

Type of funding sources: Other. Main funding source(s): This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Minister of Science and Information and Communication Technologies (NRF-2021R1F1A1063430), by the Catholic Medical Center Research Foundation (2022), and by the Research of Korea Centers for Disease Control and Prevention (2010-E63003-00, 2011-E63002-00, 2012-E63005-00, 2013-E6300300, 2014-E63003-01, 2015-E63003-02, 2016-ER6303-00, and 2017-ER6303-01).