Journal: J Card Fail

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Abstract

Impact of Mental Stress and Anger on Indices of Diastolic Function in Patients with Heart Failure.

Harris KM, Gottdiener JS, Gottlieb SS, Burg MM, Li S, Krantz DS
Background
Under controlled conditions, mental stress can provoke decrements in ventricular function, yet little is known about the effect of mental stress on diastolic function in patients with heart failure (HF).
Methods and results
Twenty-four HF patients with ischemic cardiomyopathy and reduced ejection fraction (HFrEF; n=23 men; mean LVEF=27±9%; n=13 with baseline elevated E/e\') completed daily assessment of perceived stress, anger, and negative emotion for 7 days, followed by a laboratory mental stress protocol. 2D Doppler echocardiography was performed at rest and during sequential anger recall and mental arithmetic tasks to assess indices of diastolic function (E, e\', and E/e\'). Fourteen patients (63.6%) experienced stress-induced increases in E/e\', with an average baseline to stress change of 6.5±9.3, driven primarily by decreases in early LV relaxation (e\'). Age-adjusted linear regression revealed an association between 7-day anger and baseline E/e\'; patients reporting greater anger in the week prior to mental stress exhibited higher resting LV diastolic pressure.
Conclusions
In patients with HFrEF, mental stress can provoke acute worsening of LV diastolic pressure, and recent anger is associated with worse resting LV diastolic pressure. In patients vulnerable to these effects, repeated stress exposures or experiences of anger may have implications for long-term outcomes.

Copyright © 2020. Published by Elsevier Inc.

J Card Fail: 31 Jul 2020; epub ahead of print
Harris KM, Gottdiener JS, Gottlieb SS, Burg MM, Li S, Krantz DS
J Card Fail: 31 Jul 2020; epub ahead of print | PMID: 32750485
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Abstract

Metabolomic profile in HFpEF vs HFrEF patients.

Hage C, Löfgren L, Michopoulos F, Nilsson R, ... Persson H, Linde C

Background HFpEF and HFrEF are associated with metabolic derangements which may have different pathophysiological implications. Methods and results In new onset heart failure with preserved (HFpEF;EF≥50%,n=46) and reduced ejection fraction (HFrEF;EF<40%,n=75) patients, 109 endogenous plasma metabolites including aminoacids, phospholipids and acylcarnitines were assessed using targeted metabolomics. Differentially altered metabolites and associations with clinical characteristics were explored. HFpEF patients were older, more often female with hypertension, atrial fibrillation, and diabetes compared to HFrEF. HFpEF displayed higher levels of hydroxyproline and SDMA, alanine, cystine and kynurenine reflecting fibrosis, inflammation and oxidative stress. Serine, cGMP, cAMP, L-carnitine, lysophophatidylcholine (18:2), lactate and arginine were lower compared to HFrEF. In HFpEF with diabetes, kynurenine was higher (p=0.014) and arginine lower (p=0.014) vs. no diabetes but did not differ with diabetes status in HFrEF. Decreasing kynurenine was associated with higher eGFR only in HFpEF (p=0.020). CONCLUSIONS New onset HFpEF compared to HFrEF patients display a different metabolic profile associated with co-morbidities such as diabetes and kidney dysfunction. HFpEF is associated with indices of increased inflammation and oxidative stress, impaired lipid metabolism, increased collagen synthesis and down-regulated NO-signalling. Together, these findings suggest a more predominant systemic microvascular endothelial dysfunction and inflammation linked to increased fibrosis in HFpEF compared to HFrEF. Clinical Trial registration: ClinicalTrials.gov NCT03671122 https://clinicaltrials.gov.

Copyright © 2020. Published by Elsevier Inc.

J Card Fail: 31 Jul 2020; epub ahead of print
Hage C, Löfgren L, Michopoulos F, Nilsson R, ... Persson H, Linde C
J Card Fail: 31 Jul 2020; epub ahead of print | PMID: 32750486
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Abstract

The ACTN3 577XX null genotype is associated with low left ventricular dilation-free survival rate in patients with Duchenne muscular dystrophy: ACTN3 genotype relates cardiomyopathy in DMD.

Nagai M, Awano H, Yamamoto T, Bo R, Matsuo M, Iijima K
Background
Duchenne muscular dystrophy (DMD) is a fatal progressive muscle-wasting disease caused by mutations in the DMD gene. Dilated cardiomyopathy is the leading cause of death in DMD; therefore, further understanding of this complication is essential to reduce morbidity and mortality.
Methods
A common null variant (R577X) in the ACTN3 gene, which encodes α-actinin-3, has been studied in association with muscle function in healthy individuals, however not yet examined with cardiac phenotype in DMD. Here, we determined the ACTN3 genotype in 163 Patients with DMD and examined the correlation between ACTN3 genotypes and echocardiographic findings in 77 of the 163 patients.
Results
The genotypes 577RR(RR), 577RX(RX), and 577XX(XX) were identified in 13 (17%), 44 (57%), and 20 (26%) of 77 patients, respectively. We estimated cardiac involvement-free survival rate analyses using Kaplan-Meier curves. Remarkably, the left ventricular (LV) dilation (LVDd>55 mm)-free survival rate was significantly lower in XX null genotype patients (P<0.01). XX null genotype showed a higher risk for LV dilation (hazard ratio 9.04).
Conclusions
This study revealed that ACTN3 XX null genotype was associated with a lower LV dilation-free survival rate in DMD. These results suggest that ACTN3 genotype should be determined at the time of diagnosis of DMD to improve patients\' cardiac outcomes.

Copyright © 2020. Published by Elsevier Inc.

J Card Fail: 09 Aug 2020; epub ahead of print
Nagai M, Awano H, Yamamoto T, Bo R, Matsuo M, Iijima K
J Card Fail: 09 Aug 2020; epub ahead of print | PMID: 32791185
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Abstract

Pulmonary Vascular Pressures and Gas Exchange Response to Exercise in Heart Failure with Preserved Ejection Fraction.

Fermoyle CC, Stewart GM, Borlaug BA, Johnson BD

Elevated left ventricular filling pressure (measured as mean pulmonary capillary wedge pressure, PCWPm) at rest or with exercise is diagnostic of heart failure with preserved ejection fraction (HFpEF). However, the capacity of the right ventricle to compensate for a high PCWPm and thus maintain an appropriate transpulmonary gradient (TPG) and perfusion of the pulmonary capillaries is likely an important contributor to gas exchange efficiency and exercise capacity. Therefore, this study aimed to determine whether a higher TPG at peak exercise is associated with superior exercise capacity and gas exchange. Gas exchange data from dyspneic patients referred for exercise right heart catheterization were retrospectively analyzed and patients were split into two groups based on TPG. Patients with a higher TPG at peak exercise had a higher peak VO (1025±227 vs.823±276, p=0.038), end-tidal partial pressure of CO (PETCO; 42.2±7.9 vs. 38.0±4.7, p=0.044), and gas exchange estimates of pulmonary vascular capacitance (GX; 408±90 vs. 268±108, p=0.001). A higher TPG at peak exercise correlated with a higher peak VO, O pulse, and stroke volume (R=0.42, 0.44 and 0.42, respectively, all p<0.05). These findings indicate that a greater TPG with exercise might be important for improving exercise capacity in HFpEF.

Copyright © 2020. Published by Elsevier Inc.

J Card Fail: 31 Jul 2020; epub ahead of print
Fermoyle CC, Stewart GM, Borlaug BA, Johnson BD
J Card Fail: 31 Jul 2020; epub ahead of print | PMID: 32750488
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Abstract

Cystatin C and muscle mass in patients with heart failure.

Ivey-Miranda JB, Inker LA, Griffin M, Rao V, ... Levey AS, Testani JM
Background
Estimated glomerular filtration rate (GFR) from cystatin C (eGFRcys) is often considered a more accurate method to assess GFR compared to estimated GFR from creatinine (eGFRcr) in the setting of heart failure (HF) and sarcopenia because cystatin C is hypothesized to be less affected by muscle mass than creatinine. We evaluated: 1) the association of muscle mass with cystatin C; 2) the accuracy of eGFRcys; 3) association of eGFRcys with mortality given muscle mass.
Methods and results
We included 293 patients admitted with HF. Muscle mass was estimated with a validated creatinine excretion-based equation. Accuracy of eGFRcys and eGFRcr was compared to measured creatinine clearance (mClcr). Cystatin C and creatinine were 31.7% and 59.9% higher per 14 kg higher muscle mass at multivariable analysis (both p<0.001). At lower muscle mass, eGFRcys and eGFRcr overestimated mClcr. At higher muscle mass, eGFRcys underestimated mClcr but eGFRcr did not. After adjusting for muscle mass, neither eGFRcys nor eGFRcr were associated with mortality (both p>0.19).
Conclusions
Cystatin C levels were associated with muscle mass in patients with HF, which could potentially decrease the accuracy of eGFRcys. In HF where aberrations in body composition are common eGFRcys, like eGFRcr may not provide accurate GFR estimations and results should be interpreted cautiously.

Copyright © 2020. Published by Elsevier Inc.

J Card Fail: 31 Jul 2020; epub ahead of print
Ivey-Miranda JB, Inker LA, Griffin M, Rao V, ... Levey AS, Testani JM
J Card Fail: 31 Jul 2020; epub ahead of print | PMID: 32750487
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Abstract

Performance of Electronic Health Record Diagnosis Codes for Ambulatory Heart Failure Encounters.

Goyal P, Bose B, Creber RM, Krishnan U, ... Brady J, Pathak J
Background
There is interest in leveraging the electronic medical record (EMR) to improve knowledge and understanding of patient characteristics and outcomes of ambulatory heart failure (HF) patients. However, the diagnostic performance of ICD-10 diagnosis codes from the EMR for patients with heart failure with reduced and preserved ejection fraction (HFrEF and HFpEF) in the ambulatory setting are unknown.
Methods
We examined a cohort of patients aged ≥18 with at least 1 outpatient encounter for HF between January 2016 and June 2018, and an echocardiogram conducted within 180 days of the outpatient encounter for HF. We defined HFrEF encounters as those with ICD-10 codes of I50.2x (systolic heart failure); and defined HFpEF encounters as those with ICD-10 codes of I50.3x (diastolic heart failure). The referent definitions of HFrEF and HFpEF were based on echocardiograms conducted within 180 days of the ambulatory encounter for HF Results: We examined 68,952 encounters among 14,796 unique patients with HF. The diagnostic performance parameters for HFrEF (based on ICD-10 I50.2x only) depended on LVEF cutoff, with a sensitivity ranging from 68-72%, specificity 63-68%, PPV 47-63%, and NPV 73-84%. The diagnostic performance parameters for HFpEF depended on LVEF cutoff, with a sensitivity ranging from 34-39%, specificity 92-94%, PPV 86-93%, and NPV 39%-54%.
Conclusions
ICD-10 coding abstracted from the EMR for HFrEF vs. HFpEF in the ambulatory setting had suboptimal diagnostic performance, and thus should not be used alone to examine HFrEF and HFpEF in the ambulatory setting.

Copyright © 2020. Published by Elsevier Inc.

J Card Fail: 01 Aug 2020; epub ahead of print
Goyal P, Bose B, Creber RM, Krishnan U, ... Brady J, Pathak J
J Card Fail: 01 Aug 2020; epub ahead of print | PMID: 32755626
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Abstract

Pregnancy after Heart Transplantation.

DeFilippis EM, Kittleson MM

As post-transplant survival improves, many heart transplant (HT) recipients are of, or are surviving to, childbearing age. Solid organ transplant recipients who become pregnant should be managed by a multidisciplinary cardio-obstetrics team including specialists in maternal and fetal medicine, cardiology and transplant medicine, as well as anesthesia, neonatology, psychology, genetics, and social services. With careful patient selection, pregnancy after HT can been managed safely. The purpose of this comprehensive review is to summarize the current evidence and recommendations surrounding pre-conception counseling, medical management and surveillance, maternal outcomes, breastfeeding, and remaining gaps in knowledge.

Copyright © 2020 Elsevier Ltd. All rights reserved.

J Card Fail: 05 Aug 2020; epub ahead of print
DeFilippis EM, Kittleson MM
J Card Fail: 05 Aug 2020; epub ahead of print | PMID: 32771397
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Abstract

Clinical significance of reactive oxidative metabolites in patients with heart failure with reduced left ventricular ejection fraction.

Nishihara T, Tokitsu T, Sueta D, Oike F, ... Yamamoto E, Tsujita K
Background
We investigated the clinical significance of the derivative of reactive oxygen metabolites (DROM), a new marker of reactive oxygen species (ROS), in heart failure (HF) with reduced left ventricular ejection fraction (LVEF) (HFrEF) patients.
Methods and results
Serum DROM concentrations were measured in 201 consecutive HFrEF (EF<50%) patients in stable condition. DROM values were significantly higher in HFrEF than in risk-matched non-HF patients (p<0.01). They also correlated significantly with high-sensitivity C-reactive protein and BNP. Kaplan-Meier analysis demonstrated significantly higher probabilities of HF-related events in the high-DROM group than in the low-DROM group (log-rank test, p<0.01). Multivariable-Cox-hazard analysis revealed that DROM were independent and significant predictors for cardiovascular events. In a subgroup analysis, DROM levels were also measured at the aortic root and coronary sinus in 49 patients. The transcardiac gradient of DROM values was significantly higher in HFrEF than in non-HF patients (p=0.04), indicating an association between DROM production in the coronary circulation and HFrEF development. Changes in DROM following optimal therapy were significantly associated with LVEF improvement (r=0.34, p=0.04).
Conclusions
The higher levels of DROM and their association with cardiovascular events suggest the clinical benefit of DROM measurements in the risk stratification of HFrEF patients.

Copyright © 2020. Published by Elsevier Inc.

J Card Fail: 09 Aug 2020; epub ahead of print
Nishihara T, Tokitsu T, Sueta D, Oike F, ... Yamamoto E, Tsujita K
J Card Fail: 09 Aug 2020; epub ahead of print | PMID: 32791184
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Abstract

Patient-stratification for risk of heart failure readmission using nationwide administrative data.

Constantinou P, Pelletier-Fleury N, Olié V, Gastaldi-Ménager C, Juillère Y, Tuppin P
Background
Identifying heart failure (HF) patients most at-risk of readmission permits targeting adapted interventions. The use of administrative data enables regulators to support the implementation of such interventions.
Methods and results
In a French nationwide cohort of patients aged 65 years or older surviving an index hospitalization for HF in 2015 (N = 70 657), we studied HF readmission predictors available in administrative data, distinguishing HF severity from overall morbidity and taking into account the competing mortality risk, over a 1-year follow-up period. We also computed cumulative incidences and daily rates of HF readmission for patient groups defined upon HF severity and overall morbidity. 31.8% (n = 22 475) of patients were readmitted at least once for HF and 17.6% (n = 12 416) died without any HF readmission. HF severity and overall morbidity were the strongest HF readmission predictors (subdistibution Hazard Ratios 2.66 [95% CI: 2.52-2.81] and 1.37 [1.30-1.45] respectively, when comparing extreme categories). Overall morbidity and age were more strongly associated with the competing rate of death without HF readmission (cause-specific Hazard Ratios). Defined risk-groups had approximately 40% of separation in HF readmission proportion (21.9%, n = 2 144/9 786 versus 60.4%, n = 618/0 1023).
Conclusions
Segmentation of HF patients into readmission risk-groups is possible using administrative data and enables targeting of preventive interventions.

Copyright © 2020. Published by Elsevier Inc.

J Card Fail: 11 Aug 2020; epub ahead of print
Constantinou P, Pelletier-Fleury N, Olié V, Gastaldi-Ménager C, Juillère Y, Tuppin P
J Card Fail: 11 Aug 2020; epub ahead of print | PMID: 32801005
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Abstract

Characterization of the Progression from Ambulatory to Hospitalized Heart Failure with Preserved Ejection Fraction.

Reddy YNV, Obokata M, Jones AD, Lewis GD, ... Redfield MM, Borlaug BA
Background
Heart failure (HF) with preserved ejection fraction (HFpEF) is a heterogeneous syndrome. Some patients develop elevated filling pressures exclusively during exercise and never require hospitalization, whereas others periodically develop congestion that requires inpatient treatment. The features differentiating these cohorts are unclear.
Methods
We performed a secondary analysis of 7 NIH sponsored multicenter trials of HFpEF (EF≥50%, n=727). Patients were stratified by history of HF hospitalization, comparing patients never hospitalized (HFpEF) to those with a prior hospitalization (HFpEF). Currently hospitalized (HFpEF) patients were included to fill the spectrum. Clinical characteristics, cardiac structure, biomarkers, quality of life (QOL), functional capacity, activity levels, and outcomes were compared.
Results
As expected, HFpEF (n=338) displayed the greatest severity of congestion, as assessed by NTproBNP levels, edema, and orthopnea. As compared to HFpEF (n=109), HFpEF (n=280) displayed greater comorbidity burden with more lung disease, renal dysfunction and anemia, along with lower activity levels (accelerometry), poorer exercise capacity (6 minute walk distance and peak exercise capacity), and more orthopnea. Patients with current or prior hospitalization displayed higher rates of future HF hospitalization, but QOL was similarly impaired in all HFpEF patients, regardless of hospitalization history.
Conclusions
A greater burden of non-cardiac organ dysfunction, sedentariness, functional impairment, and higher event rates distinguish patients with HFpEF and prior HF hospitalization from those never hospitalized. Despite lower event rates, quality of life is severely and similarly in patients with no history of hospitalization. These data suggest that the two clinical profiles of HFpEF may require different treatment strategies.

Copyright © 2020. Published by Elsevier Inc.

J Card Fail: 18 Aug 2020; epub ahead of print
Reddy YNV, Obokata M, Jones AD, Lewis GD, ... Redfield MM, Borlaug BA
J Card Fail: 18 Aug 2020; epub ahead of print | PMID: 32827644
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Abstract

Effects of Angiotensin-Neprilysin Inhibition in Canines with Experimentally-Induced Cardiorenal Syndrome.

Sabbah HN, Zhang K, Gupta RC, Jiang-Xu , Singh-Gupta V
Background
Sacubitril/Valsartan (Sac/Val), a combined angiotensin-II receptor blocker (Val) and neprilysin inhibitor (Sac) in a 1:1 molar ratio, was shown to reduce the risk of cardiovascular death or heart failure (HF) hospitalization in patients with HF and reduced LV ejection fraction (EF). This study examined the effects of Sac/Val on LV structure, function and bioenergetics and on biomarkers of kidney injury and kidney function in dogs with experimental cardiorenal syndrome (CRS).
Methods and results
14 dogs with CRS (coronary microembolization-induced HF and renal dysfunction) were randomized to 3 months Sac/Val therapy (100 mg once daily, n=7) or no therapy (control, n=7). LV EF and troponin-I (TnI) as well as biomarkers of kidney injury/function including serum creatinine (sCr) and urinary kidney injury molecule-1 (KIM-1) were measured before and at end of therapy and the change (treatment effect Δ) calculated. Mitochondrial function measures including maximum rate of ATP synthesis (ATPsyn) were measured in isolated cardiomyocytes at end of therapy. In Sac/Val dogs, ΔEF increased compared to controls (6.9±1.4 vs. 0.7±0.6 %, p<0.002) while ΔTnI decreased (-0.16±0.03 vs. -0.03±0.02 ng/ml, p<0.001). Urinary ΔKIM-1 decreased in Sac/Val treated dogs compared to controls (-17.2±7.9 vs. 7.7±3.0 mg/ml, p<0.007) whereas ΔsCr was not significantly different. Treatment with Sac/Val increased ATPsyn compared to control (3,240±121 vs. 986±84 RLU/µg protein, p<0.05).
Conclusions
In dogs with CRS, Sac/Val improves LV systolic function, improves mitochondrial function and decreases biomarkers of heart and kidney injury. The results offer mechanistic insights into the benefits of Sac/Val in HF with compromised renal function.

Copyright © 2020. Published by Elsevier Inc.

J Card Fail: 21 Aug 2020; epub ahead of print
Sabbah HN, Zhang K, Gupta RC, Jiang-Xu , Singh-Gupta V
J Card Fail: 21 Aug 2020; epub ahead of print | PMID: 32841710
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Abstract

Sex Differences in the Phenotype of Transthyretin Cardiac Amyloidosis due to Val122Ile Mutation: Insights from Non-Invasive Pressure-Volume Analysis.

Batra J, Rosenblum H, DeFilippis EM, Griffin JM, ... Burkhoff D, Maurer MS
Background
Transthyretin cardiac amyloidosis (ATTR-CA) is an under-recognized cause of heart failure with preserved ejection fraction. In the United States, the valine-to-isoleucine substitution (Val122Ile) is the most common inherited variant. Data on sex differences in presentation and outcomes of Val122Ile ATTR-CA are lacking.
Methods and results
In a retrospective, single-center study of 73 patients diagnosed with Val122Ile ATTR-CA between 2001-2018, sex differences in clinical and echocardiographic data at the time of diagnosis were evaluated. Pressure-volume analysis using non-invasive single beat techniques was used to compare chamber performance. Compared to men (n=46), women (n=27) were significantly older at diagnosis (76 years vs 69 years, p<0.001). End-systolic pressure-volume relationship (5.1mmHg*m/mL vs 4.3 mmHg*m/mL, p = 0.27), arterial elastance (5.5mmHg*m/mL vs 5.7mmHg*m/mL, p = 0.62), and left ventricular capacitance were similar between sexes as was pressure-volume areas indexed to a left ventricular end-diastolic pressure of 30 mmHg, a measure of overall pump function. Three-year mortality rates were also similar (34% vs 43%, p = 0.64).
Conclusions
Despite being significantly older at time of diagnosis with Val122Ile ATTR-CA, women have similar overall cardiac chamber function and rates of mortality to men, suggesting a less aggressive disease trajectory. These findings should be confirmed with longitudinal studies.

Copyright © 2020. Published by Elsevier Inc.

J Card Fail: 19 Aug 2020; epub ahead of print
Batra J, Rosenblum H, DeFilippis EM, Griffin JM, ... Burkhoff D, Maurer MS
J Card Fail: 19 Aug 2020; epub ahead of print | PMID: 32829019
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Abstract

Association of Coronary Microvascular Dysfunction with Heart Failure Hospitalizations and Mortality in Heart Failure with Preserved Ejection Fraction - a follow-up in the PROMIS-HFpEF study.

Hage C, Svedlund S, Saraste A, Faxén UL, ... Lam CSP, Lund LH
Background
Coronary microvascular dysfunction (CMD) is common in heart failure with preserved ejection fraction (HFpEF). We assessed the association of CMD with hospitalization and mortality in HFpEF.
Methods
We assessed one-year outcomes in patients from the PROMIS-HFpEF study, a prospective observational study of patients with chronic stable HFpEF undergoing coronary flow reserve (CFR) measurements. Outcomes were 1) time to CV death/first HF hospitalization 2) CV death/recurrent HF hospitalizations 3) all-cause death/first HF hospitalization and 4) first and 5) recurrent all-cause hospitalizations. CMD was defined as CFR<2.5. Time to CV death/first hospitalization was compared by log-rank test and recurrent HF and all-cause hospitalizations by Poisson test.
Results
Of 263 patients enrolled, 257 were evaluable at one year. Where CFR was interpretable (n=201) CMD was present in 150 (75%). Median follow-up was 388 days (Q1;Q3 365;418). The outcome of CV death/first HF hospitalization occurred in 15 patients (4 CV deaths). The incidence rate was in CMD 96/1000 (95% CI 54-159) vs. non-CMD 0/1000 person-years (0-68); p=0.023 and remained significant after accounting for selected clinical variables. In patients with CMD, incidence rates were significantly higher also for CV death/recurrent HF hospitalizations, all-cause death/first HF, and recurrent but not first all-cause hospitalization.
Conclusions
In this exploratory assessment of the prognostic role of CMD in HFpEF, CMD was independently associated with primarily CV and HF specific events. The high prevalence of CMD and its CV and HF specific prognostic role suggest CMD may be a potential treatment target in HFpEF.

Copyright © 2020. Published by Elsevier Inc.

J Card Fail: 22 Aug 2020; epub ahead of print
Hage C, Svedlund S, Saraste A, Faxén UL, ... Lam CSP, Lund LH
J Card Fail: 22 Aug 2020; epub ahead of print | PMID: 32846205
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Abstract

Uric Acid Is a Biomarker of Oxidative Stress in the Failing Heart: Lessons Learned from Trials With Allopurinol and SGLT2 Inhibitors.

Packer M

Hyperuricemia increases the risk of heart failure, and higher levels of serum uric acid are seen in patients who have worse ventricular function, functional capacity and prognosis. Heart failure is also accompanied by upregulation of xanthine oxidase, the enzyme that catalyzes the formation of uric acid and a purported source of reactive oxygen species. However, the available evidence does not support the premise that either uric acid or the activation of xanthine oxidase has direct injurious effects on the heart in the clinical setting. Xanthine oxidase inhibitors (allopurinol and oxypurinol) have had little benefit and may exert detrimental effects in patients with chronic heart failure in randomized controlled trials, and the more selective and potent inhibitor febuxostat increases the risk of cardiovascular death more than allopurinol. Instead, the available evidence indicates that changes in xanthine oxidase and uric acid are biomarkers of oxidative stress (particularly in heart failure) and that xanthine oxidase may provide an important source of nitric oxide that quenches the injurious effects of reactive oxygen species. A primary determinant of the cellular redox state is nicotinamide adenine dinucleotide (NAD+), whose levels drive an inverse relationship between xanthine oxidase and sirtuin-1 (SIRT1), a nutrient deprivation sensor that exerts important antioxidant and cardioprotective effects. Interestingly, sodium-glucose cotransporter 2 (SGLT2) inhibitors induce a state of nutrient deprivation that includes activation of sirtuin-1, suppression of xanthine oxidase and lowering of serum uric acid. The intermediary role of sirtuin-1 in both uric acid-lowering and cardioprotection may explain why, in mediation analyses of large-scale cardiovascular trials, the effect of SGLT2 inhibitors to decrease serum uric acid is a major predictor of the ability of these drugs to reduce serious heart failure events.

Copyright © 2020. Published by Elsevier Inc.

J Card Fail: 01 Sep 2020; epub ahead of print
Packer M
J Card Fail: 01 Sep 2020; epub ahead of print | PMID: 32890737
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Abstract

Resting Oxygen Consumption and Heart Failure: Importance of Measurement for Determination of Cardiac Output With the Use of the Fick Principle.

Grafton G, Cascino TM, Perry D, Ashur C, Koelling TM
Background
Resting oxygen consumption (VO) is often estimated and frequently used to guide therapeutic decisions in symptomatic heart failure (HF) patients. The relationship between resting VO and symptomatic HF and the accuracy of estimations of VO in this population are unknown.
Methods and results
We performed a cross-sectional study of HF patients (n = 691) and healthy control subjects (n = 77). VO was measured with the use of a metabolic cart, and estimated VO was calculated with the use of the Dehmer, LaFarge, and Bergstra formulas and the thermodilution method. The measured and estimated VO were compared and the potential impact of estimations determined. In the multivariable model, resting VO decreased with increasing New York Heart Association (NYHA) functional class in a stepwise fashion (β NYHA functional class IV vs control = -36 mL O/min; P < .001). Estimations of VO with the use of derived equations diverged from measured values, particularly for patients with NYHA functional class IV limitations. The percentage difference of measured VO versus estimated VO was >25% in 39% (n = 271), 25% (n = 170), 82% (n = 566), and 39% (n = 271) of HF patients when using the Dehmer, LaFarge, Bergstra, and thermodilution-derived estimations of VO respectively.
Conclusions
Resting VO decreases with increasing NYHA functional class and is lower than in control subjects. Using estimations of VO to calculate CO may introduce clinically important error.

Copyright © 2019 Elsevier Inc. All rights reserved.

J Card Fail: 30 Jul 2020; 26:664-672
Grafton G, Cascino TM, Perry D, Ashur C, Koelling TM
J Card Fail: 30 Jul 2020; 26:664-672 | PMID: 30753933
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Abstract

Clinical and imaging response to tumor necrosis factor alpha inhibitors in treatment of cardiac sarcoidosis: a multicenter experience.

Gilotra NA, Wand AL, Pillarisetty A, Devraj M, ... Chen ES, Sheikh FH
Background
Cardiac sarcoidosis (CS) is an increasingly recognized cause of cardiomyopathy, however data on immunosuppressive strategies are limited. Treatment with tumor necrosis factor (TNF) alpha inhibitors is not well described; moreover, there may be heart failure (HF)-related safety concerns.
Methods
Retrospective multicenter study of TNF alpha inhibitor treated CS patients. Baseline characteristics, treatments, and outcomes were adjudicated.
Results
Thirty-eight patients with CS (mean 49.9 years old, 42% women, 53% African American) were treated with TNF alpha inhibitor (30 infliximab, 8 adalimumab). Prednisone dose decreased from time of TNF alpha inhibitor initiation (21.7±17.5 mg) to 6-months (10.4±6.1 mg, p=0.001) and 12-months post (7.3±7.3 mg, p=0.002). On pre-TNF alpha inhibitor treatment 18-flourodoxyglucose position emission tomography (FDG-PET), 84% of patients had cardiac FDG uptake. Post-treatment, there was a significant decrease in number of segments involved (3.5±3.8 to 1±2.5, p=0.008) and maximum standardized uptake value (3.59±3.7 to 0.57±1.6, p=0.0005), with 73% of patients demonstrating complete resolution or improvement of cardiac FDG uptake. Left ventricular ejection fraction remained stable (45±16.5 to 47±15.0%, p=0.10). Four patients required inpatient HF treatment, and 8 had infections; 2 required treatment cessation.
Conclusions
TNF alpha inhibitor treatment guided by FDG-PET may minimize corticosteroid use and effectively reduce cardiac inflammation without significant adverse effect on cardiac function. However infections were common, some of which were serious, and therefore patients require close monitoring for both infection and cardiac symptoms.

Copyright © 2020. Published by Elsevier Inc.

J Card Fail: 31 Aug 2020; epub ahead of print
Gilotra NA, Wand AL, Pillarisetty A, Devraj M, ... Chen ES, Sheikh FH
J Card Fail: 31 Aug 2020; epub ahead of print | PMID: 32889044
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Abstract

The effect of decongestion on intrarenal venous flow patterns in acute heart failure patients.

Ter Maaten JM, Dauw J, Martens P, Somers F, ... Dupont M, Mullens W
Background
Discontinuous intrarenal venous flow patterns, as assessed by renal Doppler ultrasound, are associated with changes in hemodynamics such as volume expansion and poorer diuretic response in patients with HF. We aimed to study intrarenal venous and arterial flow patterns following decongestive treatment in patients with acute heart failure (HF).
Methods and results
15 acute HF patients were enrolled. Intrarenal venous and arterial flow patterns were assessed at baseline, 1 hour after administration of loop diuretics, at day 2 and day 3. In patients hospitalized for acute HF, 13 (87%) patients had a discontinuous venous flow pattern at admission. Following decongestive treatment, a significant improvement of the venous impedance index (P=0.021) and venous discontinuity index (P=0.004) was observed at day 3 compared to baseline. There was no effect on the intrarenal arterial flow patterns.
Conclusions
In patients who exhibit discontinuous renal venous flow patterns hospitalized for acute HF decongestive treatment led to a normalization of intrarenal venous flow to a continuous pattern.

Copyright © 2020. Published by Elsevier Inc.

J Card Fail: 10 Sep 2020; epub ahead of print
Ter Maaten JM, Dauw J, Martens P, Somers F, ... Dupont M, Mullens W
J Card Fail: 10 Sep 2020; epub ahead of print | PMID: 32927066
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Abstract

Do Patients With Acute Heart Failure and Preserved Ejection Fraction Have Heart Failure at Follow-Up: Implications of the Framingham Criteria.

Hage C, LÖfstrÖm U, Donal E, Oger E, ... Linde C, Lund LH
Background
Heart failure (HF) with preserved ejection fraction (HFpEF) may be misdiagnosed. We assessed prevalence and consistency of Framingham criteria signs and symptoms in acute vs subsequent stable HFpEF.
Methods
Three hundred ninety-nine patients with acute HFpEF according to Framingham criteria were re-assessed in stable condition. Four definitions of HFpEF at follow-up: (1) Framingham criteria alone, (2) Framingham criteria and natriuretic peptides (NPs), (3) Framingham criteria, NPs, and European Society of Cardiology HF guidelines echocardiographic criteria, (4) Framingham criteria, NPs, and the Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction (PARAGON) trial echocardiographic criteria.
Results
At follow-up, HFpEF was still present in 27%, 22%, 21%, and 22%, respectively. Most prevalent in acute HFpEF were dyspnea at exertion (90%), pulmonary rales (71%), persisting at follow-up in 70% and 13%, respectively. Characteristics at acute HF with greater or lesser odds of stable HFpEF; (1) jugular venous distention (odds ratio [OR] 1.80, 95% confidence interval [CI] 1.13-2.87; P = .013) and pleural effusion (OR 0.45, 95% CI 0.24-0.85; P = .014) and (4), older age (1.04, 95% CI 1.01-1.08; P = .014) and tachycardia (>100 bpm) 0.52, 95% CI 0.27-1.00; P = .048).
Conclusions
In patients with acute HFpEF, one-quarter met the HF definition according to Framingham criteria at ambulatory follow-up. The proportion of patients with postdischarge HFpEF was largely unaffected by additional echocardiographic or NP criteria Older age and jugular venous distention at acute presentation predicted persistent HFpEF at follow-up, whereas pleural effusion and tachycardia may yield false HFpEF diagnoses. This finding has implications for HFpEF trial design.

Copyright © 2019 Elsevier Inc. All rights reserved.

J Card Fail: 30 Jul 2020; 26:673-684
Hage C, LÖfstrÖm U, Donal E, Oger E, ... Linde C, Lund LH
J Card Fail: 30 Jul 2020; 26:673-684 | PMID: 31035008
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Abstract

Cardiovascular Magnetic Resonance may avoid unnecessary coronary angiography in patients with unexplained left ventricular systolic dysfunction: a retrospective diagnostic pilot study.

Desroche LM, Milleron O, Safar B, Ou P, ... Ronchard T, Jondeau G
Backgrounds
Coronary angiography(CA) is usually performed in patients with reduced left ventricular ejection fraction(LVEF) to SEARCH: ischemic cardiomyopathy. Our aim was to examine the agreement between CA and cardiovascular magnetic resonance(CMR) among a cohort of patients with unexplained reduced LVEF, and estimate what would have been the consequences of using CMR as the first-line exam.
Methods
Three hundred and five patients with unexplained reduced LVEF≤ 45% who underwent both CA and CMR were retrospectively registered. Patients were classified as CMR or CMR according to presence or absence of myocardial ischemic scar, and classified CA or CA according to presence or absence of significant coronary artery disease(CAD).
Results
CMR+(n=89) included all 54CA+ patients, except 2 with distal CAD in whom no revascularization was proposed. Among the 247CA patients, 15% were CMR. CMR had 96% sensitivity, 85% specificity, 99% negative predictive value, and 58% positive predictive value for detecting CA+ patients. Revascularization was performed in 6.5% of the patients (all CMR). Performing CA only for CMR patients would have decreased the number of CAs by 71%.
Conclusions
In reduced LVEF, performing CA only in CMR patients may significantly reduce the number of unnecessary CAs performed, without missing any patients requiring revascularization.

Copyright © 2020. Published by Elsevier Inc.

J Card Fail: 13 Sep 2020; epub ahead of print
Desroche LM, Milleron O, Safar B, Ou P, ... Ronchard T, Jondeau G
J Card Fail: 13 Sep 2020; epub ahead of print | PMID: 32942010
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Abstract

Prominent Longitudinal Strain Reduction of Basal Left Ventricular Segments in Patients with COVID-19.

Goerlich E, Gilotra NA, Minhas AS, Bavaro N, Hays AG, Cingolani OH
Background
COVID-19 has been associated with overt and subclinical myocardial dysfunction. We observed a recurring pattern of reduced basal left ventricular (LV) longitudinal strain (LS) on speckle-tracking echocardiography (STE) in hospitalized COVID-19 patients and subsequently aimed to identify characteristics of affected patients. We hypothesized that COVID-19 patients with reduced basal LV strain would demonstrate elevated cardiac biomarkers.
Methods
81 consecutive COVID-19 patients underwent STE. Those with poor quality STE (n=2) or known LV ejection fraction<50% (n=4) were excluded. Patients with absolute value basal LS<13.9% (2SD below normal) were designated as cases (n=39); those with basal LS≥13.9% as controls (n=36). Demographics and clinical variables were compared.
Results
Of 75 included patients (mean age 62±14 years, 41% women), 52% had reduced basal strain. Cases had higher BMI (median[IQR]) (34.1[26.5-37.9]kg/m vs. 26.9[24.8-30.0]kg/m, p=0.009), and greater proportions of Black (74% vs. 36%, p=0.0009), hypertensive (79% vs. 56%, p=0.026) and diabetic patients (44% vs. 19%, p=0.025) compared to controls. Troponin and NT-proBNP levels trended higher in cases but were not significantly different.
Conclusions and relevance
Reduced basal LV strain is common in COVID-19 patients. Patients with hypertension, diabetes, obesity, and Black race were more likely to have reduced basal strain. Further investigation into the significance of this strain pattern is warranted.

Copyright © 2020. Published by Elsevier Inc.

J Card Fail: 25 Sep 2020; epub ahead of print
Goerlich E, Gilotra NA, Minhas AS, Bavaro N, Hays AG, Cingolani OH
J Card Fail: 25 Sep 2020; epub ahead of print | PMID: 32991982
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Abstract

Novel BAG3 Variants in African American Patients with Cardiomyopathy: Reduced β-Adrenergic Responsiveness in Excitation-Contraction.

Feldman AM, Gordon J, Wang J, Song J, ... Khalili K, Cheung JY
Background
We reported 3 novel non-synonymous single-nucleotide variants of Bcl2-associated athanogene 3 (BAG3) in African Americans with heart failure (HF) which are associated with 2-fold increase in cardiac events (HF hospitalization, heart transplant or death).
Methods
We expressed BAG3 variants (P63A, P380S and A479V) via adenovirus-mediated gene transfer in adult left ventricular myocytes isolated from either wild-type (WT) or cardiac-specific BAG3 haplo-insufficient (cBAG3) mice: the latter to simulate the clinical situation in which BAG3 variants are only found on one allele.
Results
Compared to WT myocytes, cBAG3 myocytes expressed ∼50% of endogenous BAG3 levels and exhibited decreased [Ca] and contraction amplitudes after isoproterenol due to reduced L-type Ca current. BAG3 repletion with WT BAG3 but not P380S, A479V or P63A/P380S variants restored contraction amplitudes in cBAG3 myocytes to those measured in WT myocytes, suggesting excitation-contraction (EC) abnormalities partly account for HF in patients harboring these mutants. Since P63A is near the WW domain (residues 21-55) and A479V is in the BAG domain (residues 420-499), we expressed BAG3 deletion mutants (Δ1-61 and Δ421-575) in WT myocytes and demonstrated that the BAG but not the WW domain was involved in enhancement of EC by isoproterenol.
Conclusion
The BAG3 variants contribute to heart failure in African American patients partly by reducing myocyte excitation-contraction under stress, and that both the BAG and PXXP domains are involved in mediating β-adrenergic responsiveness in myocytes.

Copyright © 2020. Published by Elsevier Inc.

J Card Fail: 17 Sep 2020; epub ahead of print
Feldman AM, Gordon J, Wang J, Song J, ... Khalili K, Cheung JY
J Card Fail: 17 Sep 2020; epub ahead of print | PMID: 32956817
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Abstract

Cognition, Physical Function and Quality-of-Life in Older Patients with Acute Decompensated Heart Failure.

Pastva AM, Hugenschmidt CE, Kitzman DW, Nelson MB, ... Chen H, Duncan PW
Background
Older adults with acute decompensated heart failure (ADHF) have persistently poor clinical outcomes. Cognitive impairment (CI) may be a contributing factor. However, the prevalence of CI and the relationship of cognition with other patient-centered factors such a physical function and quality-of-life (QOL) that also may contribute to poor outcomes are incompletely understood.
Methods
Older (≥60 years) hospitalized patients with ADHF were assessed for cognition [Montreal Cognitive Assessment (MoCA)], physical function [(short physical performance battery (SPPB), 6-minute walk distance (6MWD)], and QOL [Kansas City Cardiomyopathy Questionnaire (KCCQ), Short Form-12 (SF-12)].
Results
Among patients (N=198, 72.1±7.6 years), 78% screened positive for CI (MoCA <26) despite rare medical record documentation (2%). Participants also had severely diminished physical function (SPPB 6.0±2.5 units, 6MWD 186±100m) and QOL (scores <50). MoCA positively related to SPPB (ß=0.47, p<0.001), 6MWD ß=0.01, p=0.006) and inversely related to KCCQ Overall Score (ß=-0.05, p<0.002) and SF-12 Physical Component Score (ß=-0.09, p=0.006). MoCA was a small but significant predictor of SPPB, 6MWD, and KCCQ.
Conclusion
Among older hospitalized patients with ADHF, CI is highly prevalent, is underrecognized clinically, and is associated with severe physical dysfunction and poor QOL. Formal screening may reduce adverse events by identifying patients who may require more tailored care.

Copyright © 2020. Published by Elsevier Inc.

J Card Fail: 17 Sep 2020; epub ahead of print
Pastva AM, Hugenschmidt CE, Kitzman DW, Nelson MB, ... Chen H, Duncan PW
J Card Fail: 17 Sep 2020; epub ahead of print | PMID: 32956816
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Abstract

The differential impact of the Left Atrial pressure components on Pulmonary Arterial Compliance-Resistance relationship in Heart Failure.

Najjar E, Lund LH, Hage C, Nagy AI, Johnson J, Manouras A
Purpose
The pulmonary capillary wedge pressure (PAWP) rise has been shown to impact on the inherent relationship between the pulmonary arterial compliance (PAC) and pulmonary vascular resistance (PVR), thus augmenting the pulsatile relative to the resistive load of the right ventricle (RV). However, the PAWP comprises the integration of both the steady and the pulsatile pressure components. We sought to address the differential impact of the these distinct PAWP components on the PAC-PVR relationship in a cohort of heart failure (HF) patients.
Methods and results
The study population consisted of 192 patients with hemodynamic findings diagnostic for HF. Off-line analysis was performed using the MATLAB software. The steady (PAWPS) and pulsatile (PAWPP) PAWP components were calculated as mid-A pressure and mean pressure during the V-wave oscillation, respectively. The PAC and PVR were hyperbolically and inversely associated and the subgroup of patients with PAWP above the median (>18 mmHg) displayed a significant left and downward shift of the curve fit (p<0.001). The shift in the PAC-PVR fit between patients with higher vs. low PAWPS was not significant (p=0.43). In contrast, there was a significant downward and leftward shift of the PVR-PAC curve fit for the subgroup with higher PAWPP (p<0.001). Furthermore, only PAWPP was significantly associated with the RC-time, assessed as the PAC × PVR product (p<0.001).
Conclusion
In HF patients, the pulsatile rather than the steady PAWP component stands for the previously documented shift of the PAC-PVR relationship occurring at elevated PAWP.

Copyright © 2020. Published by Elsevier Inc.

J Card Fail: 17 Sep 2020; epub ahead of print
Najjar E, Lund LH, Hage C, Nagy AI, Johnson J, Manouras A
J Card Fail: 17 Sep 2020; epub ahead of print | PMID: 32956814
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Abstract

Enhanced Echo Intensity of Skeletal Muscle Is Associated With Exercise Intolerance in Patients With Heart Failure.

Nakano I, Hori H, Fukushima A, Yokota T, ... Abe T, Anzai T
Background
Skeletal muscle is quantitatively and qualitatively impaired in patients with heart failure (HF), which is closely linked to lowered exercise capacity. Ultrasonography (US) for skeletal muscle has emerged as a useful, noninvasive tool to evaluate muscle quality and quantity. Here we investigated whether muscle quality based on US-derived echo intensity (EI) is associated with exercise capacity in patients with HF.
Methods and results
Fifty-eight patients with HF (61 ± 12 years) and 28 control subjects (58 ± 14 years) were studied. The quadriceps femoris echo intensity (QEI) was significantly higher and the quadriceps femoris muscle thickness (QMT) was significantly lower in the patients with HF than the controls (88.3 ± 13.4 vs 81.1 ± 7.5, P= .010; 5.21 ± 1.10 vs 6.54 ±1.34 cm, P< .001, respectively). By univariate analysis, QEI was significantly correlated with age, peak oxygen uptake (VO), and New York Heart Association class in the HF group. A multivariable analysis revealed that the QEI was independently associated with peak VO after adjustment for age, gender, body mass index, and QMT: β-coefficient = -11.80, 95%CI (-20.73, -2.86), P= .011.
Conclusion
Enhanced EI in skeletal muscle was independently associated with lowered exercise capacity in HF. The measurement of EI is low-cost, easily accessible, and suitable for assessment of HF-related alterations in skeletal muscle quality.

Copyright © 2019 Elsevier Inc. All rights reserved.

J Card Fail: 30 Jul 2020; 26:685-693
Nakano I, Hori H, Fukushima A, Yokota T, ... Abe T, Anzai T
J Card Fail: 30 Jul 2020; 26:685-693 | PMID: 31533068
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Abstract

Fibroblast Growth Factor 23 and Exercise Capacity in Heart Failure with Preserved Ejection Fraction.

Ghuman J, Cai X, Patel R, Khan S, ... Isakova T, Mehta R
Background
Heart failure with preserved ejection fraction (HFpEF) is characterized by left ventricular hypertrophy (LVH) and reduced exercise capacity. Fibroblast growth factor 23 (FGF23), a hormone involved in phosphate, vitamin D and iron homeostasis, is linked to LVH and HF. We measured c-terminal FGF23 (cFGF23) and intact FGF23 (iFGF23) levels and examined their associations with exercise capacity in patients with HFpEF.
Methods
Using multivariable linear regression and linear mixed models, we studied the associations of cFGF23 and iFGF23 with baseline and mean weekly change over 24 weeks in peak oxygen consumption (VO) and 6-minute walk distance (6MWD) in individuals enrolled in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in HFpEF trial. Our study population comprised of 172 individuals with available plasma for cFGF23 and iFGF23 measurements.
Results
Median (25-75 percentile) baseline cFGF23 and iFGF23 levels were 208.7 (132.1-379.5) RU/ml and 90.3 (68.6-128.5) pg/ml, respectively. After adjustment for cardiovascular disease, hematologic and kidney parameters, higher cFGF23 was independently associated with lower peak VO at baseline. Higher iFGF23 was independently associated with shorter 6MWD at baseline. No significant associations were appreciated with the longitudinal outcomes.
Conclusion
In patients with HFpEF, higher FGF23 levels are independently associated with reduced exercise capacity at baseline.

Copyright © 2020. Published by Elsevier Inc.

J Card Fail: 05 Oct 2020; epub ahead of print
Ghuman J, Cai X, Patel R, Khan S, ... Isakova T, Mehta R
J Card Fail: 05 Oct 2020; epub ahead of print | PMID: 33035687
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Abstract

Validity of hemodynamic monitoring using inert gas rebreathing method in patients with chronic heart failure and those implanted with a left ventricular assist device.

Okwose NC, Bouzas-Cruz N, Fernandez OG, Koshy A, ... MacGowan GA, Jakovljevic DG
Objective
The present study assessed agreement between resting cardiac output estimated by inert gas rebreathing (IGR) and thermodilution methods in patients with heart failure and those implanted with a left ventricular assist device (LVAD).
Methods and results
Haemodynamic measurements were obtained in 42 patients: 22 with chronic heart failure and 20 with implanted continuous flow LVAD (34 males; aged 50 ± 11 years). Measurements were performed at rest using thermodilution and inert gas rebreathing methods. Cardiac output derived by thermodilution and IGR were not significantly different in LVAD (4.4±0.9 vs 4.7±0.8 l/min; P=0.27) or heart failure patients (4.4±1.4 vs 4.5 ± 1.3 l/min; P=0.75). There was a strong relationship between thermodilution and IGR cardiac index (r=0.81, p=0.001) and stroke volume index (r=0.75, p=0.001). Bland-Altman analysis showed acceptable limits of agreement for cardiac index derived by thermodilution and IGR i.e. mean difference (lower and upper limits of agreement) for heart failure patients -0.002 (-0.65 - 0.66) l/min/m, and -0.14 (-0.78 - 0.49) l/min/m for patients with LVAD.
Conclusion
Inert gas rebreathing is a valid method for estimating cardiac output and should be used in clinical practice to complement evaluation and management of chronic heart failure and LVAD patients.

Copyright © 2020. Published by Elsevier Inc.

J Card Fail: 05 Oct 2020; epub ahead of print
Okwose NC, Bouzas-Cruz N, Fernandez OG, Koshy A, ... MacGowan GA, Jakovljevic DG
J Card Fail: 05 Oct 2020; epub ahead of print | PMID: 33035686
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Abstract

HFPEF Score Reflects the Left Atrial Strain and Predicts Prognosis in Patients with Heart Failure with Preserved Ejection Fraction.

Hwang IC, Cho GY, Choi HM, Yoon YE, ... Kim HK, Kim YJ
Background
The HFPEF score is a validated algorithm for the diagnosis of heart failure with preserved ejection fraction (HFpEF). We investigated the associations of the HFPEF score with echocardiographic parameters and prognosis in patients with HFpEF admitted for acute heart failure (AHF).
Methods and results
In total, 4312 patients at 3 tertiary centers were identified. Among 1335 patients with HFpEF, the HFPEF score was available in 1105 patients (39% male) with a median age of 77 years (interquartile range, 69-82). The median HFPEF score was 4 (interquartile range, 3-6). Patients with higher HFPEF scores had worse left atrial (LA) size, peak atrial longitudinal strain of the LA (PALS), mitral E/e\' ratio, and peak tricuspid regurgitation velocity. PALS demonstrated a significant association with the HFPEF score, in patients without atrial fibrillation (AF) and those without AF. After adjustment for clinical factors and echocardiographic parameters, patients with higher HFPEF scores had higher risk of mortality and HF hospitalization regardless of the presence of AF.
Conclusions
HFPEF score reflects LA function in patients with HFpEF admitted for AHF. This association supports the clinical usefulness of the HFPEF score as an indicator of diastolic dysfunction, a diagnostic algorithm for HFpEF, and a prognostic factor in patients with HFpEF.

Copyright © 2020 Elsevier Inc. All rights reserved.

J Card Fail: 05 Oct 2020; epub ahead of print
Hwang IC, Cho GY, Choi HM, Yoon YE, ... Kim HK, Kim YJ
J Card Fail: 05 Oct 2020; epub ahead of print | PMID: 33035685
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Abstract

VENTILATION DISPERSION INDEX AS AN OBJECTIVE EVALUATION TOOL OF EXERCISE OSCILLATORY VENTILATION IN PATIENTS WITH HEART FAILURE.

Corte RC, de Sá J, Carlos R, Felismino AS, ... Pereira E, Bruno S
Introduction
Exercise oscillatory ventilation (EOV) is related to worse prognosis in patients with heart failure (HF). However, its determination is subjective and there is no standard measure to identify it. The aim of the study was to evaluate and characterize the EOV of patients with HF using the ventilation dispersion index (VDI).
Methods
Patients underwent cardiopulmonary exercise testing (CPX), EOV was assessed by two reviewers and the VDI was calculated. The ROC curve analysis was used to assess the ability of the VDI to predict EOV. Pearson\'s correlation test was performed to determine the relationship between VDI and CPX variables.
Results
43 HF patients underwent CPX and were divided into two groups: with VDI<0.601; and VDI≥0.601. An AUC=0.759 was observed in the ROC curve analysis between VDI and EOV (p=0.008). The VDI showed a significant correlation with the ventilatory CPX variables. According to the cut-off point obtained on the ROC curve, patients with VDI≥0.601 had lower left ventricular ejection fraction (LVEF) and higher values of resting minute ventilation (VE) and peak VE.
Conclusion
VDI proved to be a good predictor of EOV in patients with HF.

Copyright © 2020. Published by Elsevier Inc.

J Card Fail: 06 Oct 2020; epub ahead of print
Corte RC, de Sá J, Carlos R, Felismino AS, ... Pereira E, Bruno S
J Card Fail: 06 Oct 2020; epub ahead of print | PMID: 33038533
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Abstract

Plasma Volume Status and its Association with In-Hospital and Post-Discharge Outcomes in Decompensated Heart Failure.

Fudim M, Lerman JB, Page C, Alhanti B, ... O\'Connor CM, Mentz RJ
Background
Prior analyses suggest an association between formula-based plasma volume (PV) estimates and outcomes in heart failure (HF). We assessed the association between estimated PV-status by the Duarte-ePV and Kaplan Hakim (KH-ePVS) formulas, and in-hospital and post-discharge clinical outcomes, in the ASCEND-HF trial.
Methods and results
KH-ePVS and Duarte-ePV were calculated on admission. We assessed associations with in-hospital worsening HF, 30-day composite cardiovascular mortality or HF rehospitalization and 180-day all-cause mortality. 6,373 (89.2%), and 6,354 (89.0%), patients had necessary characteristics to calculate KH-ePVS and Duarte-ePV, respectively. There was no association between PV by either formula with in-hospital worsening HF. KH-ePVS showed a weak correlation with NT-proBNP, and with measures of decongestion such as body weight change and urine output (r<0.3 for all). Duarte-ePV was trending towards an association with worse 30-day (adjusted-OR 1.07, 95%CI 1.00-1.15, p=0.058), but not 180-day outcomes (adjusted-HR 1.03, 95%CI 0.97-1.09, p=0.289). Continuous KH-ePVS>0 (per 10 unit increase) was associated with improved 30-day outcomes (adjusted-OR 0.75, 95%CI 0.62-0.91, p=0.004). Continuous KH-ePVS was not associated with 180-day outcomes (adjusted-HR 1.05, 95%CI 0.98-1.12, p=0.139).
Conclusions
Baseline PV estimates had a weak association with in-hospital measures of decongestion. Duarte-ePV, trended towards an association with early clinical outcomes in decompensated HF, and may improve risk stratification in HF.

Copyright © 2020. Published by Elsevier Inc.

J Card Fail: 06 Oct 2020; epub ahead of print
Fudim M, Lerman JB, Page C, Alhanti B, ... O'Connor CM, Mentz RJ
J Card Fail: 06 Oct 2020; epub ahead of print | PMID: 33038532
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Abstract

sST2 and Diuretic Efficiency in Acute Heart Failure and Concomitant Renal Dysfunction.

Espriella R, Bayés-Genis A, Revuelta E, Miñana G, ... Núñez J,
Background
Identifying patients at risk of poor diuretic response in acute heart failure (AHF) is critical to make prompt adjustments in therapy. The objective of this study was to investigate whether the circulating levels of soluble ST2 predict the cumulative diuretic efficiency (DE) at 24- and 72-hour in patients with AHF and concomitant renal dysfunction (RD).
Methods and results
This is a post-hoc analysis of the IMPROVE-HF trial, in which we enrolled 160 patients with AHF and RD [estimated glomerular filtrate rate (eGFR) <60 mL/min/1.73m2]. DE was calculated as the net fluid output produced per 40 mg of furosemide equivalents. The association between sST2 and diuretic efficiency was evaluated by using multivariate linear regression analysis. The median (interquartile range) cumulative DE at 24- and 72-hour was 747 ml (490-1167) and 1844 ml (1142-2625), respectively. The median (interquartile range) sST2, and mean eGFR were 72 ng/mL (47-117), and 34.0±8.5 ml/min/1.73m2, respectively. In a multivariable setting, higher sST2 were significant and non-linearly related to lower DE both at 24- and 72-hour (P=0.002 and P=0.019, respectively).
Conclusions
In patients with AHF and RD at presentation, circulating levels of sST2 were independently and negatively associated with a poor diuretic response, both at 24- and 72-hour.

Copyright © 2020. Published by Elsevier Inc.

J Card Fail: 07 Oct 2020; epub ahead of print
Espriella R, Bayés-Genis A, Revuelta E, Miñana G, ... Núñez J,
J Card Fail: 07 Oct 2020; epub ahead of print | PMID: 33038531
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Abstract

Vagus Nerve Stimulation Provides Multiyear Improvements in Autonomic Function and Cardiac Electrical Stability in the ANTHEM-HF Study.

Nearing BD, Anand IS, Libbus I, DiCarlo LA, KenKnight BH, Verrier RL
Background
Patients with heart failure with reduced LVEF (HFrEF) experience long-term deterioration of autonomic function and cardiac electrical stability linked to increased mortality risk. ANTHEM-HF reported improved heart rate variability (HRV) and heart rate turbulence (HRT) and reduced T-wave alternans (TWA) after 12 months of vagus nerve stimulation (VNS). We investigated whether the benefits of chronic VNS persist long-term.
Methods and results
Effects of chronic VNS on heart rate, HRV, HRT, TWA, R-wave and T-wave heterogeneity (RWH, TWH), and nonsustained ventricular tachycardia (NSVT) incidence were evaluated in all ANTHEM-HF patients with ambulatory ECG data at 24 and 36 months (n=25). Autonomic markers improved significantly at 24 months and 36 months compared to baseline (heart rate, rMSSD, SDNN, HF-HRV, HRT slope, p<0.05). Peak TWA levels remained reduced at 24 and 36 months (p<0.0001). Reductions in RWH and TWH at 6 and 12 months persisted at 24 and 36 months (p<0.01). NSVT decreased at 12, 24, and 36 months (p<0.025). No sudden cardiac deaths, ventricular fibrillation, or sustained ventricular tachycardia occurred.
Conclusion
In symptomatic patients with HFrEF, chronic VNS appears to confer wide-ranging, persistent improvements in autonomic tone (HRV), baroreceptor sensitivity (HRT), and cardiac electrical stability (TWA, RWH, TWH).

Copyright © 2020. Published by Elsevier Inc.

J Card Fail: 09 Oct 2020; epub ahead of print
Nearing BD, Anand IS, Libbus I, DiCarlo LA, KenKnight BH, Verrier RL
J Card Fail: 09 Oct 2020; epub ahead of print | PMID: 33049374
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Abstract

Very High-Dose Furosemide Continuous Infusions: A Case Series.

Wilczynski JA, Decaro MV, Marhefka GD, Thoma BN, ... Austin M, Danelich IM
Background
There is paucity of data evaluating the efficacy and safety of very high-dose furosemide continuous infusions (≥40 mg/h) for volume removal. This infusion is a novel strategy of loop diuretic administration that may add valuable data to current literature.
Methods and results
This was a retrospective chart review. Patients were eligible for inclusion if prescribed a very high-dose furosemide infusion (defined as ≥40 mg/h, up to 240 mg/h) from April 1, 2017, to January 1, 2019, at Thomas Jefferson University Hospital. Data collected included the change in cumulative urine output, net urine output, incidence of acute kidney injury, occurrences of hypotension, electrolyte abnormalities, body weight, and ototoxicity. Twenty-two patients were included in this analysis. The median change in 24-hour urine output from before to after very high-dose continuous furosemide infusion increased from 1193 mL at 24 hours before infusion initiation to 3518 mL at 24 hours after infusion initiation (P < .01). Serum creatinine increased 24 hours after infusion initiation but decreased within 48 hours. There were no electrolyte abnormalities. Out of 22 patients, only 2 had an occurrence of hypotension. No patients were reported to have ototoxicity.
Conclusions
Very high-dose furosemide continuous infusions provide a significant increase in diuresis without worsening renal function, disturbing electrolytes, or increasing the risk of ototoxicity. Further studies are necessary to examine the efficacy and safety of this novel strategy.

Copyright © 2020 Elsevier Inc. All rights reserved.

J Card Fail: 30 Aug 2020; 26:794-797
Wilczynski JA, Decaro MV, Marhefka GD, Thoma BN, ... Austin M, Danelich IM
J Card Fail: 30 Aug 2020; 26:794-797 | PMID: 32505817
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Impact:
Abstract

Left Ventricular Assist Device Caregiver Experiences and Health Outcomes: A Systematic Review of Qualitative and Quantitative Studies.

Streur MM, Auld JP, Liberato ACS, Beckman JA, ... Thompson EA, Dougherty CM
Background
Knowledge synthesis is lacking regarding outcomes and experiences of caregivers of adult patients living with continuous flow left ventricular assist devices (CF-LVAD). The purpose of this systematic review was to summarize qualitative data related to the experience of caregivers of adult patients living with CF-LVAD as well as quantitative data related to health outcomes of caregivers.
Methods and results
Multiple databases were systematically queried for studies of qualitative experiences and quantitative health outcomes for caregivers of adult CF-LVAD recipients. Search dates were constrained to articles published between 2004 and August of 2018 because CF-LVADs were not routinely implanted before 2004. Two authors independently screened 683 articles; 15 met predetermined inclusion criteria. Eligible articles reported results from 13 studies. Of those, 8 used either qualitative or mixed methods and 5 used quantitative methods. Caregivers were primarily female (81%) and their mean age was 59 years. Qualitative studies revealed 3 overarching themes related to the caregiver role, coping strategies, and LVAD decisions. Quantitative studies revealed caregiver strain peaked between 1 and 3 months after implantation, anxiety and depression were relatively stable, mental health status improved, and physical health status was stable from before to after implantation.
Conclusions
CF-LVAD caregivers experience significant, sustained emotional strain for 3 months after implantation, reporting considerable stress in meeting their personal needs and those of their loved one.

Copyright © 2020 Elsevier Inc. All rights reserved.

J Card Fail: 30 Jul 2020; 26:713-726
Streur MM, Auld JP, Liberato ACS, Beckman JA, ... Thompson EA, Dougherty CM
J Card Fail: 30 Jul 2020; 26:713-726 | PMID: 32505816
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Abstract

Differential Impact of Class I and Class II Panel Reactive Antibodies on Post-Heart Transplant Outcomes.

Ivey-Miranda JB, Kunnirickal S, Bow L, Maulion C, ... Kransdorf EP, Bellumkonda L
Background
Sensitized patients awaiting heart transplantation spend a longer time on the waitlist and have higher mortality. We are now able to further characterize sensitization by discriminating antibodies against class I and II, but the differential impact of these has not been assessed systematically.
Methods and results
Using United Network for Organ Sharing data (2004-2015), we analyzed 17,361 adult heart transplant patients whose class I and II panel reactive antibodies were reported. Patients were divided into 4 groups: class I and II ≤25% (group 1); class I ≤25% and class II ˃25% (group 2); class II ≤25% and class I >25% (group 3); and both class I and II >25% (group 4). Outcomes assessed were treated rejection at 1-year mortality, all-cause mortality, and rejection-related mortality. Compared with group 1, only group 4 was associated with a higher risk of treated rejection at 1 year (odds ratio 1.31, 95% confidence interval [CI] 1.05-1.64), all-cause mortality (hazard ratio 1.24, 95% CI 1.06-1.46), and mortality owing to rejection (subhazard ratio 1.84, 95% CI 1.18-2.85), whereas groups 2 and 3 were not (P > .05).
Conclusions
Combined elevation in class I and II panel reactive antibodies seem to increase the risk of treated rejection and all-cause mortality, whereas risk with isolated elevation is unclear.

Copyright © 2020 Elsevier Inc. All rights reserved.

J Card Fail: 31 Jul 2020; epub ahead of print
Ivey-Miranda JB, Kunnirickal S, Bow L, Maulion C, ... Kransdorf EP, Bellumkonda L
J Card Fail: 31 Jul 2020; epub ahead of print | PMID: 32750489
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Abstract

Transition to Advanced Therapies in Elderly Patients Supported by Extracorporeal Membrane Oxygenation Therapy.

Chouairi F, Vallabhajosyula S, Mullan C, Mori M, ... Ahmad T, Miller PE
Background
Although the use of extracorporeal membrane oxygenation (ECMO) continues to increase, very little is known about how age influences the transition to definitive advanced therapies.
Methods
Using the National Inpatient Sample database from 2008 to 2017, we analyzed patients supported by ECMO for cardiogenic shock and separated patients into 2 age cohorts: < 65 years and ≥ 65 years. Primary outcomes of interest included the proportion of patients undergoing orthotopic cardiac transplantation (OHT) and left ventricular assist device (LVAD) implantation.
Results
Over the study period, we identified 16,132 hospitalizations of people with cardiogenic shock requiring ECMO support. Significantly fewer patients in the older group underwent OHT compared to the younger group (0.4% vs 1.2%, P < 0.001). Compared to the younger group, a lower proportion of those ≥ 65 years received an LVAD (3.7% vs 5.8%, P < 0.001). LVAD implantation increased over the study period in both age cohorts, whereas OHT increased only in the < 65 group (P < 0.05, all). After multivariable adjustment, patients in the oldest age group were still less likely to receive an LVAD (odds ratio 0.54; confidence interval: 0.43-0.69, P < 0.001) and continued to have the highest odds of in-hospital mortality (odds ratio 1.53; confidence interval : 1.39-1.69, P < 0.001).
Conclusions
Survival of patients ≥ 65 years requiring ECMO for cardiogenic shock is poor and less commonly includes transition to definitive advanced therapies. Although we must stress that no patient should be denied ECMO based solely on age, we believe our results may be helpful for providers when counseling patients and their families.

Copyright © 2020 Elsevier Inc. All rights reserved.

J Card Fail: 07 Aug 2020; epub ahead of print
Chouairi F, Vallabhajosyula S, Mullan C, Mori M, ... Ahmad T, Miller PE
J Card Fail: 07 Aug 2020; epub ahead of print | PMID: 32777479
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Abstract

Possible Association Between Body Temperature and B-Type Natriuretic Peptide in Patients With Cardiovascular Diseases.

Kang R, Nagoshi T, Kimura H, Tanaka TD, ... Kawai M, Yoshimura M
Background
In addition to various biological effects of natriuretic peptides (NP) on cardiovascular systems, we recently reported that NP raises intracellular temperature in cultured adipocytes. We herein examined the possible thermogenic action of NP in consideration of hemodynamic parameters and inflammatory reaction by proposing structural equation models.
Methods and results
The study population consisted of 1985 consecutive patients who underwent cardiac catheterization. Covariance structure analyses were performed to clarify the direct contribution of plasma B-type NP (BNP) to body temperature (BT) by excluding other confounding factors. A hierarchical path model showed increase in BNP, increase in C-reactive protein and decrease in left ventricular ejection fraction were mutually associated. As expected, C-reactive protein was positively correlated with BT. Importantly, despite a negative correlation between BNP and left ventricular ejection fraction, a decrease in the left ventricular ejection fraction was associated with BT decrease, whereas elevation in BNP level was associated with BT increase independently of C-reactive protein level (P = .007).
Conclusions
Patients with LV dysfunction tend to manifest a decrease in BT, whereas BNP elevation is associated with an increase in BT independently of inflammatory response. These findings suggest the adaptive heat-retaining property of NP (and/or NP-associated factors) when BT falls owing to unfavorable hemodynamic conditions in a state of impaired cardiac function.

Copyright © 2020 Elsevier Inc. All rights reserved.

J Card Fail: 28 Aug 2020; epub ahead of print
Kang R, Nagoshi T, Kimura H, Tanaka TD, ... Kawai M, Yoshimura M
J Card Fail: 28 Aug 2020; epub ahead of print | PMID: 32871239
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Abstract

Can Biomarkers Provide Right Ventricular-Specific Prognostication in the Perioperative Setting?

Jabagi H, Ruel M, Sun LY

Since the introduction of biomarkers in the late 1980s, considerable research has been dedicated to their validation and application. As a result, many biomarkers are now commonly used in clinical practice. However, the role of biomarkers in the prediction of right ventricular failure (RVF) and in the prognostication for patients with RVF remains underexplored. Barriers include a lack of awareness of the importance of right ventricular function, especially in the perioperative setting, as well as a lack of reproducible means to assess right ventricular function in this setting. We provide an overview of biomarkers with right ventricular prognostic capabilities that could be further explored in patients expecting cardiac surgery, who are notoriously susceptible to developing RVF. We discuss biomarkers\' mechanistic pathways and highlight their potential strengths and weaknesses in use in research and clinical care.

Copyright © 2019 Elsevier Inc. All rights reserved.

J Card Fail: 30 Aug 2020; 26:776-780
Jabagi H, Ruel M, Sun LY
J Card Fail: 30 Aug 2020; 26:776-780 | PMID: 31539620
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Abstract

Stabilization of Cardiac Function With Diflunisal in Transthyretin (ATTR) Cardiac Amyloidosis.

Lohrmann G, Pipilas A, Mussinelli R, Gopal DM, ... Maurer MS, Ruberg FL
Background
Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an underappreciated cause of heart failure that results from misfolded TTR (prealbumin) protein. Diflunisal is an approved non-steroidal anti-inflammatory drug that stabilizes TTR, with limited data available regarding effects on cardiac structure and function.
Methods and results
ATTR-CM patients (n=81, 41% treated with 250 mg twice-daily diflunisal by clinical practice) were retrospectively identified with baseline and follow-up (median interval 1 year) serum biomarker and echocardiographic data compared, including global longitudinal strain (GLS). Chi-squared and Wilcoxon tests assessed differences between subjects, divided by treatment group, and univariable and multivariable linear regression was performed. At baseline, patients treated with diflunisal were younger (68 vs 77 years, P = .0001), with lower B-type natriuretic peptide (BNP; 249 vs 545 pg/mL, P = .009) and serum creatinine (1.1 vs 1.2 mg/dL, P = .04), but similar TTR concentration (P = .31), cardiac troponin I (P = .06), and GLS (P = .67). At follow-up, diflunisal untreated versus treated patients showed differences in TTR concentration (19 vs 33 mg/dL, P = .01) and favorable differences in left atrial volume index (+4.6 vs -1.4 mL/m, P = .002) and cardiac troponin I (+0.03 vs -0.01 ng/mL, P = .01) for the entire cohort. Among the subset with wild-type ATTR (n=53), diflunisal treatment was associated with differences in GLS (+1.2% untreated vs +0.1% treated, P = .03). Changes in wall thickness (P = .2), left ventricular ejection fraction (P = .71), and BNP (P = .42) were similar between groups.
Conclusions
In ATTR-CM, diflunisal treatment resulted in measurable differences in some parameters of cardiac structure and function after only 1 year of administration. Further longer-term analysis is warranted.

Copyright © 2019 Elsevier Inc. All rights reserved.

J Card Fail: 30 Aug 2020; 26:753-759
Lohrmann G, Pipilas A, Mussinelli R, Gopal DM, ... Maurer MS, Ruberg FL
J Card Fail: 30 Aug 2020; 26:753-759 | PMID: 31805416
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Abstract

Continuous Infusion Versus Intermittent Boluses of Furosemide in Acute Heart Failure: A Systematic Review and Meta-Analysis.

Chan JSK, Kot TKM, Ng M, Harky A
Background
Acute heart failure is a common cause of hospital admission. This study aims to compare continuous infusion and intermittent boluses of furosemide in treating acute heart failure.
Methods
Electronic searches were performed on PubMed, Medline, Scopus, and EMBASE. English articles comparing intermittent boluses and continuous infusion of furosemide in treating acute heart failure were included. Non-comparative studies or articles, and articles that did not report specific data for acute heart failure patients were excluded. Primary endpoints included post-treatment daily urine output, weight, length of stay, and serum sodium, potassium, and creatinine. Secondary endpoints included other pre-treatment and treatment variables. Post hoc trial sequential analysis (TSA) was performed on selected variables.
Results
Ten randomized controlled trials were included with a total of 735 patients (371 with intermittent boluses and 364 with continuous infusion). Mean daily urine output (P < .001) and weight loss (P = .04) were significantly higher in the continuous infusion group. Other variables were not significantly different between the two groups. TSA showed that current evidence is sufficient to draw the above conclusions about mean daily urine output, but more studies were required to compare the 2 regimens in terms of weight loss.
Conclusion
Choice of furosemide regime in acute heart failure remains physician preference. Both bolus and continuous infusion yields satisfactory outcomes.

Copyright © 2019 Elsevier Inc. All rights reserved.

J Card Fail: 30 Aug 2020; 26:786-793
Chan JSK, Kot TKM, Ng M, Harky A
J Card Fail: 30 Aug 2020; 26:786-793 | PMID: 31730917
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Abstract

Sacubitril/Valsartan Improves Left Ventricular Function in Chronic Pressure Overload Independent of Intact Cyclic Guanosine Monophosphate-dependent Protein Kinase I Alpha Signaling.

Tam K, Richards DA, Aronovitz MJ, Martin GL, ... Jaffe IZ, Blanton RM
Background
Combined angiotensin receptor/neprilysin inhibition with sacubitril/valsartan (Sac/Val) has emerged as a therapy for heart failure. The presumed mechanism of benefit is through prevention of natriuretic peptide degradation, leading to increased cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG) signaling. However, the specific requirement of PKG for Sac/Val effects remains untested.
Methods and results
We examined Sac/Val treatment in mice with mutation of the cGMP-dependent protein kinase I (PKGI)α leucine zipper domain, which is required for cGMP-PKGIα antiremodeling actions in vivo. Wild-type (WT) or PKG leucine zipper mutant (LZM) mice were exposed to 56-day left ventricular (LV) pressure overload by moderate (26G) transaortic constriction (TAC). At day 14 after TAC, mice were randomized to vehicle or Sac/Val by oral gavage. TAC induced the same degree of LV pressure overload in WT and LZM mice, which was not affected by Sac/Val. Although LZM mice, but not WT, developed LV dilation after TAC, Sac/Val improved cardiac hypertrophy and LV fractional shortening to the same degree in both the WT and LZM TAC mice.
Conclusion
These findings indicate the beneficial effects of Sac/Val on LV structure and function in moderate pressure overload. The unexpected finding that PKGIα mutation does not abolish the Sac/Val effects on cardiac hypertrophy and on LV function suggests that signaling other than natriuretic peptide- cGMP-PKG mediates the therapeutic benefits of neprilysin inhibition in heart failure.

Copyright © 2020 Elsevier Inc. All rights reserved.

J Card Fail: 30 Aug 2020; 26:769-775
Tam K, Richards DA, Aronovitz MJ, Martin GL, ... Jaffe IZ, Blanton RM
J Card Fail: 30 Aug 2020; 26:769-775 | PMID: 32464187
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Abstract

The Association Between Secondhand Smoke Exposure and Survival for Patients With Heart Failure.

Psotka MA, Rushakoff J, Glantz SA, De Marco T, Fleischmann KE
Background
The effect of secondhand tobacco smoke (SHS) exposure on patients with heart failure (HF) is uncertain. We investigated the association of mortality with SHS exposure for patients with HF.
Methods
Nonsmokers with clinical HF were enrolled from 2003 to 2008 in a single-center longitudinal cohort study. The effect of SHS exposure determined by high-sensitivity urinary cotinine on mortality was estimated by multivariable proportional hazards modeling.
Results
Mortality was assessed after median 4.3 years. Of 202 patients, enrollment urinary cotinine levels were below the limit of detection for 106 (52%) considered unexposed to SHS. The median detectable cotinine was 0.47 ng/mL (interquartile range: [0.28, 1.28]). Participants were 41% female, 65 ± 17 years old, and 57% white race. Elevated cotinine was associated with increased mortality after multivariate adjustment: hazard ratio (HR) per 1 ng/mL increase in urinary cotinine: 1.15, 95% confidence interval (CI): 1.08-1.23, P < .001. Higher age (HR per 5-year increase: 1.32, 95% CI: 1.22-1.43, P < .001), male sex (HR vs female: 1.52, 95% CI: 1.02-2.28, P = .040), and New York Heart Association class (HR for class III vs I: 2.91, 95% CI: 1.71-4.99, P < .001) were also associated with mortality.
Conclusions
SHS exposure is associated with a dose-dependent increase in mortality for patients with HF.

Copyright © 2019 Elsevier Inc. All rights reserved.

J Card Fail: 30 Aug 2020; 26:745-750
Psotka MA, Rushakoff J, Glantz SA, De Marco T, Fleischmann KE
J Card Fail: 30 Aug 2020; 26:745-750 | PMID: 31926217
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Abstract

The Role of Cardiac Rehabilitation in Reducing Major Adverse Cardiac Events in Heart Transplant Patients.

Uithoven KE, Smith JR, Medina-Inojosa JR, Squires RW, Olson TP
Background
Methods for reducing major adverse cardiac events (MACE) in patients after heart transplantation (HTx) are critical for long-term quality outcomes.
Methods and results
Patients with cardiopulmonary exercise testing prior to HTx and at least 1 session of cardiac rehabilitation (CR) after HTx were included. Exercise sessions were evaluated as ≥ 23 or < 23 sessions based on recursive partitioning. We included 140 patients who had undergone HTx (women: n = 41 (29%), age: 52 ± 12 years, body mass index: 27 ± 5 kg/m). Mean follow-up was 4.1 ± 2.7 years, and 44 patients (31%) had a MACE: stroke (n = 1), percutaneous intervention (n = 5), heart failure (n = 6), myocardial infarction (n = 1), rejection (n = 16), or death (n = 15). CR was a significant predictor of MACE, with ≥ 23 sessions associated with a ∼ 60% reduction in MACE risk (hazard ratio [HR]: 0.42, 95% CI: 0.19-0.94, P = 0.035). This remained after adjusting for age, sex and history of diabetes (HR: 0.41, 95% CI: 0.18-0.94, P = 0.035) as well as body mass index and pre-HTx peak oxygen consumption (HR: 0.40, 95% CI: 0.18-0.92, P = 0.031).
Conclusions
After adjustment for covariates of age, sex, diabetes, body mass index, and pre-HTx peak oxygen consumption, CR attendance of ≥ 23 exercise sessions was predictive of lower MACE risk following HTx. In post-HTx patients, CR was associated with MACE prevention and should be viewed as a critical tool in post-HTx treatment strategies.

Copyright © 2020 Elsevier Inc. All rights reserved.

J Card Fail: 30 Jul 2020; 26:645-651
Uithoven KE, Smith JR, Medina-Inojosa JR, Squires RW, Olson TP
J Card Fail: 30 Jul 2020; 26:645-651 | PMID: 31981697
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Abstract

High-Choline Diet Exacerbates Cardiac Dysfunction, Fibrosis, and Inflammation in a Mouse Model of Heart Failure With Preserved Ejection Fraction.

Shuai W, Wen J, Li X, Wang D, Li Y, Xiang J
Background
Trimethylamine N-oxide, a gut microbe-dependent metabolite of dietary choline and other trimethylamine-containing nutrients, has been associated with a poor prognosis for patients with cardiovascular disease. However, the role and underlying mechanisms of trimethylamine N-oxide in the cardiac function of patients with heart failure with preserved ejection fraction (HFpEF) have not been elucidated.
Methods and results
C57BL/6 mice were fed a normal diet, high-choline (1.2%) diet, and/or 3-dimethyl-1-butanol diet 3 weeks before the operation (uninephrectomy followed by a continuous saline or aldosterone infusion). Mice were assessed for 4 weeks after the operation. Echocardiographic and hemodynamic measurements were performed. Blood samples were evaluated for choline, trimethylamine N-oxide, and inflammatory factor levels. Left ventricular tissues were collected to assess myocardial fibrosis and inflammation. Left ventricular hypertrophy, pulmonary congestion, and diastolic dysfunction were markedly exacerbated in HFpEF mice fed high-choline diets compared with mice fed the control diet. Myocardial fibrosis and inflammation were markedly increased in HFpEF mice fed high-choline diets compared with animals fed the control diet. Additionally, 3,3-dimethyl-1-butanol DMB markedly ameliorated cardiac diastolic dysfunction, myocardial fibrosis and inflammation in the choline-fed HFpEF mice.
Conclusions
A high-choline diet exacerbates cardiac dysfunction, myocardial fibrosis, and inflammation in HFpEF mice, and 3,3-dimethyl-1-butanol ameliorates the high-choline diet-induced cardiac remodeling.

Copyright © 2020 Elsevier Inc. All rights reserved.

J Card Fail: 30 Jul 2020; 26:694-702
Shuai W, Wen J, Li X, Wang D, Li Y, Xiang J
J Card Fail: 30 Jul 2020; 26:694-702 | PMID: 32417378
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Abstract

Patterns of Hospital Bypass and Interhospital Transfer Among Patients With Heart Failure.

Eschenroeder LW, Nguyen VP, Neradilek MB, Li S, Dardas TF
Background
We describe how patient characteristics influence hospital bypass, interhospital transfer, and in-hospital mortality in patients with heart failure in Washington. Rural patients with heart failure may bypass their nearest hospital or be transferred for appropriate therapies. The frequency, determinants, and outcomes of these practices remain uncharacterized.
Methods and results
Mean excess travel times based on hospital and patient residence ZIP codes were calculated using published methods. Hospitals and servicing areas were coded based on bed size and ZIP code, respectively. Transfer patterns were analyzed using bootstrap inference for clusters. Analysis of mortality and transfer-associated factors was performed using logistic regression with generalized estimating equations. There were 48,163 patients, representing 1106 instances of transfer, studied. The mean excess travel time increased 7.14 minutes per decrease in population density (metropolitan, micropolitan, small town, rural; P < .0001). The rural mean excess travel time was greatest at 28.56 minutes. Transfer likelihood increased with younger age, male gender, admitting hospital rurality, higher Charlson Comorbidity Index, and stroke. Transfer was less likely among women (odds ratio [OR], 0.82; 95% confidence interval [CI], 0.72-0.94) and patients over 70 years old (OR, 0.15-0.46; 95% CI, 0.10-0.65). Adjusting for comorbidities and transfer propensity, transfer exhibited a stronger association with mortality than any other measured patient risk factor (OR, 2.15; 95% CI, 1.69-2.73), excluding stroke (OR, 7.09; 95% CI, 4.99-10.06).
Conclusions
Rural hospital bypass is prevalent among patients with heart failure, although its clinical significance is unclear. Female and older patients were found to have a lesser likelihood of transfer adjusted for other factors. Interhospital transfer is associated with increased mortality when adjusted for comorbidities.

Copyright © 2020 Elsevier Inc. All rights reserved.

J Card Fail: 30 Aug 2020; 26:762-768
Eschenroeder LW, Nguyen VP, Neradilek MB, Li S, Dardas TF
J Card Fail: 30 Aug 2020; 26:762-768 | PMID: 32439325
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Abstract

The Effects of Inhaled Sodium Nitrite on Pulmonary Vascular Impedance in Patients With Pulmonary Hypertension Associated with Heart Failure With Preserved Ejection Fraction.

Bashline MJ, Bachman TN, Helbling NL, Nouraie M, Gladwin MT, Simon MA
Background
The severity of pulmonary hypertension (PH) is monitored by measuring pulmonary vascular resistance, which is a steady-state measurement and ignores the pulsatile load encountered by the right ventricle (RV). Pulmonary vascular impedance (PVZ) can depict both steady-state and pulsatile forces, and thus may better predict clinical outcomes. We sought to calculate PVZ in patients with PH associated with heart failure with preserved ejection fraction who were administered inhaled sodium nitrite to better understand the acute effects on afterload.
Methods and results
Fourteen patients with PH associated with heart failure with preserved ejection fraction underwent right heart catherization and were administered inhaled sodium nitrite. A Fourier transform was used to calculate PVZ for both before and after nitrite for comparison. Inhaled sodium nitrite decreased characteristic impedance (inversely related to proximal pulmonary artery compliance) and total work performed by the RV. RV efficiency improved, defined by a reduction in the total work divided by cardiac output. There was a mild decrease in pulmonary steady-state resistance after the administration of inhaled sodium nitrite, but this effect was not significant.
Conclusions
PVZ analysis showed administration of inhaled sodium nitrite was associated with an improvement in pulmonary vascular compliance via a decrease in characteristic impedance, more so than pulmonary steady-state resistance. This effect was associated with improved RV efficiency and total work.

Copyright © 2020 Elsevier Inc. All rights reserved.

J Card Fail: 30 Jul 2020; 26:654-661
Bashline MJ, Bachman TN, Helbling NL, Nouraie M, Gladwin MT, Simon MA
J Card Fail: 30 Jul 2020; 26:654-661 | PMID: 32446946
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Abstract

Persistent Myocardial Production of Follistatin-like 1 Is Associated With Left Ventricular Adverse Remodeling in Patients With Myocardial Infarction: Myocardial production of FSTL1 in AMI patients.

Uematsu M, Nakamura K, Nakamura T, Watanabe Y, ... Obata JE, Kugiyama K
Background
Although animal studies showed that Follistatin-like 1 (FSTL1) exerts cardioprotective effects against ischemic injury, little is known in humans. We examined whether FSTL1 is secreted in an infarcted myocardium and whether its production is associated with left ventricular (LV) remodeling in survivors of acute myocardial infarction.
Methods and results
FSTL1 levels were measured by enzyme-linked immunosorbent assay in plasma collected from the aortic root and the anterior interventricular vein in 93 patients with anterior acute myocardial infarction. Measurement of FSTL1 levels and left ventriculography were repeated during the early phase (2 weeks) and the chronic phase (6 months) after MI. A persistent increment in FSTL1 levels from the aortic root to the anterior interventricular vein, reflecting FSTL1 production in the infarcted myocardium at both the early and chronic phases, was seen in 22 patients (24%). A linear regression analysis revealed that a persistent transmyocardial increment in FSTL1 levels was significantly associated with percent changes in LV end-diastolic volume index, LV end-systolic volume index, and LV ejection fraction from the early to the chronic phase (r = 0.44, 0.51, and -0.43, respectively, all P < .001).
Conclusions
The persistent production of FSTL1 in the infarcted myocardium was associated with adverse LV remodeling in survivors of acute myocardial infarction.

Copyright © 2020 Elsevier Inc. All rights reserved.

J Card Fail: 30 Jul 2020; 26:733-738
Uematsu M, Nakamura K, Nakamura T, Watanabe Y, ... Obata JE, Kugiyama K
J Card Fail: 30 Jul 2020; 26:733-738 | PMID: 32470377
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Impact:
Abstract

Annexin A1 is a Potential Novel Biomarker of Congestion in Acute Heart Failure.

Adel FW, Rikhi A, Wan SH, Iyer SR, ... Givertz MM, Chen HH
Objectives
This study sought to identify the role of annexin A1 (AnxA1) as a congestion marker in acute heart failure (AHF) and to identify its putative role in predicting clinical outcomes.
Background
AnxA1 is a protein that inhibits inflammation following ischemia-reperfusion injury in cardiorenal tissues. Because AHF is a state of tissue hypoperfusion, we hypothesized that plasma AnxA1 levels are altered in AHF.
Methods
In the Renal Optimization Strategies Evaluation (ROSE) trial, patients hospitalized for AHF with kidney injury were randomized to receive dopamine, nesiritide, or placebo for 72 hours in addition to diuresis. In a subanalysis, plasma AnxA1 levels were measured at baseline and at 72 hours in 275 patients. Participants were divided into 3 tertiles based on their baseline AnxA1 levels.
Results
The prevalence of peripheral edema 2+ increased with increasing AnxA1 levels (P < .007). Cystatin C, blood urea nitrogen, and kidney injury molecule-1 plasma levels were higher among participants in tertile 3 vs tertiles 1 or 2 (P< .05). Patients with a congestion score of 4 had a mean baseline AnxA1 level 8.63 units higher than those with a congestion score of 0 (P = .03). Patients in tertiles 2 and 3 were twice as likely to experience creatinine elevation as patients in tertile 1 (P = .03). Patients in tertiles 2 and 3 were at a higher risk of 60-day all-cause mortality or heart failure hospitalization and 180-day all-cause mortality (P < .05).
Conclusions
Among patients hospitalized for AHF with impaired kidney function, elevated AnxA1 levels are associated with worse congestion, higher risk for further creatinine elevation, and higher rates of 60-day morbidity or all-cause mortality and 180-day all-cause mortality.
Clinical trial registration
clinicaltrials.gov Identifier: NCT01132846.

Copyright © 2020 Elsevier Inc. All rights reserved.

J Card Fail: 30 Jul 2020; 26:727-732
Adel FW, Rikhi A, Wan SH, Iyer SR, ... Givertz MM, Chen HH
J Card Fail: 30 Jul 2020; 26:727-732 | PMID: 32473378
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Impact:
Abstract

In-Hospital Management of Sleep Apnea During Heart Failure Hospitalization: A Randomized Controlled Trial.

Khayat RN, Javaheri S, Porter K, Sow A, ... Abraham WT, Jarjoura D
Background
Obstructive sleep apnea (OSA) is associated with increased mortality and readmissions in patients with heart failure (HF). The effect of in-hospital diagnosis and treatment of OSA during decompensated HF episodes remains unknown.
Methods and results
A single-site, randomized, controlled trial of hospitalized patients with decompensated HF (n = 150) who were diagnosed with OSA during the hospitalization was undertaken. All participants received guideline-directed therapy for HF decompensation. Participants were randomized to an intervention arm which received positive airway pressure (PAP) therapy during the hospitalization (n = 75) and a control arm (n = 75). The primary outcome was discharge left ventricular ejection fraction (LVEF). The LVEF changed in the PAP arm from 25.5 ± 10.4 at baseline to 27.3 ± 11.9 at discharge. In the control group, LVEF was 27.3 ± 11.7 at baseline and 28.8 ± 10.5 at conclusion. There was no significant effect on LVEF of in-hospital PAP compared with controls (P = .84) in the intention-to-treat analysis. The on-treatment analysis in the intervention arm showed a significant increase in LVEF in participants who used PAP for ≥3 hours per night (n = 36, 48%) compared with those who used it less (P = .01). There was a dose effect with higher hours of use associated with more improvement in LVEF. Follow-up of readmissions at 6 months after discharge revealed a >60% decrease in readmissions for patients who used PAP ≥3 h/night compared with those who used it <3 h/night (P < .02) and compared with controls (P < .04).
Conclusions
In-hospital treatment with PAP was safe but did not significantly improve discharge LVEF in patients with decompensated HF and newly diagnosed OSA. An exploratory analysis showed that adequate use of PAP was associated with higher discharge LVEF and decreased 6 months readmissions.

Copyright © 2020 Elsevier Inc. All rights reserved.

J Card Fail: 30 Jul 2020; 26:705-712
Khayat RN, Javaheri S, Porter K, Sow A, ... Abraham WT, Jarjoura D
J Card Fail: 30 Jul 2020; 26:705-712 | PMID: 32592897
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Impact:
Abstract

Enhanced Response to Drug-Induced QT Interval Lengthening in Patients with Heart Failure with Preserved Ejection Fraction.

Tisdale JE, Jaynes HA, Overholser BR, Sowinski KM, ... Rao VU, Kovacs RJ
Background
Patients with heart failure (HF) with reduced ejection fraction demonstrate enhanced response to drug-induced QT interval lengthening and are at increased risk for torsades de pointes. The influence of HF with preserved ejection fraction (HFpEF) on response to drug-induced QT lengthening is unknown.
Methods and results
We administered intravenous ibutilide 0.003 mg/kg to 10 patients with HFpEF and 10 age- and sex-matched control subjects without HF. Serial 12-lead electrocardiograms were obtained for determination of QT intervals. Demographics, maximum serum ibutilide concentrations, area under the serum ibutilide concentration vs time curves, and baseline Fridericia-corrected QT (QT) (417 ± 14 vs 413 ± 15 ms, P = .54) were similar in the HFpEF and control groups. Area under the effect (QTvs time) curve (AUEC) from 0 to 1.17 hours during and following the ibutilide infusion was greater in the HFpEF group (519 ± 19 vs 497 ± 18 ms·h, P= .04), as was AUEC from 0 to 8.17 hours (3576 ± 125 vs 3428 ± 161 ms·h, P = .03) indicating greater QT interval exposure. Maximum QT (454 ± 15 vs 443 ± 22 ms, P = .18) and maximum percent increase in QT from baseline (8.2 ± 2.1 vs 6.7 ± 1.9%, P = .10) in the 2 groups were not significantly different.
Conclusions
HFpEF is associated with enhanced response to drug-induced QT interval lengthening.

Copyright © 2020 Elsevier Inc. All rights reserved.

J Card Fail: 30 Aug 2020; 26:781-785
Tisdale JE, Jaynes HA, Overholser BR, Sowinski KM, ... Rao VU, Kovacs RJ
J Card Fail: 30 Aug 2020; 26:781-785 | PMID: 32592895
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Abstract

Pulmonary Artery Wedge Pressure Respiratory Variation Increases with Sodium Nitroprusside Vasodilator Challenge.

Maurides SP, Blankinship D, Panneerselvam K, Jackson GR, ... Tedford RJ, Houston BA
Background
The physiologic factors leading to pulmonary arterial wedge pressure respiratory variation (PAWP) are under-explored. We hypothesized that PAWP is associated with baseline PAWP and would predict response to sodium nitroprusside (SNP).
Methods and results
We performed a retrospective study of RHC studies in 51 subjects with SNP challenge at our institution from 2012 to 2019. PAWP was defined as expiratory minus inspiratory PAWP. Baseline %PAWP was inversely correlated with baseline PAWP (R = -0.5). SNP administration led to increased %PAWP (+27%, p<0.01; Figure 1B). Subjects with low baseline PAWP (median) did not (-0.6 ± 4 mmHg; p=0.003). Those who had >median PAWP increase with SNP had greater cardiac output (CO) augmentation compared with those who had Conclusions
Our findings indicate that PAWP is a meaningful physiologic parameter that is influenced by the compliance of the left heart / pulmonary vascular system and its relative pre-load and afterload states.

Copyright © 2020. Published by Elsevier Inc.

J Card Fail: 05 Oct 2020; epub ahead of print
Maurides SP, Blankinship D, Panneerselvam K, Jackson GR, ... Tedford RJ, Houston BA
J Card Fail: 05 Oct 2020; epub ahead of print | PMID: 33035683
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Abstract

Inclusion of Performance Parameters and Patient Context in the Clinical Practice Guidelines for Heart Failure.

Goyal P, Unlu O, Kennel PJ, Schumacher RC, ... Rich MW, Makam A
Background
To facilitate evidence-based medicine (EBM) on an individual level, it may be important for clinical practice guidelines (CPGs) to incorporate the performance parameters of diagnostic studies and therapeutic interventions (such as likelihood ratio and absolute benefit/harm), and to incorporate relevant patient contexts that may influence decision-making. We sought to determine the extent to which heart failure CPGs currently incorporate this information.
Methods
We reviewed the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) 2013 Heart Failure CPG, the 2017 ACCF/AHA/HFSA update, and European Society of Cardiology (ESC) 2016 Heart Failure CPG. We abstracted variables for each CPG recommendation from the following domains: quality of evidence, strength of recommendation, diagnostic and therapeutic performance parameters, and patient context.
Results
We examined 169 recommendations from the ACCF/AHA 2013 CPGs and 2017 update, and 187 recommendations from the 2016 ESC CPGs. Performance parameters for diagnostic studies (2013 ACCF/AHA: 13%; 2017 ACCF/AHA/HFSA update: 0%; 2016 ESC: 0%) and therapeutic interventions (2013 ACCF/AHA: 65%; 2017 ACCF/AHA/HFSA update: 64%; 2016 ESC: 16%) were not commonly included in CPGs. Patient context was included in about half of ACCF/AHA recommendations, and a quarter of ESC recommendations.
Conclusions
The majority of recommendations from heart failure CPGs lack information on diagnostic and therapeutic performance parameters and patient context. Given the importance of these components to effectively implement EBM, particularly for a heterogeneous heart failure population, innovative strategies are needed to optimize CPGs so they provide comprehensive yet succinct recommendations that can improve population-level outcomes and ensure optimal patient-centered care.

Copyright © 2020 Elsevier Inc. All rights reserved.

J Card Fail: 12 Oct 2020; epub ahead of print
Goyal P, Unlu O, Kennel PJ, Schumacher RC, ... Rich MW, Makam A
J Card Fail: 12 Oct 2020; epub ahead of print | PMID: 33065263
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Abstract

Pulsus Alternans as a Sign of Right Ventricular Failure After Left Ventricular Assist Device Implantation.

Balthazar T, Adriaenssens T, Rega F, Vandenbriele C

Temporary left ventricular assist devices such as the ImpellaTM are increasingly used in patients with cardiogenic shock. The right ventricle remains the Achilles heel of left ventricular assist device-supported circulation. However, right ventricular failure after implantation of a left ventricular assist device remains incompletely defined and understood. We describe the first case of pulsus paradoxus emerging after the initiation of circulatory support using a left ventricular ImpellaTM device, which is an early sign of right ventricular failure, that was completely abolished after the addition of a temporary right ventricular assist device.

Copyright © 2020 Elsevier Inc. All rights reserved.

J Card Fail: 18 Sep 2020; epub ahead of print
Balthazar T, Adriaenssens T, Rega F, Vandenbriele C
J Card Fail: 18 Sep 2020; epub ahead of print | PMID: 32956812
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This program is still in alpha version.