Journal: Circ Heart Fail

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Abstract

Efficacy of Implantable Cardioverter Defibrillator in Nonischemic Systolic Heart Failure According to Sex: Extended Follow-Up Study of the DANISH Trial.

Butt JH, Yafasova A, Elming MB, Dixen U, ... Thune JJ, Køber L
Background
Men and women may respond differently to certain therapies for heart failure with reduced ejection fraction, including implantable cardioverter defibrillators (ICD). In an extended follow-up study of the DANISH trial (Danish Study to Assess the Efficacy of ICDs in Patients With Non-Ischemic Systolic Heart Failure on Mortality), adding 4 years of additional follow-up, we examined the effect of ICD implantation according to sex.
Methods
In the DANISH trial, 1116 patients with nonischemic systolic heart failure were randomized to receive an ICD (N=556) or usual clinical care (N=550). The primary outcome was all-cause mortality.
Results
Of the 1116 patients randomized in the DANISH trial, 307 (27.5%) were women. During a median follow-up of 9.5 years, women had a lower associated rate of all-cause mortality (hazard ratio [HR], 0.60 [95% CI, 0.47-0.78]) cardiovascular death (HR, 0.62 [95% CI, 0.46-0.84]), nonsudden cardiovascular death (HR, 0.59 [95% CI, 0.42-0.85]), and a numerically lower rate of sudden cardiovascular death (HR, 0.70 [95% CI, 0.40-1.25]), compared with men. Compared with usual clinical care, ICD implantation did not reduce the rate of all-cause mortality, irrespective of sex (men, HR, 0.85 [95% CI, 0.69-1.06]; women, HR, 0.98 [95% CI, 0.64-1.50]; P for interaction=0.51). In addition, sex did not modify the effect of ICD implantation on sudden cardiovascular death (men, HR, 0.57 [95% CI, 0.36-0.92]; women, HR, 0.68 [95% CI, 0.26-1.77]; P for interaction=0.76).
Conclusions
In patients with nonischemic systolic heart failure, ICD implantation did not provide an overall survival benefit, but reduced sudden cardiovascular death, irrespective of sex.
Registration
URL: https://www.
Clinicaltrials
gov; Unique identifier: NCT00542945.



Circ Heart Fail: 09 Aug 2022:101161CIRCHEARTFAILURE122009669; epub ahead of print
Butt JH, Yafasova A, Elming MB, Dixen U, ... Thune JJ, Køber L
Circ Heart Fail: 09 Aug 2022:101161CIRCHEARTFAILURE122009669; epub ahead of print | PMID: 35942877
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Abstract

Temporal Trends of Heart Failure Hospitalizations in Cardiology Versus Noncardiology Wards According to Ejection Fraction: 16-Year Data From the SwedeHF Registry.

Canepa M, Kapelios CJ, Benson L, Savarese G, Lund LH
Background
Patients hospitalized for acute heart failure (AHF) may receive different care depending on type of ward. We describe temporal changes in triage of HF patients with preserved, mildly reduced, and reduced ejection fraction (HFpEF, HFmrEF, and HFrEF) hospitalized for AHF to cardiology versus noncardiology wards in Sweden.
Methods
We analyzed temporal changes in ward type for AHF for HFrEF versus HFmrEF versus HFpEF between 2000 and 2016.
Results
Among 37 918 patients with AHF, 19 777 (52%) had HFrEF, 7712 (20%) had HFmrEF, and 10 429 (28%) had HFpEF. Overall, 19 646 (52%) were hospitalized in cardiology and 18 272 (48%) in noncardiology. The proportions hospitalized in noncardiology in 2000 to 2004 versus in 2013 to 2016 were for HFrEF: 45 versus 47%, for HFmrEF: 52 versus 56%, and for HFpEF: 46 versus 64%, respectively. The overall proportion of HFrEF in 2000 to 2004 versus in 2013 to 2016 decreased (60% versus 49%) especially in noncardiology (58% versus 41%), whereas the overall proportion of HFpEF increased (20% versus 30%) especially in noncardiology (21% versus 37%). The average age and prevalence of comorbidities also increased over time, with older patients with multiple comorbidities being more frequently admitted to noncardiology wards.
Conclusions
Over time, AHF hospitalization for HFpEF occurred increasingly in noncardiology, whereas for HFrEF and HFmrEF the proportions of patients treated in cardiology versus noncardiology were substantially unchanged over time. This may have implications for implementation of emerging HFpEF therapy.



Circ Heart Fail: 08 Aug 2022:101161CIRCHEARTFAILURE121009462; epub ahead of print
Canepa M, Kapelios CJ, Benson L, Savarese G, Lund LH
Circ Heart Fail: 08 Aug 2022:101161CIRCHEARTFAILURE121009462; epub ahead of print | PMID: 35938444
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Abstract

Current Approach to the Diagnosis of Sarcopenia in Heart Failure: A Narrative Review on the Role of Clinical and Imaging Assessments.

Mirzai S, Eck BL, Chen PH, Estep JD, Tang WHW
Sarcopenia has been established as a predictor of poor outcomes in various clinical settings. It is particularly prevalent in heart failure, a clinical syndrome that poses significant challenges to health care worldwide. Despite this, sarcopenia remains overlooked and undertreated in cardiology practice. Understanding the currently proposed diagnostic process is paramount for the early detection and treatment of sarcopenia to mitigate downstream adverse health outcomes.



Circ Heart Fail: 04 Aug 2022:101161CIRCHEARTFAILURE121009322; epub ahead of print
Mirzai S, Eck BL, Chen PH, Estep JD, Tang WHW
Circ Heart Fail: 04 Aug 2022:101161CIRCHEARTFAILURE121009322; epub ahead of print | PMID: 35924562
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Abstract

Trending Cardiac Biomarkers During Pregnancy in Women With Cardiovascular Disease.

Chang SA, Khakh P, Janzen M, Lee T, ... Rychel V, Grewal J
Background
Clinical utility of cardiac biomarker testing during pregnancy in women with preexisting cardiac disease is not well known. We studied the levels and temporal trends of NT-proBNP (N-terminal pro-B-type natriuretic peptide) and hs-cTnI (high-sensitivity cardiac troponin I) throughout pregnancy in women with preexisting cardiac disease and sought to assess the association between NT-proBNP and hs-cTnI and pregnancy outcomes.
Methods
Three hundred seven pregnant women with preexisting cardiac disease were prospectively recruited. Mixed-effects linear regression analysis was used to compare the NT-proBNP and hs-cTnI levels between time periods and subgroups. Logistic regression analysis adjusted for maternal age and CARPREG II (Cardiac Disease in Pregnancy) risk score assessed the association between NT-proBNP levels and adverse events.
Results
Geometric mean NT-proBNP (95% CI) was stable through pregnancy with a transient significant increase with labor and delivery (101.4 pg/mL [87.1-118.1], 90.2 pg/mL [78.5-103.6], 153.6 pg/mL [126.8-186.1], and 112.2 pg/mL [94.2-133.7] for first/second trimester, third trimester, labor/delivery and postpartum, respectively). We observed a statistically significant difference in the NT-proBNP between women with preserved versus decreased systemic ventricular function, structurally normal versus abnormal heart, modified World Health Organization class 1, 2 versus modified World Health Organization class 3, 4 and no congenital heart disease versus congenital heart disease. Compared to those without events, median (interquartile range) NT-proBNP levels were significantly higher in those who had heart failure (204 pg/mL [51-450] versus 55 pg/mL [31-97]; P=0.001) and preeclampsia (98 pg/mL [40-319] versus 55 pg/mL [31-99]; P=0.027). NT-proBNP, adjusted for age and CARPREG II risk score, was significantly associated with combined heart failure and preeclampsia (adjusted odds ratio, 2.14 [95% CI, 1.48-3.10] per log NT-proBNP increase; P<0.001). NT-proBNP <200 pg/mL had a specificity of 91% and negative predictive value of 95% in predicting combined heart failure and preeclampsia.
Conclusions
NT-proBNP remains steady over the course of pregnancy with a transient increase during labor and delivery with higher levels in subgroups of stable cardiac patients. NT-proBNP level of 200 pg/mL can be used in the diagnosis of heart failure/preeclampsia in the pregnant cardiac population.



Circ Heart Fail: 29 Jul 2022:101161CIRCHEARTFAILURE121009018; epub ahead of print
Chang SA, Khakh P, Janzen M, Lee T, ... Rychel V, Grewal J
Circ Heart Fail: 29 Jul 2022:101161CIRCHEARTFAILURE121009018; epub ahead of print | PMID: 35904022
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Abstract

Medical Therapy for Functional Mitral Regurgitation.

Milwidsky A, Mathai SV, Topilsky Y, Jorde UP
Functional mitral regurgitation (FMR) can be broadly categorized into 2 main groups: ventricular and atrial, which often coexist. The former is secondary to left ventricular remodeling usually in the setting of heart failure with reduced ejection fraction or less frequently due to ischemic papillary muscle remodeling. Atrial FMR develops due to atrial and annular dilatation related to atrial fibrillation/flutter or from increased atrial pressures in the setting of heart failure with preserved ejection fraction. Guideline-directed medical therapy is the first step and prevails as the mainstay in the treatment of FMR. In this review, we address the medical therapeutic options for FMR management and highlight a targeted approach for each FMR category. We further address important clinical and echocardiographic characteristics to aid in determining when medical therapy is expected to have a low yield and an appropriate window for effective interventional approaches exists.



Circ Heart Fail: 13 Jul 2022:101161CIRCHEARTFAILURE122009689; epub ahead of print
Milwidsky A, Mathai SV, Topilsky Y, Jorde UP
Circ Heart Fail: 13 Jul 2022:101161CIRCHEARTFAILURE122009689; epub ahead of print | PMID: 35862021
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Abstract

Transcutaneous Vagus Nerve Stimulation Ameliorates the Phenotype of Heart Failure With Preserved Ejection Fraction Through Its Anti-Inflammatory Effects.

Elkholey K, Niewiadomska M, Morris L, Whyte S, ... Humphrey MB, Stavrakis S
Background
A systemic proinflammatory state plays a central role in the development of heart failure with preserved ejection fraction (HFpEF). Low-level transcutaneous vagus nerve stimulation (LLTS) suppresses inflammation in animals and humans, mediated by an α7nAchR (alpha7 nicotinic acetylcholine receptor)-dependent pathway. We examined the effects of LLTS on cardiac function, inflammation, and fibrosis in the presence of α7nAchR pharmacological blockade in a rat model of HFpEF.
Methods
Dahl salt-sensitive rats at 7 weeks of age were treated with high-salt diet for 6 weeks to induce HFpEF, followed by 4 weeks of (1) LLTS, (2) LLTS with the α7nAchR blocker methyllycaconitine, (3) sham, and (4) olmesartan. Blood pressure, cardiac function by echocardiography, heart rate variability, and serum cytokines were measured at 13 and 17 weeks of age. Cardiac fibrosis, inflammatory cell infiltration, and gene expression were determined at 17 weeks.
Results
LLTS attenuated the increase in blood pressure; improved cardiac function; decreased inflammatory cytokines, macrophage infiltration, and fibrosis; and improved survival compared with other groups. Methyllycaconitine attenuated these effects, whereas olmesartan did not improve cardiac function or fibrosis despite maintaining similar blood pressure as LLTS. Heart rate variability was similarly improved in the LLTS and LLTS plus methyllycaconitine groups but remained low in the other groups. LLTS reversed the dysregulated inflammatory signaling pathways in HFpEF hearts.
Conclusions
Neuromodulation with LLTS improved cardiac function in a rat model of HFpEF through its anti-inflammatory and antifibrotic effects. These results provide the basis for further clinical trials in humans.



Circ Heart Fail: 07 Jul 2022:101161CIRCHEARTFAILURE122009288; epub ahead of print
Elkholey K, Niewiadomska M, Morris L, Whyte S, ... Humphrey MB, Stavrakis S
Circ Heart Fail: 07 Jul 2022:101161CIRCHEARTFAILURE122009288; epub ahead of print | PMID: 35862007
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Abstract

Variation in Left Ventricular Assist Device Postdischarge Caregiver Requirements: Results From a Mixed-Methods Study With Equity Implications.

Knoepke CE, Siry-Bove B, Mayton C, Latimer A, ... Matlock DD, Khazanie P
Background
Left ventricular assist device (LVAD) evaluation includes a psychosocial assessment, conducted by social workers (SWs) on the advanced heart failure multidisciplinary team. Postdischarge caregiving plans are central to psychosocial evaluation. Caregiving\'s relationship with LVAD outcomes is mixed, and testing patients\' social resources may disadvantage those from historically undertreated groups. We describe variation in policies defining adequate caregiving plans post-LVAD implant and possible impacts on patients from marginalized groups.
Methods
This was a 2-phase sequential mixed-methods study: (1) phase 1, survey of US-based LVAD SWs, describing assessment structure and policies guiding candidacy outcomes; and (2) phase 2, individual interviews with SWs to further describe how caregiving plan adequacy impacts LVAD candidacy.
Results
Sixty-seven SWs returned surveys (rr=47%) from unique programs. Caregiving plan inadequacy (n=30) was the most common psychosocial dealbreaker. When asked what duration of caregiving is required, 23% indicated ≥3 months, 27% 4 to 12 weeks, and 30% <4 weeks. Two reported no duration requirement, 6 stated an indefinite 24/7 commitment was necessary. Across 22 interviews, SWs mirrored that caregiving plans were the most common psychosocial contraindication. How caregiving is operationalized varied. Participants voiced a tension between extended caregiving improving outcomes and the sense that some people of color, women, or low socioeconomic status patients struggle to meet stringent requirements.
Conclusions
Policies regarding adequate duration of 24/7 caregiving vary, but inadequate caregiving plans are the most common psychosocial contraindication. Participants worry about patients\' ability to meet restrictive requirements, particularly from historically undertreated groups. This highlights a need to operationalize quality caregiving, standardize assessment, and support medically appropriate patients with strained social resources.



Circ Heart Fail: 07 Jul 2022:101161CIRCHEARTFAILURE122009583; epub ahead of print
Knoepke CE, Siry-Bove B, Mayton C, Latimer A, ... Matlock DD, Khazanie P
Circ Heart Fail: 07 Jul 2022:101161CIRCHEARTFAILURE122009583; epub ahead of print | PMID: 35862012
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Abstract

Impact of Tafamidis and Optimal Background Treatment on Physical Performance in Patients With Transthyretin Amyloid Cardiomyopathy.

Badr Eslam R, Öztürk B, Rettl R, Capelle CDJ, ... Vila G, Bonderman D
Background
In patients with transthyretin amyloid cardiomyopathy, tafamidis was shown to slow the decline in 6-minute walking distance as compared with placebo. We aimed to define the impact of tafamidis and optimal background treatment on functional capacity as determined by cardiopulmonary exercise testing (CPET).
Methods
Seventy-eight consecutive patients were enrolled in the study. They underwent CPET at baseline, and outcome defined as death or heart failure hospitalization was obtained for a time period of up to 30 months. Fifty-four patients completed a follow-up CPET at 9±3 months (range, 4-16 months). Improvement in peak VO2 at follow-up was defined as ∆peak VO2≥1.0 mL/(kg·min), stable peak VO2 was defined as 0≤∆peak VO2<1.0 mL/(kg·min), and decline in peak VO2 was defined by ∆peak VO2<0 mL/(kg·min).
Results
Baseline peak VO2>14 mL/(kg·min) as well as minute ventilation/carbon dioxide production slope≤34 were associated with a lower risk of death or heart failure hospitalization (P=0.002, P=0.007, respectively). In 54 patients, who received tafamidis and underwent repeat CPET testing, an improvement in physical performance (P=0.002) was observed at follow-up. When comparing pre and post-treatment parameters, 29 patients (54%) showed an increase in percent predicted peak VO2 (P<0.0001), an improvement of peak VO2 (P<0.0001), and better physical performance at follow-up (P<0.0001). Patients with stable or improved peak VO2 had less advanced heart disease at baseline (P=0.046).
Conclusions
Our findings demonstrate that baseline peak VO2 and baseline minute ventilation/carbon dioxide production slope predict outcomes and an improvement in physical performance as measured by CPET was observed in patients receiving tafamidis, who had less advanced disease at baseline, emphasizing the importance of early diagnosis.



Circ Heart Fail: 29 Jun 2022:101161CIRCHEARTFAILURE121008381; epub ahead of print
Badr Eslam R, Öztürk B, Rettl R, Capelle CDJ, ... Vila G, Bonderman D
Circ Heart Fail: 29 Jun 2022:101161CIRCHEARTFAILURE121008381; epub ahead of print | PMID: 35766028
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Abstract

Rationale and Design of the Cardiac CARE Trial: A Randomized Trial of Troponin-Guided Neurohormonal Blockade for the Prevention of Anthracycline Cardiotoxicity.

Henriksen PA, Hall P, Oikonomidou O, MacPherson IR, ... Mills NL, Lang NN
Background
Anthracyclines are effective cytotoxic drugs used in the treatment of breast cancer and lymphoma but are associated with myocardial injury, left ventricular dysfunction, and heart failure. Anthracycline-induced cardiotoxicity is highly variable in severity and without a proven therapeutic intervention. β-Adrenergic receptor blockers and renin-angiotensin-system inhibitor therapies have been associated with modest cardioprotective effects in unselected patients.
Methods
The Cardiac CARE trial is a multicentre prospective randomized open-label blinded end point trial of combination β-adrenergic receptor blocker and renin-angiotensin-system inhibitor therapy in patients with breast cancer and non-Hodgkin lymphoma receiving anthracycline chemotherapy that is associated with myocardial injury. Patients at higher risk of cardiotoxicity with plasma high-sensitivity cTnI (cardiac troponin I) concentrations in the upper tertile at the end of chemotherapy are randomized to standard of care plus combination candesartan and carvedilol therapy or standard of care alone. All patients undergo cardiac magnetic resonance imaging before and 6 months after anthracycline treatment. The primary end point is the change in left ventricular ejection fraction at 6 months after chemotherapy. In low-risk nonrandomized patients, left ventricular ejection fraction before and 6 months after anthracycline will be compared with define the specificity of the high-sensitivity cTnI assay for identifying low-risk participants who do not develop left ventricular systolic dysfunction.
Discussion
Cardiac CARE will examine whether cardiac biomarker monitoring identifies patients at risk of left ventricular dysfunction following anthracycline chemotherapy and whether troponin-guided treatment with combination candesartan and carvedilol therapy prevents the development of left ventricular dysfunction in these high-risk patients.



Circ Heart Fail: 29 Jun 2022:101161CIRCHEARTFAILURE121009445; epub ahead of print
Henriksen PA, Hall P, Oikonomidou O, MacPherson IR, ... Mills NL, Lang NN
Circ Heart Fail: 29 Jun 2022:101161CIRCHEARTFAILURE121009445; epub ahead of print | PMID: 35766037
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Abstract

Hemodynamic Effects of Cyclic Guanosine Monophosphate-Dependent Signaling Through β3 Adrenoceptor Stimulation in Patients With Advanced Heart Failure: A Randomized Invasive Clinical Trial.

Bundgaard H, Axelsson Raja A, Iversen K, Valeur N, ... Rasmussen HH, Vissing CR
Background
β3-AR (β3-adrenergic receptor) stimulation improved systolic function in a sheep model of systolic heart failure (heart failure with reduced ejection fraction [HFrEF]). Exploratory findings in patients with New York Heart Association functional class II HFrEF treated with the β3-AR-agonist mirabegron supported this observation. Here, we measured the hemodynamic response to mirabegron in patients with severe HFrEF.
Methods
In this randomized, double-blind, placebo-controlled trial we assigned patients with New York Heart Association functional class III-IV HFrEF, left ventricular ejection fraction <35% and increased NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels to receive mirabegron (300 mg daily) or placebo orally for a week, as add on to recommended HF therapy. Invasive hemodynamic measurements during rest and submaximal exercise at baseline, 3 hours after first study dose and repeated after 1 week\'s treatment were obtained. Predefined parameters for analyses were changes in cardiac- and stroke volume index, pulmonary and systemic vascular resistance, heart rate, and blood pressure.
Results
We randomized 22 patients (age 66±11 years, 18 men, 16, New York Heart Association functional class III), left ventricular ejection fraction 20±7%, median NT-proBNP 1953 ng/L. No significant changes were seen after 3 hours, but after 1 week, there was a significantly larger increase in cardiac index in the mirabegron group compared with the placebo group (mean difference, 0.41 [CI, 0.07-0.75] L/min/BSA; P=0.039). Pulmonary vascular resistance decreased significantly more in the mirabegron group compared with the placebo group (-1.6 [CI, -0.4 to -2.8] Wood units; P=0.02). No significant differences were seen during exercise. There were no differences in changes in heart rate, systemic vascular resistance, blood pressure, or renal function between groups. Mirabegron was well-tolerated.
Conclusions
Oral treatment with the β3-AR-agonist mirabegron for 1 week increased cardiac index and decreased pulmonary vascular resistance in patients with moderate to severe HFrEF. Mirabegron may be useful in patients with worsening or terminal HF.
Registration
URL: https://www.
Clinicaltrials
gov; Unique identifier: 2016-002367-34.



Circ Heart Fail: 27 Jun 2022:101161CIRCHEARTFAILURE121009120; epub ahead of print
Bundgaard H, Axelsson Raja A, Iversen K, Valeur N, ... Rasmussen HH, Vissing CR
Circ Heart Fail: 27 Jun 2022:101161CIRCHEARTFAILURE121009120; epub ahead of print | PMID: 35758031
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Abstract

Estrogen Receptor-β Agonists Modulate T-Lymphocyte Activation and Ameliorate Left Ventricular Remodeling During Chronic Heart Failure.

Rosenzweig R, Kumar V, Gupta S, Bermeo-Blanco O, ... Gumina RJ, Bansal SS
Background
CD4+ T cells temporally transition from protective to pathological during ischemic heart failure (HF; 8 weeks postmyocardial infarction). Cellular mechanisms mediating this shift are unknown.
Methods
RNA-sequencing of cardiac CD4+ T cells and flow cytometric analysis of immune cells was conducted.
Results
RNA-sequencing of CD4+ T cells from the failing hearts of male mice indicated activation of ER (estrogen receptor)-α signaling. Flow cytometric analysis showed that ERα in CD4+ T cells decreases significantly at 3-day postmyocardial infarction but increases during HF. To antagonize ERα, we tested a novel ERβ agonist (OSU-ERb-012) to inhibit T cells and blunt left ventricular remodeling. Proliferation assays showed that OSU-ERb-012 dose-dependently inhibited proliferation and proinflammatory cytokine expression in anti-CD3/CD28 stimulated splenic T cells isolated from both the sexes. For in vivo efficacy, 10- to 12-week-old male and ovariectomized female mice were randomized at 4 weeks postmyocardial infarction and treated with either vehicle or drug (60 mg/kg per day; oral). While vehicle-treated HF mice displayed progressive left ventricular dilatation with significantly increased end-systolic and end-diastolic volumes from 4 to 8 weeks postmyocardial infarction, treatment with OSU-ERb-012 significantly blunted these changes and stopped left ventricular remodeling in both the sexes. Reduction in tibia-normalized heart and left ventricular weights, cardiomyocyte hypertrophy and interstitial fibrosis further supported these results. Additionally, OSU-ERb-012 treatment selectively inhibited cardiac, splenic, and circulating CD4+ T cells without affecting other myeloid and lymphoid cells in the HF mice.
Conclusions
Our studies indicate that ERβ agonists and OSU-ERb-012, in particular, could be used as selective immunomodulatory drugs to inhibit CD4+ T cells during chronic HF.



Circ Heart Fail: 22 Jun 2022:CIRCHEARTFAILURE121008997; epub ahead of print
Rosenzweig R, Kumar V, Gupta S, Bermeo-Blanco O, ... Gumina RJ, Bansal SS
Circ Heart Fail: 22 Jun 2022:CIRCHEARTFAILURE121008997; epub ahead of print | PMID: 35730443
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Abstract

Role of Implantable Cardioverter Defibrillator in Heart Failure With Contemporary Medical Therapy.

Butler J, Talha KM, Aktas MK, Zareba W, Goldenberg I
Implantable cardioverter defibrillator therapy is indicated in a subset of patients with heart failure with reduced ejection as primary prevention for sudden cardiac death. The advent of novel medical therapies including mineralocorticoid receptor antagonists, angiotensin receptor blocker/neprilysin inhibitors, and sodium-glucose transporter 2 inhibitor in the past 2 decades has revolutionized heart failure with reduced ejection management. Current guideline-directed medical therapy has reduced all-cause mortality and sudden cardiac death and confers a considerable improvement in left ventricular ejection fraction over a short period of time. However, there is limited evidence at present to suggest whether implantable cardioverter defibrillator therapy continues to have the same benefit in sudden cardiac death prevention at current left ventricular ejection fraction cutoff indications for patients on contemporary guideline-directed medical therapy for heart failure with reduced ejection. In this review, the authors propose in lieu of current evidence that it is reasonable to reevaluate indications for implantable cardioverter defibrillator therapy in patients on contemporary guideline-directed medical therapy for heart failure with reduced ejection.



Circ Heart Fail: 21 Jun 2022:CIRCHEARTFAILURE122009634; epub ahead of print
Butler J, Talha KM, Aktas MK, Zareba W, Goldenberg I
Circ Heart Fail: 21 Jun 2022:CIRCHEARTFAILURE122009634; epub ahead of print | PMID: 35726617
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Abstract

Donor Utilization in the Recent Era: Effect of Sex, Drugs, and Increased Risk.

Baran DA, Long A, Lansinger J, Copeland JG, Copeland H
Background
Heart transplantation volumes have increased in recent years, yet less than a third of donors are typically accepted for transplantation. Whether donor sex, donor drug use, or perception of increased risk affects utilization for transplantation is unclear.
Methods
The United Network for Organ Sharing database was queried for donors from January 1, 2007, to December 31, 2017. Donor toxicology was collected when available. Multivariate analysis was conducted to examine correlations with donor utilization.
Results
Between January 1, 2007, and December 31, 2017, there were 87 816 heart donors aged ≥15 years. The mean age was 42.7±15.8 years, and 24 831 donors (28.3%) were utilized for heart transplantation. Subsequent analyses focused on donors between 15 and 39 years old. The strongest associations with donor acceptance were for male donor sex, blood type, hepatitis C antibody, donor age, left ventricular hypertrophy, and history of donor drug use. After removing hepatitis C, Public Health Service Increased Risk was identified as a strong negative predictor. Most positive drug toxicology results were associated with donor nonuse except for donors between 15 and 19 years of age. Exceptions included alcohol, marijuana, and cocaine. Opiates were associated with less utilization at all donor ages. The Public Health Service Increased Risk status was associated with significantly less utilization in all age groups except 15- to 19-year-old donors.
Conclusions
While male donors were preferentially utilized, donors with drug use or those deemed Public Health Service Increased Risk were significantly less utilized for heart transplantation. Further consideration of such donors would be appropriate particularly as the demand for transplantation continues to increase.



Circ Heart Fail: 21 Jun 2022:101161CIRCHEARTFAILURE122009547; epub ahead of print
Baran DA, Long A, Lansinger J, Copeland JG, Copeland H
Circ Heart Fail: 21 Jun 2022:101161CIRCHEARTFAILURE122009547; epub ahead of print | PMID: 35726629
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Abstract

Diurnal Variations in Natriuretic Peptide Levels: Clinical Implications for the Diagnosis of Acute Heart Failure.

Breidthardt T, van Doorn WPTM, van der Linden N, Diebold M, ... Meex SJR, Mueller C
Background
Current guidelines recommend interpreting concentrations of NPs (natriuretic peptides) irrespective of the time of presentation to the emergency department. We hypothesized that diurnal variations in NP concentration may affect their diagnostic accuracy for acute heart failure.
Methods
In a secondary analysis of a multicenter diagnostic study enrolling patients presenting with acute dyspnea to the emergency department and using central adjudication of the final diagnosis by 2 independent cardiologists, the diagnostic accuracy for acute heart failure of BNP (B-type NP), NT-proBNP (N-terminal pro-B-type NP), and MR-proANP (midregional pro-atrial NP) was compared among 1577 daytime presenters versus 908 evening/nighttime presenters. In a validation study, the presence of a diurnal rhythm in BNP and NT-proBNP concentrations was examined by hourly measurements in 44 stable individuals.
Results
Among patients adjudicated to have acute heart failure, BNP, NT-proBNP, and MR-proANP concentrations were comparable among daytime versus evening/nighttime presenters (all P=nonsignificant). Contrastingly, among patients adjudicated to have other causes of dyspnea, evening/nighttime presenters had lower BNP (median, 44 [18-110] versus 74 [27-168] ng/L; P<0.01) and NT-proBNP (median, 212 [72-581] versus 297 [102-902] ng/L; P<0.01) concentrations versus daytime presenters. This resulted in higher diagnostic accuracy as quantified by the area under the curve of BNP and NT-proBNP among evening/nighttime presenters (0.97 [95% CI, 0.95-0.98] and 0.95 [95% CI, 0.93-0.96] versus 0.94 [95% CI, 0.92-0.95] and 0.91 [95% CI, 0.90-0.93]) among daytime presenters (both P<0.01). These differences were not observed for MR-proANP. Diurnal variation of BNP and NT-proBNP with lower evening/nighttime concentration was confirmed in 44 stable individuals (P<0.01).
Conclusions
BNP and NT-proBNP, but not MR-proANP, exhibit a diurnal rhythm that results in even higher diagnostic accuracy among evening/nighttime presenters versus daytime presenters.
Registration
URL: https://www.
Clinicaltrials
gov; Unique identifiers: NCT01831115, NCT02091427, and NCT02210897.



Circ Heart Fail: 07 Jun 2022:101161CIRCHEARTFAILURE121009165; epub ahead of print
Breidthardt T, van Doorn WPTM, van der Linden N, Diebold M, ... Meex SJR, Mueller C
Circ Heart Fail: 07 Jun 2022:101161CIRCHEARTFAILURE121009165; epub ahead of print | PMID: 35670217
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Abstract

Right Heart Failure Following Left Ventricular Device Implantation: Natural History, Risk Factors, and Outcomes: An Analysis of the STS INTERMACS Database.

Kapelios CJ, Lund LH, Wever-Pinzon O, Selzman CH, ... Kirklin JK, Drakos SG
Background
Our current understanding of right heart failure (RHF) post-left ventricular assist device (LVAD) is lacking. Recently, a new Interagency Registry for Mechanically Assisted Circulatory Support definition of RHF was introduced. Based on this definition, we investigated natural history, risk factors, and outcomes of post-LVAD RHF.
Methods
Patients implanted with continuous flow LVAD between June 2, 2014, and June 30, 2016 and registered in the Interagency Registry for Mechanically Assisted Circulatory Support/Society of Thoracic Surgeons Database were included. RHF incidence and predictors, and survival after RHF were assessed. The manifestations of RHF which were separately analyzed were elevated central venous pressure, peripheral edema, ascites, and use of inotropes.
Results
Among 5537 LVAD recipients (mean 57±13 years, 49% destination therapy, support 18.9 months) prevalence of 1-month RHF was 24%. Of these, RHF persisted at 12 months in 5.3%. In contrast, de novo RHF, first identified at 3 months, occurred in 5.1% and persisted at 12 months in 17% of these, and at 6 months occurred in 4.8% and persisted at 12 months in 25%. Higher preimplant blood urea nitrogen (ORs,1.03-1.09 per 5 mg/dL increase; P<0.0001), previous tricuspid valve repair/replacement (ORs, 2.01-10.09; P<0.001), severely depressed right ventricular systolic function (ORs,1.17-2.20; P=0.004); and centrifugal versus axial LVAD (ORs,1.15-1.78; P=0.001) represented risk factors for RHC incidence at 3 months. Patients with persistent RHF at 3 months had the lowest 2-year survival (57%) while patients with de novo RHF or RHF which resolved by 3 months had more favorable survival outcomes (75% and 78% at 2 years, respectively; P<0.001).
Conclusions
RHF at 1 or 3 months post-LVAD was a common and frequently transient condition, which, if resolved, was associated with relatively favorable prognosis. Conversely, de novo, late RHF post-LVAD (>6 months) was more frequently a persistent disorder and associated with increased mortality. The 1-, 3-, and 6-month time points may be used for RHF assessment and risk stratification in LVAD recipients.



Circ Heart Fail: 06 Jun 2022:101161CIRCHEARTFAILURE121008706; epub ahead of print
Kapelios CJ, Lund LH, Wever-Pinzon O, Selzman CH, ... Kirklin JK, Drakos SG
Circ Heart Fail: 06 Jun 2022:101161CIRCHEARTFAILURE121008706; epub ahead of print | PMID: 35658464
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Abstract

Vericiguat and Health-Related Quality of Life in Patients With Heart Failure With Reduced Ejection Fraction: Insights From the VICTORIA Trial.

Butler J, Stebbins A, Melenovský V, Sweitzer NK, ... Armstrong PW, VICTORIA Study Group
Background
We examined the effects of vericiguat compared with placebo in patients with heart failure with reduced ejection fraction enrolled in VICTORIA (Vericiguat Global Study in Patients With Heart Failure With Reduced Ejection Fraction) on health status outcomes measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) and evaluated whether clinical outcomes varied by baseline KCCQ score.
Methods
KCCQ was completed at baseline and 4, 16, and 32 weeks. We assessed treatment effect on KCCQ using a mixed-effects model adjusting for baseline KCCQ and stratification variables. Cox proportional-hazards modeling was performed to evaluate the effect of vericiguat on clinical outcomes by tertiles of baseline KCCQ clinical summary score (CSS), total symptom score (TSS), and overall summary score (OSS).
Results
Of 5050 patients, 4664, 4741, and 4470 had KCCQ CSS (median [25th to 75th], 65.6 [45.8-81.8]), TSS (68.8 [47.9-85.4]), and OSS (59.9 [42.0-77.1]) at baseline; 94%, 88%, and 82% had data at 4, 16, and 32 weeks. At 16 weeks, CSS improved by a median of 6.3 in both arms; no significant differences in improvement were seen for TSS and OSS between the 2 groups (P=0.69, 0.97, and 0.13 for CSS, TSS, and OSS). Trends were similar at 4 and 32 weeks. Vericiguat versus placebo reduced cardiovascular death or heart failure hospitalization risk similarly across tertiles of baseline KCCQ CSS, TSS, and OSS (interaction P=0.13, 0.21, and 0.65).
Conclusions
Vericiguat did not significantly improve KCCQ scores compared with placebo. Vericiguat reduced the risk of cardiovascular death or heart failure hospitalization across the range of baseline health status.
Registration
URL: https://www.
Clinicaltrials
gov; Unique identifier: NCT02861534.



Circ Heart Fail: 03 Jun 2022:101161CIRCHEARTFAILURE121009337; epub ahead of print
Butler J, Stebbins A, Melenovský V, Sweitzer NK, ... Armstrong PW, VICTORIA Study Group
Circ Heart Fail: 03 Jun 2022:101161CIRCHEARTFAILURE121009337; epub ahead of print | PMID: 35656822
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Abstract

Alcohol Intake in Patients With Cardiomyopathy and Heart Failure: Consensus and Controversy.

Andersson C, Schou M, Gustafsson F, Torp-Pedersen C
Alcohol is often cited to be a common cause of cardiomyopathy and heart failure. However, in most available population-based studies, a modest-to-moderate alcohol consumption has been associated with favorable effects on the cardiovascular system, including a lowered risk of heart failure, compared with no alcohol consumption. Available genetic epidemiological data have not supported a causal association between alcohol consumption and heart failure risk, suggesting that alcohol may not be a common cause of heart failure in the community. Data linking alcohol intake with cardiomyopathy risk are sparse, and the concept of alcoholic cardiomyopathy stems mainly from case series of selected patients with dilated cardiomyopathy, where a large proportion reported a history of excessive alcohol intake. This state-of-the-art paper addresses the current knowledge of the epidemiology of alcoholic cardiomyopathy and the role of alcohol intake in patients with non-alcohol-related heart failure. It also offers directions to future research in the area. The review questions the validity of current clinical teaching in the area. It is not well known how much alcohol is needed to cause disease, and the epidemiological pathways linking alcohol consumption to cardiomyopathy and heart failure are not well understood. Until more evidence becomes available, caution is warranted before labeling patients as having alcoholic cardiomyopathy due to a risk of neglecting other contributors, such as genetic causes of cardiomyopathy. In non-alcohol-related heart failure, it is unknown whether total abstinence is improving outcomes (compared with moderate drinking). Ideally, randomized clinical trials are needed to answer this question.



Circ Heart Fail: 20 May 2022:101161CIRCHEARTFAILURE121009459; epub ahead of print
Andersson C, Schou M, Gustafsson F, Torp-Pedersen C
Circ Heart Fail: 20 May 2022:101161CIRCHEARTFAILURE121009459; epub ahead of print | PMID: 35593142
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Abstract

Estrogen Protects Cardiac Function and Energy Metabolism in Dilated Cardiomyopathy Induced by Loss of Cardiac IRS1 and IRS2.

Yan H, Yang W, Zhou F, Pan Q, ... Tong C, Guo S
Background
Type 2 diabetes (T2D) is a high-risk factor for incident of cardiovascular diseases. Women at young ages show a reduced incidence of both T2D and cardiovascular diseases compared with men, but these disparities disappear in postmenopausal women versus age-matched men. Thus, ovaries and ovarian hormones, such as estrogen, are expected to protect from T2D and cardiovascular diseases. In this study, we aimed to investigate the role of ovaries and ovarian hormone estrogen in cardiac function and energy metabolism using the cardiac IRS (insulin receptor substrate) 1 and IRS2 double genes knockout mice that mimic cardiac insulin resistance.
Methods
Control and heart-specific IRS1/2 double genes knockout mice were treated with placebo or 17β-estradiol (E2) pellets, respectively, through subcutaneous implantation. Female mice were subjected to a bilateral ovariectomy surgery to remove endogenous E2. The cardiac function and energy metabolism were determined using echocardiography and indirect calorimeter, respectively.
Results
All male heart-specific IRS1/2 double genes knockout mice died of heart failure at 6 to 8 weeks as we previously described (Qi et al), but all female heart-specific IRS1/2 double genes knockout mice survived >1 year. Removal of ovaries in heart-specific IRS1/2 double genes knockout female mice resulted in cardiac dysfunction, and ultimately animal death. However, E2 supplementation prevented the dilated cardiomyopathy, improved cardiac function and energy metabolism, and enhanced lifespan in both male and ovariectomy female mice deficient for cardiac IRS1 and IRS2 genes, largely owing to the activation of Akt (protein kinase B)-Foxo1 (O1 class of forkhead/winged helix transcription factor) signaling cascades.
Conclusions
These results show that estrogen protects mice from cardiac insulin resistance-induced diabetic cardiomyopathy. This may provide a fundamental mechanism for the gender difference for the incidence of both T2D and cardiovascular diseases. This study highlights that estrogen signaling could be a potential target for improving cardiac function and energy metabolism in humans with T2D.



Circ Heart Fail: 17 May 2022:101161CIRCHEARTFAILURE121008758; epub ahead of print
Yan H, Yang W, Zhou F, Pan Q, ... Tong C, Guo S
Circ Heart Fail: 17 May 2022:101161CIRCHEARTFAILURE121008758; epub ahead of print | PMID: 35579013
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Abstract

Defects in the Proteome and Metabolome in Human Hypertrophic Cardiomyopathy.

Previs MJ, O\'Leary TS, Morley MP, Palmer BM, ... Kelly DP, Day SM
Background
Defects in energetics are thought to be central to the pathophysiology of hypertrophic cardiomyopathy (HCM); yet, the determinants of ATP availability are not known. The purpose of this study is to ascertain the nature and extent of metabolic reprogramming in human HCM, and its potential impact on contractile function.
Methods
We conducted proteomic and targeted, quantitative metabolomic analyses on heart tissue from patients with HCM and from nonfailing control human hearts.
Results
In the proteomic analysis, the greatest differences observed in HCM samples compared with controls were increased abundances of extracellular matrix and intermediate filament proteins and decreased abundances of muscle creatine kinase and mitochondrial proteins involved in fatty acid oxidation. These differences in protein abundance were coupled with marked reductions in acyl carnitines, byproducts of fatty acid oxidation, in HCM samples. Conversely, the ketone body 3-hydroxybutyrate, branched chain amino acids, and their breakdown products, were all significantly increased in HCM hearts. ATP content, phosphocreatine, nicotinamide adenine dinucleotide and its phosphate derivatives, NADP and NADPH, and acetyl CoA were also severely reduced in HCM compared with control hearts. Functional assays performed on human skinned myocardial fibers demonstrated that the magnitude of observed reduction in ATP content in the HCM samples would be expected to decrease the rate of cross-bridge detachment. Moreover, left atrial size, an indicator of diastolic compliance, was inversely correlated with ATP content in hearts from patients with HCM.
Conclusions
HCM hearts display profound deficits in nucleotide availability with markedly reduced capacity for fatty acid oxidation and increases in ketone bodies and branched chain amino acids. These results have important therapeutic implications for the future design of metabolic modulators to treat HCM.



Circ Heart Fail: 11 May 2022:CIRCHEARTFAILURE121009521; epub ahead of print
Previs MJ, O'Leary TS, Morley MP, Palmer BM, ... Kelly DP, Day SM
Circ Heart Fail: 11 May 2022:CIRCHEARTFAILURE121009521; epub ahead of print | PMID: 35543134
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This program is still in alpha version.