Journal: Circ Heart Fail

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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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Abstract

Cardiogenic Shock From Heart Failure Versus Acute Myocardial Infarction: Clinical Characteristics, Hospital Course, and 1-Year Outcomes.

Sinha SS, Rosner CM, Tehrani BN, Maini A, ... O\'Connor CM, Batchelor WB
Background
Little is known about clinical characteristics, hospital course, and longitudinal outcomes of patients with cardiogenic shock (CS) related to heart failure (HF-CS) compared to acute myocardial infarction (AMI; CS related to AMI [AMI-CS]).
Methods
We examined in-hospital and 1-year outcomes of 520 (219 AMI-CS, 301 HF-CS) consecutive patients with CS (January 3, 2017-December 31, 2019) in a single-center registry.
Results
Mean age was 61.5±13.5 years, 71% were male, 22% were Black patients, and 63% had chronic kidney disease. The HF-CS cohort was younger (58.5 versus 65.6 years, P<0.001), had fewer cardiac arrests (15.9% versus 35.2%, P<0.001), less vasopressor utilization (61.8% versus 82.2%, P<0.001), higher pulmonary artery pulsatility index (2.14 versus 1.51, P<0.01), lower cardiac power output (0.64 versus 0.77 W, P<0.01) and higher pulmonary capillary wedge pressure (25.4 versus 22.2 mm Hg, P<0.001) than patients with AMI-CS. Patients with HF-CS received less temporary mechanical circulatory support (34.9% versus 76.3% P<0.001) and experienced lower rates of major bleeding (17.3% versus 26.0%, P=0.02) and in-hospital mortality (23.9% versus 39.3%, P<0.001). Postdischarge, 133 AMI-CS and 229 patients with HF-CS experienced similar rates of 30-day readmission (19.5% versus 24.5%, P=0.30) and major adverse cardiac and cerebrovascular events (23.3% versus 28.8%, P=0.45). Patients with HF-CS had lower 1-year mortality (n=123, 42.6%) compared to the patients with AMI-CS (n=110, 52.9%, P=0.03). Cumulative 1-year mortality was also lower in patients with HF-CS (log-rank test, P=0.04).
Conclusions
Patients with HF-CS were younger, and despite lower cardiac power output and higher pulmonary capillary wedge pressure, less likely to receive vasopressors or temporary mechanical circulatory support. Although patients with HF-CS had lower in-hospital and 1-year mortality, both cohorts experienced similarly high rates of postdischarge major adverse cardiovascular and cerebrovascular events and 30-day readmission, highlighting that both cohorts warrant careful long-term follow-up.
Registration
URL: https://www.
Clinicaltrials
gov; Unique identifier: NCT03378739.



Circ Heart Fail: 05 May 2022:101161CIRCHEARTFAILURE121009279; epub ahead of print
Sinha SS, Rosner CM, Tehrani BN, Maini A, ... O'Connor CM, Batchelor WB
Circ Heart Fail: 05 May 2022:101161CIRCHEARTFAILURE121009279; epub ahead of print | PMID: 35510546
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Abstract

Blood Pressure and Glycemic Control Among Ambulatory US Adults With Heart Failure: National Health and Nutrition Examination Survey 2001 to 2018.

Rethy L, Vu TT, Shah NS, Carnethon MR, ... Lloyd-Jones DM, Khan SS
Background
Multisociety guidelines recommend a goal systolic blood pressure (BP) <130 mm Hg and a hemoglobin A1c (HbA1c) <8% in patients with heart failure (HF), regardless of ejection fraction. Few studies have described BP and glycemic control in ambulatory patients with HF and racial and ethnic disparities in this subset of the population.
Methods
We evaluated prevalence of uncontrolled BP and HbA1c in non-Hispanic Black, non-Hispanic White, and Mexican American adults aged ≥20 years with self-reported HF (National Health and Nutrition Examination Surveys: 2001-2018). Prevalence ratios (95% CI) for uncontrolled BP and HbA1c were calculated by race and ethnicity and adjusted for sex, age, treatment, and socioeconomic status. In secondary analyses, we examined trends in the prevalence of uncontrolled BP and HbA1c.
Results
Uncontrolled BP was present in 48% (95% CI, 49%-56%) of adults with HF (representing 2.3 million people). Non-Hispanic Black participants had a higher prevalence of uncontrolled BP compared with non-Hispanic White participants (53% [48%-58%] compared with 47% [43%-51%], P<0.05). In adjusted models, non-Hispanic Black participants were 1.19 (1.02-1.39) times more likely to have uncontrolled BP than non-Hispanic White participants. Overall, uncontrolled HbA1c was found in 8% (6%, 10%) with no differences by race and ethnicity. Prevalence of uncontrolled BP improved over time but uncontrolled risk factors remained high-2017 to 2018: 41% (36%, 47%) and 7% (5%, 12%) had uncontrolled BP and HbA1c, respectively.
Conclusions
We document an unacceptably high prevalence of uncontrolled BP and HbA1c in a nationally representative, ambulatory HF sample with significant differences in BP control by race and ethnicity.



Circ Heart Fail: 28 Apr 2022:101161CIRCHEARTFAILURE121009229; epub ahead of print
Rethy L, Vu TT, Shah NS, Carnethon MR, ... Lloyd-Jones DM, Khan SS
Circ Heart Fail: 28 Apr 2022:101161CIRCHEARTFAILURE121009229; epub ahead of print | PMID: 35477292
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Abstract

Management of Hypertension in Patients With Ventricular Assist Devices: A Scientific Statement From the American Heart Association.

Eisen HJ, Flack JM, Atluri P, Bansal N, ... Rowe T, American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; Council on Hypertension; and Council on Lifelong Congenital Heart Disease and Heart Health in the Young
Mechanical circulatory support with durable continuous-flow ventricular assist devices has become an important therapeutic management strategy for patients with advanced heart failure. As more patients have received these devices and the duration of support per patient has increased, the postimplantation complications have become more apparent, and the need for approaches to manage these complications has become more compelling. Continuous-flow ventricular assist devices, including axial-flow and centrifugal-flow pumps, are the most commonly used mechanical circulatory support devices. Continuous-flow ventricular assist devices and the native heart have a constant physiological interplay dependent on pump speed that affects pressure-flow relationships and patient hemodynamics. A major postimplantation complication is cerebrovascular vascular accidents. The causes of cerebrovascular vascular accidents in ventricular assist device recipients may be related to hypertension, thromboembolic events, bleeding from anticoagulation, or some combination of these. The most readily identifiable and preventable cause is hypertension. Hypertension management in these patients has been hampered by the fact that it is difficult to accurately measure blood pressure because these ventricular assist devices have continuous flow and are often not pulsatile. Mean arterial pressures have to be identified by Doppler or oscillometric cuff and treated. Although guidelines for hypertension management after ventricular assist device implantation are based largely on expert consensus and conventional wisdom, the mainstay of treatment for hypertension includes guideline-directed medical therapy for heart failure with reduced ejection fraction because this may reduce adverse effects associated with hypertension and increase the likelihood of favorable ventricular remodeling. The use of systemic anticoagulation in ventricular assist device recipients may at a given blood pressure increase the risk of stroke.



Circ Heart Fail: 18 Apr 2022:101161HHF0000000000000074; epub ahead of print
Eisen HJ, Flack JM, Atluri P, Bansal N, ... Rowe T, American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; Council on Hypertension; and Council on Lifelong Congenital Heart Disease and Heart Health in the Young
Circ Heart Fail: 18 Apr 2022:101161HHF0000000000000074; epub ahead of print | PMID: 35430896
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Abstract

Mitochondrial Sirtuin-3 (SIRT3) Prevents Doxorubicin-Induced Dilated Cardiomyopathy by Modulating Protein Acetylation and Oxidative Stress.

Tomczyk MM, Cheung KG, Xiang B, Tamanna N, ... Tong Q, Dolinsky VW
Background
High doses of doxorubicin put cancer patients at risk for developing dilated cardiomyopathy. Previously, we showed that doxorubicin treatment decreases SIRT3 (sirtuin 3), the main mitochondrial deacetylase and increases protein acetylation in rat cardiomyocytes. Here, we hypothesize that SIRT3 expression can attenuate doxorubicin induced dilated cardiomyopathy in vivo by preventing the acetylation of mitochondrial proteins.
Methods
Nontransgenic, M3-SIRT3 (truncated SIRT3; short isoform), and M1-SIRT3 (full-length SIRT3; mitochondrial localized) transgenic mice were treated with doxorubicin for 4 weeks (8 mg/kg body weight per week). Echocardiography was performed to assess cardiac structure and function and validated by immunohistochemistry and immunofluorescence (n=4-10). Mass spectrometry was performed on cardiac mitochondrial peptides in saline (n=6) and doxorubicin (n=5) treated hearts. Validation was performed in doxorubicin treated primary rat and human induced stem cell derived cardiomyocytes transduced with adenoviruses for M3-SIRT3 and M1-SIRT3 and deacetylase deficient mutants (n=4-10).
Results
Echocardiography revealed that M3-SIRT3 transgenic mice were partially resistant to doxorubicin induced changes to cardiac structure and function whereas M1-SIRT3 expression prevented cardiac remodeling and dysfunction. In doxorubicin hearts, 37 unique acetylation sites on mitochondrial proteins were altered. Pathway analysis revealed these proteins are involved in energy production, fatty acid metabolism, and oxidative stress resistance. Increased M1-SIRT3 expression in primary rat and human cardiomyocytes attenuated doxorubicin-induced superoxide formation, whereas deacetylase deficient mutants were unable to prevent oxidative stress.
Conclusions
Doxorubicin reduced SIRT3 expression and markedly affected the cardiac mitochondrial acetylome. Increased M1-SIRT3 expression in vivo prevented doxorubicin-induced cardiac dysfunction, suggesting that SIRT3 could be a potential therapeutic target for mitigating doxorubicin-induced dilated cardiomyopathy.



Circ Heart Fail: 14 Apr 2022:101161CIRCHEARTFAILURE121008547; epub ahead of print
Tomczyk MM, Cheung KG, Xiang B, Tamanna N, ... Tong Q, Dolinsky VW
Circ Heart Fail: 14 Apr 2022:101161CIRCHEARTFAILURE121008547; epub ahead of print | PMID: 35418250
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Abstract

Testosterone, Hypogonadism, and Heart Failure.

Di Lodovico E, Facondo P, Delbarba A, Pezzaioli LC, ... Cappelli C, Ferlin A
Male hypogonadism is defined as low circulating testosterone level associated with signs and symptoms of testosterone deficiency. Although the bidirectional link between hypogonadism and cardiovascular disease has been clarified, the association between testosterone and chronic heart failure (HF) is more controversial. Herein, we critically review published studies relating to testosterone, hypogonadism, and HF and provide practical clinical information on proper diagnosis and treatment of male hypogonadism in patients with HF. In general, published studies are extremely heterogeneous, frequently have not adhered to hypogonadism guidelines, and suffer from many intrinsic methodological inaccuracies; therefore, data provide only low-quality evidence. Nevertheless, by selecting the few methodologically robust studies, we show the prevalence of testosterone deficiency (30%-50%) and symptomatic hypogonadism (15%) in men with HF is significant. Low testosterone correlates with HF severity, New York Heart Association class, exercise functional capacity, and a worse clinical prognosis and mortality. Interventional studies on testosterone treatment in men with HF are inconclusive but do suggest beneficial effects on exercise capacity, New York Heart Association class, metabolic health, and cardiac prognosis. We suggest that clinicians should measure testosterone levels in men with HF who have symptoms of a testosterone deficiency and conditions that predispose to hypogonadism, such as obesity and diabetes. These patients-if diagnosed as hypogonadal-may benefit from the short- and long-term effects of testosterone replacement therapy, which include improvements in both cardiac prognosis and systemic outcomes. Further collaborative studies involving both cardiologists and endocrinologists are warranted.



Circ Heart Fail: 08 Apr 2022:101161CIRCHEARTFAILURE121008755; epub ahead of print
Di Lodovico E, Facondo P, Delbarba A, Pezzaioli LC, ... Cappelli C, Ferlin A
Circ Heart Fail: 08 Apr 2022:101161CIRCHEARTFAILURE121008755; epub ahead of print | PMID: 35392658
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Abstract

Skeletal Muscle Mass Recovery Early After Left Ventricular Assist Device Implantation in Patients With Advanced Systolic Heart Failure.

Vest AR, Wong WW, Chery J, Coston A, ... Kawabori M, Saltzman E
Background
Patients with advanced systolic heart failure are at risk of unintentional weight loss and muscle wasting. It has been observed that left ventricular assist device (LVAD) recipients gain weight after device implantation, although it is unknown whether this represents skeletal muscle mass gains. We aimed to determine whether skeletal muscle mass increases early during LVAD support.
Methods
We prospectively recruited 30 adults with systolic heart failure ±21 days from LVAD implantation. Participants underwent whole-body dual X-ray absorptiometry to measure fat free mass, appendicular lean mass (ALM, lean mass in the arms and legs) and fat mass. Dual X-ray absorptiometry imaging was repeated at 3 and 6 months after LVAD implantation, with participation ending after the 6-month visit or heart transplantation, whichever occurred first. Changes in body composition were evaluated using mixed effects linear regression models.
Results
The cohort was 87% male, with mean age 56±12 (SD) years, and mean body mass index 26.4±5.4 kg/m2. Per sarcopenia ALM criteria, 52% of participants had muscle wasting at baseline. At baseline, mean fat free mass and ALM were 56.4±11.7 and 21.0±5.3 kg, respectively. Both measures increased significantly (P<0.001) over 6 months of LVAD support: mean fat free mass change at 3 and 6 months: 2.3 kg (95% CI, 1.0-3.5) and 4.2 kg (95% CI, 2.2-6.1); mean ALM change at 3 and 6 months: 1.5 kg (95% CI, 0.7-2.3) and 2.3 kg (95% CI, 0.9-3.6).
Conclusions
Among LVAD recipients with advanced systolic heart failure and high baseline prevalence of muscle wasting, there were significant gains in skeletal muscle mass, as represented by dual X-ray absorptiometry fat free mass and ALM, over the first 6 months of LVAD support.



Circ Heart Fail: 05 Apr 2022:101161CIRCHEARTFAILURE121009012; epub ahead of print
Vest AR, Wong WW, Chery J, Coston A, ... Kawabori M, Saltzman E
Circ Heart Fail: 05 Apr 2022:101161CIRCHEARTFAILURE121009012; epub ahead of print | PMID: 35378982
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Impact:
Abstract

The RAISE Trial: A Novel Device and First-in-Man Trial.

Sun W, Zou H, Yong Y, Liu B, ... Lotan C, Kong X
Background
Currently, standard medical therapies have limited effects on heart failure with preserved ejection fraction (HFpEF), which impacts on the life quality and survival of patients. This study aimed to evaluate the safety and efficacy of the percutaneous radiofrequency ablation-based interatrial shunting for HFpEF with a novel atrial septostomy device.
Methods
A preclinical study in 11 normal domestic pigs and the first-in-man study in 10 patients with HFpEF were performed. The major safety events and interatrial shunt performance were evaluated at baseline, 1 month, 3 months, and 6 months post-procedure in both animals and human patients. The clinical functional status was also assessed in the first-in-man study.
Results
Percutaneous radiofrequency ablation-based interatrial shunting therapy was performed successfully both in animals and patients. In the animal study, a left-to-right interatrial shunt was created with a mean defect size of 5.5±2.2 mm without procedure-related safety events. Seven pigs showed the continuous shunting with a mean defect size of 4.1±1.5 mm at 6 months. In the first-in-man study, a median interatrial defect diameter of 5.0 (4.0-6.0) mm was measured immediately. No major safety events including death and thromboembolism were observed. The continuous shunting with the defect size of 4.0 (3.0-4.0) mm could still be observed in 7 patients at 6 months. The clinical status was significantly improved with NT-proBNP (N-terminal pro-B-type natriuretic peptide) reduced by 2149 pg/mL ([95% CI, 204-3301] P=0.028), with 6-minute walk distance increased by 88 m ([95% CI, 50-249] P=0.008) and with New York Heart Association class improved in 8 patients at 6 months.
Conclusions
The present results showed that percutaneous radiofrequency ablation-based interatrial shunting was a safe and potentially effective therapy for HFpEF, providing a nonpharmacological and nonimplanted option for HFpEF management.
Registration
URL: https://www.chictr.org.cn; Unique identifier: ChiCTR1900027664.



Circ Heart Fail: 31 Mar 2022; 15:e008362
Sun W, Zou H, Yong Y, Liu B, ... Lotan C, Kong X
Circ Heart Fail: 31 Mar 2022; 15:e008362 | PMID: 35378984
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Abstract

The Value of Passive Leg Raise During Right Heart Catheterization in Diagnosing Heart Failure With Preserved Ejection Fraction.

van de Bovenkamp AA, Wijkstra N, Oosterveer FPT, Vonk Noordegraaf A, ... Borlaug BA, Handoko ML
Background
Because of limited accuracy of noninvasive tests, diastolic stress testing plays an important role in the diagnostic work-up of patients with heart failure with preserved ejection fraction (HFpEF). Exercise right heart catheterization is considered the gold standard and indicated when HFpEF is suspected but left ventricular filling pressures at rest are normal. However, performing exercise during right heart catheterization is not universally available. Here, we examined whether pulmonary capillary wedge pressure (PCWP) during a passive leg raise (PLR) could be used as simple and accurate method to diagnose or rule out occult-HFpEF.
Methods
In our tertiary center for pulmonary hypertension and HFpEF, all patients who received a diagnostic right heart catheterization with PCWP-measurements at rest, PLR, and exercise were evaluated (2014-2020). The diagnostic value of PCWPPLR was compared with the gold standard (PCWPEXERCISE). Cut-offs derived from our cohort were subsequently validated in an external cohort (N=74).
Results
Thirty-nine non-HFpEF, 33 occult-HFpEF, and 37 manifest-HFpEF patients were included (N=109). In patients with normal PCWPREST (<15 mmHg), PCWPPLR significantly improved diagnostic accuracy compared with PCWPREST (AUC=0.82 versus 0.69, P=0.03). PCWPPLR ≥19 mmHg (24% of cases) had a specificity of 100% for diagnosing occult-HFpEF, irrespective of diuretic use. PCWPPLR ≥11 mmHg had a 100% sensitivity and negative predictive value for diagnosing occult-HFpEF. Both cut-offs retained a 100% specificity and 100% sensitivity in the external cohort. Absolute change in PCWPPLR or V-wave derived parameters had no incremental value in diagnosing occult-HFpEF.
Conclusions
PCWPPLR is a simple and powerful tool that can help to diagnose or rule out occult-HFpEF.



Circ Heart Fail: 31 Mar 2022; 15:e008935
van de Bovenkamp AA, Wijkstra N, Oosterveer FPT, Vonk Noordegraaf A, ... Borlaug BA, Handoko ML
Circ Heart Fail: 31 Mar 2022; 15:e008935 | PMID: 35311526
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Impact:
Abstract

Outcomes With Phosphodiesterase-5 Inhibitor Use After Left Ventricular Assist Device: An STS-INTERMACS Analysis.

Grandin EW, Gulati G, Nunez JI, Kennedy K, ... Teuteberg J, Kiernan MS
Background
Elevated right ventricular afterload following continuous-flow left ventricular assist device (CF-LVAD) may contribute to late right heart failure (LRHF). PDE5i (phosphodiesterase-5 inhibitors) are used to treat pulmonary hypertension and right heart dysfunction after CF-LVAD, but their impact on outcomes is uncertain.
Methods
We queried Interagency Registry for Mechanically Assisted Circulatory Support from 2012 to 2017 for adults receiving a primary CF-LVAD and surviving ≥30 days from index discharge. Patients receiving early PDE5i (ePDE5i) at 1 month were propensity-matched 1:1 with controls. The primary outcome was the cumulative incidence of LRHF, defined using prevailing Interagency Registry for Mechanically Assisted Circulatory Support criteria; secondary outcomes included all-cause mortality and major bleeding.
Results
Among 9627 CF-LVAD recipients analyzed, 2463 (25.6%) received ePDE5i and 1600 were propensity-matched 1:1 with controls. Before implant, ePDE5i patients had more severe RV dysfunction (13.1% versus 9.6%) and higher pulmonary vascular resistance (2.8±2.7 versus 2.2±2.4 WU), both P<0.001, but clinical factors were well-balanced after propensity-matching. In the unmatched cohort, ePDE5i patients had a higher 3-year cumulative incidence of LRHF, mortality, and major bleeding, but these differences were attenuated in the propensity-matched cohort: LRHF 40.8% versus 35.7% (hazard ratio, 1.14 [95% CI, 0.99-1.32]; P=0.07); mortality 38.6% versus 35.8% (hazard ratio, 0.99 [95% CI, 0.86-1.15]; P=0.93); major bleeding 51.2% versus 46.0% (hazard ratio, 1.12 [95% CI, 0.99-1.27]; P=0.06).
Conclusions
Compared with propensity-matched controls, adult CF-LVAD patients receiving ePDE5i had similar rates of LRHF, mortality, and major bleeding. While intrinsic patient risk factors likely account for more adverse outcomes with ePDE5i in the unmatched cohort, there is no obvious benefit of ePDE5i in the LVAD population.



Circ Heart Fail: 31 Mar 2022; 15:e008613
Grandin EW, Gulati G, Nunez JI, Kennedy K, ... Teuteberg J, Kiernan MS
Circ Heart Fail: 31 Mar 2022; 15:e008613 | PMID: 35332780
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Abstract

Proposed Cardiac End Points for Clinical Trials in Immunoglobulin Light Chain Amyloidosis: Report From the Amyloidosis Forum Cardiac Working Group.

Maurer MS, Dunnmon P, Fontana M, Quarta CC, ... Lousada I, Merlini G
Immunoglobulin light chain amyloidosis is a rare, multisystemic, phenotypically heterogenous disease affecting cardiovascular, renal, neurological, and gastrointestinal systems to varying degrees. Its underlying cause is a plasma cell dyscrasia characterized by misfolding of monoclonal immunoglobulin light chains which leads to aggregation and deposition of insoluble amyloid fibrils in target organs. Prognosis is primarily dependent on extent of cardiac involvement and depth of hematologic response to treatment. To facilitate development of new therapies, a public-private partnership was formed between the nonprofit Amyloidosis Research Consortium and the US Food and Drug Administration Center for Drug Evaluation and Research. In 2020, the Amyloidosis Forum launched an initiative to identify novel/composite end points and analytic strategies to expedite clinical trials for development of new therapies for the primary hematologic disorder and organ system manifestations. Specialized working groups identified organ-specific end points; additional working groups reviewed health-related quality of life measures and statistical approaches to data analysis. Each working group comprised amyloidosis experts, patient representatives, statisticians, and representatives from the Food and Drug Administration, the UK Medicines and Healthcare Products Regulatory Agency, and pharmaceutical companies. This review summarizes the proceedings and recommendations of the Cardiac Working Group. Using a modified Delphi method, the group identified, reviewed, and prioritized cardiac end points relevant to immunoglobulin light chain amyloidosis in the context of an antiplasma cell therapy. Prioritized cardiovascular end points included overall survival, hospitalization, N-terminal pro-B-type natriuretic peptide level, 6-minute walk test, Kansas City Cardiac Questionnaire, and cardiac deterioration progression-free survival. These recommended components will be further explored through evaluation of clinical trial datasets and formal guidance from regulatory authorities.



Circ Heart Fail: 25 Mar 2022:CIRCHEARTFAILURE121009038; epub ahead of print
Maurer MS, Dunnmon P, Fontana M, Quarta CC, ... Lousada I, Merlini G
Circ Heart Fail: 25 Mar 2022:CIRCHEARTFAILURE121009038; epub ahead of print | PMID: 35331001
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Abstract

Development of Advanced Heart Failure: A Population-Based Study.

Subramaniam AV, Weston SA, Killian JM, Schulte PJ, ... Blecker SB, Dunlay SM
Background
Some patients with heart failure (HF) will go on to develop advanced HF, characterized by severe HF symptoms despite attempts to optimize medical therapy. The goals of this study were to examine the risk of developing advanced HF in patients with newly diagnosed HF, identify risk factors for developing advanced HF, and evaluate the impact of advanced HF on outcomes.
Methods
This was a population-based, retrospective cohort study of Olmsted County, Minnesota, residents with a new clinical diagnosis of HF between 2007 and 2017. Risk factors for the development of advanced HF (2018 European Society of Cardiology criteria) were examined using cause-specific Cox proportional hazard regression models. The associations of development of advanced HF with risks of hospitalization and mortality were examined using the Andersen-Gill and Cox models, respectively.
Results
There were 4597 residents with incident HF from 2007 to 2017. The cumulative incidence of advanced HF was 11.5% (95% CI, 10.5%-12.5%) at 6 years after incident HF diagnosis overall and was 14.4% (95% CI, 12.3%-16.9%), 11.4% (95% CI, 8.9%-14.6%), and 11.7% (95% CI, 10.3%-13.2%) in patients with incident HF with reduced, mildly reduced, and preserved ejection fraction, respectively. Key demographics, comorbidities, and echocardiographic characteristics were independently associated with the development of advanced HF. Development of advanced HF was associated with increased risks of all-cause hospitalization (adjusted hazard ratio, 3.0 [95% CI, 2.7-3.4]; P<0.001), HF hospitalization (hazard ratio, 10.2 [95% CI, 8.7-12.1]), all-cause mortality (hazard ratio, 5.0 [95% CI, 4.5-5.6]; P<0.001), and cardiovascular mortality (hazard ratio, 7.8 [95% CI, 6.7-9.1]).
Conclusions
In this population-based study, development of advanced HF was common and was associated with markedly increased morbidity and mortality.



Circ Heart Fail: 25 Mar 2022:CIRCHEARTFAILURE121009218; epub ahead of print
Subramaniam AV, Weston SA, Killian JM, Schulte PJ, ... Blecker SB, Dunlay SM
Circ Heart Fail: 25 Mar 2022:CIRCHEARTFAILURE121009218; epub ahead of print | PMID: 35332793
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Impact:
Abstract

Combining Minimally Invasive Surgery With Ultra-Fast-Track Anesthesia in HeartMate 3 Patients: A Pilot Study.

Ahmad U, Khattab MA, Schaelte G, Goetzenich A, ... Schnoering H, Zayat R
Background
Minimally invasive surgery for left ventricular assist device implantation may have advantages over conventional sternotomy (CS). Additionally, ultra-fast-track anesthesia has been linked to better outcomes after cardiac surgery. This study summarizes our early experience of combining minimally invasive surgery with ultra-fast-track anesthesia (MIFTA) in patients receiving HeartMate 3 devices and compares the outcomes between MIFTA and CS.
Methods
From October 2015 to January 2019, 18 of 49 patients with Interagency Registry for Mechanically Assisted Circulatory Support profiles >1 underwent MIFTA for HeartMate 3 implantation. For bias reduction, propensity scores were calculated and used as a covariate in a regression model to analyze outcomes. Weighted parametric survival analysis was performed.
Results
In the MIFTA group, intensive care unit stays were shorter (mean difference, 8 days [95% CI, 4-13]; P<0.001), and the incidences of pneumonia and right heart failure were lower than those in the CS group (odds ratio, 1.36 [95% CI, 1.01-1.75]; P=0.016, respectively). At 6 and 12 hours postoperatively, MIFTA patients had a better hemodynamic performance with lower pulmonary wedge pressure (mean difference, 2.23 mm Hg [95% CI, 0.41-4.06]; P=0.028) and a higher right ventricular stroke work index (mean difference, -1.49 g·m/m2 per beat [95% CI, -2.95 to -0.02]; P=0.031). CS patients had a worse right heart failure-free survival rate (hazard ratio, 2.35 [95% CI, 0.96-5.72]; P<0.01).
Conclusions
Compared with CS, MIFTA is a beneficial approach for non-Interagency Registry for Mechanically Assisted Circulatory Support 1 HeartMate 3 patients with lower adverse event incidences, better hemodynamic performance, and preserved right heart function. Future large multicentric investigations are required to verify MIFTA\'s effects on outcomes.



Circ Heart Fail: 06 Mar 2022:CIRCHEARTFAILURE121008358; epub ahead of print
Ahmad U, Khattab MA, Schaelte G, Goetzenich A, ... Schnoering H, Zayat R
Circ Heart Fail: 06 Mar 2022:CIRCHEARTFAILURE121008358; epub ahead of print | PMID: 35249368
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Impact:
Abstract

Validating an Idiopathic Dilated Cardiomyopathy Diagnosis Using Cardiovascular Magnetic Resonance: The Dilated Cardiomyopathy Precision Medicine Study.

Haas GJ, Zareba KM, Ni H, Bello-Pardo E, ... Hershberger RE, DCM Consortium Institutions and Personnel Participating in This Study
Background
Coronary angiography to identify coronary artery disease has been foundational to distinguish the cause of dilated cardiomyopathy (DCM), including the assignment of idiopathic or ischemic cardiomyopathy. Late gadolinium enhancement (LGE) with cardiovascular magnetic resonance (CMR) has emerged as an approach to identify myocardial scar and identify etiology.
Methods
The DCM Precision Medicine Study included patients with left ventricular dilation and dysfunction attributed to idiopathic DCM, after expert clinical review excluded ischemic or other cardiomyopathies. Ischemic cardiomyopathy was defined as coronary artery disease with >50% narrowing at angiography of ≥1 epicardial coronary artery. CMR was not required for study inclusion, but in a post hoc analysis of available CMR reports, patterns of LGE were classified as (1) no LGE, (2) ischemic-pattern LGE: subendocardial/transmural, (3) nonischemic LGE: midmyocardial/epicardial.
Results
Of 1204 idiopathic DCM patients evaluated, 396 (32.9%) had a prior CMR study; of these, 327 (82.6% of 396) had LGE imaging (mean age 46 years; 53.2% male; 55.4% White); 178 of the 327 (54.4%) exhibited LGE, and 156 of the 178 had LGE consistent with idiopathic DCM. The remaining 22 had transmural or subendocardial LGE. Of these 22, coronary angiography was normal (13), showed luminal irregularities (3), a distant thrombus (1), coronary artery disease with <50% coronary artery narrowing (1), or was not available (4).
Conclusions
Of 327 probands enrolled in the DCM Precision Medicine Study cohort who had LGE-CMR data available, an ischemic-pattern of LGE was identified in 22 (6.7%), all of whom had idiopathic DCM as adjudicated by expert clinical review.
Registration
URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037632.



Circ Heart Fail: 03 Mar 2022:CIRCHEARTFAILURE121008877; epub ahead of print
Haas GJ, Zareba KM, Ni H, Bello-Pardo E, ... Hershberger RE, DCM Consortium Institutions and Personnel Participating in This Study
Circ Heart Fail: 03 Mar 2022:CIRCHEARTFAILURE121008877; epub ahead of print | PMID: 35240856
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Impact:
Abstract

Management and Outcomes of Acute Myocardial Infarction-Cardiogenic Shock in Uninsured Compared With Privately Insured Individuals.

Vallabhajosyula S, Kumar V, Sundaragiri PR, Cheungpasitporn W, ... Bell MR, Barsness GW
Background
There are limited data on uninsured patients presenting with acute myocardial infarction-cardiogenic shock (AMI-CS). This study sought to compare the management and outcomes of AMI-CS between uninsured and privately insured individuals.
Methods
Using the National Inpatient Sample (2000-2016), a retrospective cohort of adult (≥18 years) uninsured admissions (primary payer-self-pay or no charge) were compared with privately insured individuals. Interhospital transfers were excluded. Outcomes of interest included in-hospital mortality, temporal trends in admissions, use of cardiac procedures, do-not-resuscitate status, palliative care referrals, and resource utilization.
Results
Of 402 182 AMI-CS admissions, 21 966 (5.4%) and 93 814 (23.3%) were uninsured and privately insured. Compared with private insured individuals, uninsured admissions were younger, male, from a lower socioeconomic status, had lower comorbidity, higher rates of acute organ failure, ST-segment elevation AMI-CS (77.3% versus 76.4%), and concomitant cardiac arrest (33.8% versus 31.9%; all P<0.001). Compared with 2000, in 2016, there were more uninsured (adjusted odds ratio, 1.15 [95% CI, 1.13-1.17]; P<0.001) and less privately insured admissions (adjusted odds ratio, 0.85 [95% CI, 0.83-0.87]; P<0.001). Uninsured individuals received less frequent coronary angiography (79.5% versus 81.0%), percutaneous coronary intervention (60.8% versus 62.2%), mechanical circulatory support (54% versus 55.5%), and had higher palliative care (3.8% versus 3.2%) and do-not-resuscitate status use (4.4% versus 3.2%; all P<0.001). Uninsured admissions had higher in-hospital mortality (adjusted odds ratio, 1.62 [95% CI, 1.55-1.68]; P<0.001) and resource utilization.
Conclusions
Uninsured individuals have higher in-hospital mortality and lower use of guideline-directed therapies in AMI-CS compared with privately insured individuals.



Circ Heart Fail: 03 Mar 2022:CIRCHEARTFAILURE121008991; epub ahead of print
Vallabhajosyula S, Kumar V, Sundaragiri PR, Cheungpasitporn W, ... Bell MR, Barsness GW
Circ Heart Fail: 03 Mar 2022:CIRCHEARTFAILURE121008991; epub ahead of print | PMID: 35240866
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Impact:
Abstract

Developments in Exercise Capacity Assessment in Heart Failure Clinical Trials and the Rationale for the Design of METEORIC-HF.

Lewis GD, Docherty KF, Voors AA, Cohen-Solal A, ... Meng L, Felker GM
Heart failure with reduced ejection fraction (HFrEF) is a highly morbid condition for which exercise intolerance is a major manifestation. However, methods to assess exercise capacity in HFrEF vary widely in clinical practice and in trials. We describe advances in exercise capacity assessment in HFrEF and a comparative analysis of how various therapies available for HFrEF impact exercise capacity. Current guideline-directed medical therapy has indirect effects on cardiac performance with minimal impact on measured functional capacity. Omecamtiv mecarbil is a novel selective cardiac myosin activator that directly increases cardiac contractility and in a phase 3 cardiovascular outcomes study significantly reduced the primary composite end point of time to first heart failure event or cardiovascular death in patients with HFrEF. The objective of the METEORIC-HF trial (Multicenter Exercise Tolerance Evaluation of Omecamtiv Mecarbil Related to Increased Contractility in Heart Failure) is to assess the effect of omecamtiv mecarbil versus placebo on multiple components of functional capacity in HFrEF. The primary end point is to test the effect of omecamtiv mecarbil compared with placebo on peak oxygen uptake as measured by cardiopulmonary exercise testing after 20 weeks of treatment. METEORIC-HF will provide state-of-the-art assessment of functional capacity by measuring ventilatory efficiency, circulatory power, ventilatory anaerobic threshold, oxygen uptake recovery kinetics, daily activity, and quality-of-life assessment. Thus, the METEORIC-HF trial will evaluate the potential impact of increased myocardial contractility with omecamtiv mecarbil on multiple important measures of functional capacity in ambulatory patients with symptomatic HFrEF. Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT03759392.



Circ Heart Fail: 02 Mar 2022:CIRCHEARTFAILURE121008970; epub ahead of print
Lewis GD, Docherty KF, Voors AA, Cohen-Solal A, ... Meng L, Felker GM
Circ Heart Fail: 02 Mar 2022:CIRCHEARTFAILURE121008970; epub ahead of print | PMID: 35236099
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Impact:
Abstract

Targeting Preload in Heart Failure: Splanchnic Nerve Blockade and Beyond.

Fudim M, Khan MS, Paracha AA, Sunagawa K, Burkhoff D
Preload augmentation represents a critical mechanism for the cardiovascular system to increase effective circulating blood volume to increase cardiac filling pressures and, subsequently, for the heart to increase cardiac output. The splanchnic vascular compartment is the primary source of vascular capacity and thus the primary target for preload recruitment in humans. Under normal conditions, sympathetic stimulation of these primary venous vessels promotes the shift of blood from the splanchnic to the thoracic compartment and elevates preload and cardiac output. However, in heart failure, since filling pressures may be elevated at rest due to decreased venous capacitance, incremental recruitment of preload to enhance cardiac output may exacerbate congestion and limit exercise capacity. Accordingly, recent attention has focused on therapies designed to regulate splanchnic vascular redistribution to improve cardiac filling pressures and patient-centered outcomes such as quality of life and exercise capacity in patients with heart failure. In this review, we discuss the relevance of splanchnic circulation as a venous reservoir, the contribution of stressed blood volume to heart failure pathogenesis, and the implications for pharmacological therapeutic interventions to prevent heart failure decompensation. Further, we review emerging device-based approaches for cardiac preload reduction such as partial/complete occlusion of the superior vena cava or the inferior vena cava.



Circ Heart Fail: 27 Feb 2022; 15:e009340
Fudim M, Khan MS, Paracha AA, Sunagawa K, Burkhoff D
Circ Heart Fail: 27 Feb 2022; 15:e009340 | PMID: 35290092
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Impact:
Abstract

Peripheral Venous Pressure-Assisted Exercise Stress Echocardiography in the Evaluation of Pulmonary Hypertension During Exercise in Patients With Suspected Heart Failure With Preserved Ejection Fraction.

Yang JH, Harada T, Choi KH, Kato T, ... Chang SA, Obokata M
Background
Identification of elevated pulmonary artery (PA) pressures during exercise may provide diagnostic, prognostic, and therapeutic implications in heart failure with preserved ejection fraction. Although widely performed, exercise stress echocardiography may underestimate true PA pressures due to the difficulty in estimating right atrial pressure (RAP) during exercise. We hypothesized that peripheral venous pressure (PVP) could allow for reliable estimation of RAP, and thus PA pressures during exercise stress echocardiography.
Methods
In protocol 1, we investigated the accuracy of PVP compared with simultaneously measured RAP at rest and during exercise right heart catheterization in 19 subjects. In protocol 2, we examined whether the addition of PVP to Doppler exercise echocardiography (tricuspid regurgitant velocity) would increase the ability to identify exercise-induced pulmonary hypertension compared with inferior vena cava-based RAP estimation in 60 patients with dyspnea.
Results
In protocol 1, PVP was strongly correlated with simultaneously measured RAP at rest and during exercise (r=0.77 and 0.90), with little overestimation of invasively measured RAP (bias 3.4 mm Hg at rest and 1.7 mm Hg during exercise). In protocol 2, PVP increased dramatically during exercise echocardiography (14±5 mm Hg) while an increase in inferior vena cava-based RAP was modest (6±4 mm Hg). Exercise PA pressures calculated from PVP and tricuspid regurgitant velocity were significantly higher than those estimated from inferior vena cava and the use of PVP increased the proportion of patients with exercise-induced pulmonary hypertension from 40% to 68%.
Conclusions
PVP may prevent underestimation of PA pressures during exercise echocardiography and could be a preferred approach to identify exercise-induced pulmonary hypertension in patients with suspected heart failure with preserved ejection fraction.



Circ Heart Fail: 21 Feb 2022:CIRCHEARTFAILURE121009028; epub ahead of print
Yang JH, Harada T, Choi KH, Kato T, ... Chang SA, Obokata M
Circ Heart Fail: 21 Feb 2022:CIRCHEARTFAILURE121009028; epub ahead of print | PMID: 35189688
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Impact:
Abstract

Blood Pressure Drops During Hospitalization for Acute Heart Failure Treated With Serelaxin: A Patient-Level Analysis of 4 Randomized Controlled Trials.

Grand J, Miger K, Sajadieh A, Køber L, ... Holbro T, Nielsen OW
Background
Hypotensive events and drops in systolic blood pressure (SBP-drop) are frequent in patients hospitalized with acute heart failure. We investigated whether SBP-drops are associated with outcomes in patients treated with serelaxin.
Methods
Patient-level retrospective analyses of 4 prospective trials investigating serelaxin in acute heart failure. Main inclusion criteria were SBP 125 to 180 mm Hg, pulmonary congestion, and elevated NT-proBNP (N-terminal pro-B-type natriuretic peptide). SBP-drops were prospectively defined as SBP<100 mm Hg, or, if SBP remained >100 mm Hg, a drop from baseline of 40 mm Hg from baseline. Outcomes were a short-term composite outcome (worsening heart failure, hospital readmission for heart failure or all-cause mortality through 14 days) and 180-day mortality.
Results
Overall, 2559/11 226 (23%) patients had an SBP-drop. SBP-drop, versus no SBP-drop, was associated with a worse outcome: cumulative incidence of 180-day mortality (11% versus 9%, hazard ratio [HR]. 1.21 [95% CI, 1.05-1.39]; P=0.009) and the short-term outcome (11% versus 9%, HR, 1.29 [95% CI, 1.13-1.49]; P<0.001). Of the 2 SBP-drop components, an SBP<100 mm Hg was associated with the worst outcome compared with a 40 mm Hg drop: short-term outcome (11% versus 10%) and HRs of 1.32 (95% CI, 1.13-1.55; P=0.0005) and 1.22 (95% CI, 0.97-1.56; P=0.09), for each component respectively, with a P value for interaction of 0.05. SBP-drops were associated with a worse short-term outcome in the placebo group (HR, 1.46 [95% CI, 1.19-1.79]; P=0.0003), but not in the serelaxin-group (HR, 1.18 [95% CI, 0.97-1.42]; P=0.10); P interaction=0.003.
Conclusions
SBP-drops in patients with acute heart failure and normal to high SBP at admission is associated with worse short- and long-term outcomes especially for SBP <100 mm Hg. However, in patients treated with the intravenous vasodilator serelaxin, SBP-drops seemed less harmful.
Registration
URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02064868, NCT02007720, NCT01870778, NCT00520806.



Circ Heart Fail: 20 Feb 2022:CIRCHEARTFAILURE121009199; epub ahead of print
Grand J, Miger K, Sajadieh A, Køber L, ... Holbro T, Nielsen OW
Circ Heart Fail: 20 Feb 2022:CIRCHEARTFAILURE121009199; epub ahead of print | PMID: 35184572
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Impact:
Abstract

Diastolic Dysfunction Is Unmasked on Exercise in Patients With Asymptomatic, Severe Aortic Stenosis: An Invasive Hemodynamic Study.

Kvaslerud AB, Gude E, Eriksen G, Andreassen AK, Gullestad L, Broch K
Background
Optimal timing of aortic valve replacement remains difficult in patients with asymptomatic, severe aortic stenosis (AS). More accurate diagnostic methods are warranted for the detection of subtle ventricular impairment. We aimed to evaluate diastolic function in asymptomatic patients with severe AS.
Methods
In this cross-sectional study, patients with asymptomatic, severe AS were evaluated with right heart catheterization at rest and during moderate exercise. The patients also underwent cardiopulmonary exercise testing to objectify functional capacity and confirm the absence of symptoms.
Results
Between February 2019 and May 2021, we included 50 patients aged 70±12 years. The patients had severe AS with peak velocity 4.4±0.4 m/s, mean gradient 46±9 mm Hg, and an indexed valve area of 0.47±0.08 cm2 at rest. All patients were asymptomatic and had normal left ventricular ejection fraction. Five patients had postcapillary pulmonary hypertension at rest. During exercise, 44 patients (88%) had an increase in the mean pulmonary artery pressure per increase in cardiac output of >3 mm Hg/L per minute, of whom 93% had a concomitant increase in the pulmonary artery wedge pressure per increase in cardiac output >2 mm Hg/L per minute, suggesting exercise-induced pulmonary hypertension due to left heart disease. Female gender and increasing age were associated with a higher increase in the pulmonary artery wedge pressure per increase in cardiac output ratio. The catheterization was well tolerated, and there were no adverse events.
Conclusions
A large proportion of asymptomatic patients with severe, degenerative AS have exercise-induced postcapillary pulmonary hypertension.



Circ Heart Fail: 08 Feb 2022:CIRCHEARTFAILURE121009253; epub ahead of print
Kvaslerud AB, Gude E, Eriksen G, Andreassen AK, Gullestad L, Broch K
Circ Heart Fail: 08 Feb 2022:CIRCHEARTFAILURE121009253; epub ahead of print | PMID: 35137599
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Impact:
Abstract

Association of Pulmonary Artery Pulsatility Index With Adverse Cardiovascular Events Across a Hospital-Based Sample.

Zern EK, Wang D, Rambarat P, Bernard S, ... Picard MH, Ho JE
Background
The pulmonary artery pulsatility index (PAPi), calculated from the ratio of the pulmonary artery pulse pressure to right atrial pressure, is a predictor of right ventricular failure after inferior myocardial infarction and left ventricular assist device implantation. Whether PAPi is associated with adverse outcomes across a heterogeneous population is unknown.
Methods
We examined consecutive patients undergoing right heart catheterization between 2005 and 2016 in a hospital-based cohort. Multivariable Cox models were utilized to examine the association between PAPi and all-cause mortality, major adverse cardiac events, and heart failure hospitalizations.
Results
We studied 8285 individuals (mean age 63 years, 39% women) with median PAPi across quartiles 1.7, 2.8, 4.2, and 8.7, who were followed over a mean follow-up of 6.7±3.3 years. Patients in the lowest PAPi quartile had a 60% greater risk of death compared with the highest quartile (multivariable-adjusted hazard ratio, 1.60 [95% CI, 1.36-1.88], P<0.001) and a higher risk of major adverse cardiac events and heart failure hospitalizations (hazard ratio, 1.80 [95% CI, 1.56-2.07], P<0.001 and hazard ratio, 2.08 [95% CI, 1.76-2.47], P<0.001, respectively). Of note, patients in quartiles 2 and 3 also had increased risk of cardiovascular events compared with quartile 4 (multivariable P<0.05 for all).
Conclusions
Compared with the highest PAPi quartile, patients in PAPi quartiles 1 to 3 had a greater risk of all-cause mortality, major adverse cardiac events, and heart failure hospitalizations, with greatest risk observed in the lowest quartile. A low PAPi, even at values higher than previously reported, may serve an important role in identifying high-risk individuals across a broad spectrum of cardiovascular disease.



Circ Heart Fail: 08 Feb 2022:CIRCHEARTFAILURE121009085; epub ahead of print
Zern EK, Wang D, Rambarat P, Bernard S, ... Picard MH, Ho JE
Circ Heart Fail: 08 Feb 2022:CIRCHEARTFAILURE121009085; epub ahead of print | PMID: 35135302
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Impact:
Abstract

Impact of Pretransplant Malignancy on Heart Transplantation Outcomes: Contemporary United Network for Organ Sharing Analysis Amidst Evolving Cancer Therapies.

Batra J, DeFilippis EM, Golob S, Clerkin K, ... Raikelkar J, Uriel N
Background
An aging population and improved cancer survivorship have increased the number of individuals with treated malignancy who develop advanced heart failure. The benefits of heart transplantation (HT) in patients with a pretransplant malignancy (PTM) must be balanced against risks of posttransplant malignancy in the setting of immunosuppression.
Methods
Adult patients in the United Network for Organ Sharing registry who received HT between January 1, 2010, and December 31, 2020 were included. Trends, patient characteristics, and posttransplant outcomes in HT recipients with PTM were evaluated.
Results
From 2000 to 2020, the proportion of HT recipients with PTM increased from 3.2% to 8.2%. From 2010 to 2020, 2113 (7.7%) of 27 344 HT recipients had PTM. PTM was associated with higher rates of 1-year mortality after HT (11.9% versus 9.2%; adjusted hazard ratio, 1.25 [95% CI, 1.09-1.44], P=0.001), driven by increased mortality in patients with hematologic PTM (adjusted hazard ratio, 2.00 [95% CI, 1.61-2.48]; P<0.001). For recipients who survived the first year, 5-year survival was similar between patients with and without PTM. Rates of malignancy at 5-years posttransplant were higher in the PTM group (20.4% versus 13.1%; adjusted hazard ratio, 1.57 [95% CI, 1.38-1.79], P<0.001).
Conclusions
Prevalence of PTM in HT recipients nearly tripled over the past 2 decades. Patients with hematologic PTM were at increased risk of early mortality after HT. Patients with PTM were also at higher risk for posttransplant malignancy. Guidelines that reflect contemporary oncological care are needed to inform care of this heterogenous and expanding group of individuals.



Circ Heart Fail: 30 Jan 2022:CIRCHEARTFAILURE121008968; epub ahead of print
Batra J, DeFilippis EM, Golob S, Clerkin K, ... Raikelkar J, Uriel N
Circ Heart Fail: 30 Jan 2022:CIRCHEARTFAILURE121008968; epub ahead of print | PMID: 35094567
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Impact:
Abstract

Trends in Characteristics and Outcomes in Primary Heart Failure Hospitalizations Among Older Population in the United States, 2004-2018.

Minhas AMK, Ijaz SH, Jamal S, Dani SS, ... Nasir K, Khan SU
Background
Heart failure (HF) accounts for a significant proportion of morbidity, mortality, and health care costs among older adults in the United States. We evaluated trends in clinical outcomes and the economic burden of HF hospitalizations in older patients (≥80 years).
Methods
This analysis included data from the National Inpatient Sample between January 2004 and December 2018. We examined the trends of clinical characteristics, inpatient mortality, and health care cost utilization in older US adults for HF hospitalizations.
Results
We identified 6 034 951 weighted HF hospitalizations for older adults (3527 per 100 000 person-years). After an initial decline in HF hospitalizations per 100 000 older US older adults from 4211 in 2004 to 3089 in 2014, there was increase to 3388 in 2018 (P trend <0.001 for both). There was an overall increase in cardiometabolic and chronic comorbidities during the study period. Overall, inpatient mortality was 4.7%; the adjusted inpatient mortality decreased from 6.1% in 2004 to 3.6% in 2018 (P trend <0.001). There was a decrease in adjusted mean length of stay (from 6.0 days in 2004 to 4.7 days in 2018) and adjusted inflation-adjusted care costs (from $11 865 in 2004 to $9677 in 2018) during the study period (P trend <0.001 for both). In comparison with younger adults (<80 years), older adults had higher inpatient mortality (4.7% versus 2.2%) but lower inflation-adjusted care costs ($10 587 versus $14 088).
Conclusions
This 15-year national data suggests that despite a higher comorbidity burden and the recent increase in hospitalizations for HF in older patients, there has been an encouraging trend towards lower inpatient mortality, health care cost, and hospital length of stay among older adults in the United States.



Circ Heart Fail: 25 Jan 2022:CIRCHEARTFAILURE121008943; epub ahead of print
Minhas AMK, Ijaz SH, Jamal S, Dani SS, ... Nasir K, Khan SU
Circ Heart Fail: 25 Jan 2022:CIRCHEARTFAILURE121008943; epub ahead of print | PMID: 35078346
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Impact:
Abstract

Insights Into Myocardial Oxygenation and Cardiovascular Magnetic Resonance Tissue Biomarkers in Heart Failure With Preserved Ejection Fraction.

Fischer K, Guensch DP, Jung B, King I, ... Eberle B, Friedrich MG
Background
The pathophysiology of heart failure with preserved ejection fraction is not well understood, but evidence strongly suggests involvement of microvascular dysfunction. We studied the myocardial oxygenation reserve as a direct marker of coronary vascular function and its relation to myocardial deformation and tissue characteristics by cardiovascular magnetic resonance (CMR).
Methods
In a dual-center case-control study, patients with heart failure and preserved ejection fraction (>50%) and healthy controls older than 50 years underwent quantitative CMR for ventricular volumes and functional assessment with feature tracking, as well as tissue characterization (T1, T2, extracellular volume). Coronary vascular function was measured by oxygenation-sensitive (OS)-CMR of the myocardial oxygenation response to a vasoactive breathing maneuver.
Results
Twenty-nine patients completed the CMR exam. Compared with cutoffs derived from 12 control subjects, circumferential peak strain was attenuated in 97% of patients. Native T1 was elevated in 93%, extracellular volume was elevated in 83%. Sixty-six percent of patients revealed either regional or global myocardial edema, defined by an increased myocardial T2. An attenuated global myocardial oxygenation reserve (<4.4%) was observed in 96% of the patients (1.7±3.9% versus 9.1±5.3% in controls, P<0.001). This was correlated with septal wall thickness (r=-0.54, P=0.003), edema (myocardial T2; β=-0.26% oxygenation-sensitive/ms [95% CI, -0.49 to -0.03], P=0.029), and reduced diastolic strain rate (β=1.50% oxygenation-sensitive/s-1 [95% CI, 0.06-2.90], P=0.042).
Conclusions
In patients with clinical heart failure with preserved ejection fraction, vascular dysfunction as measured by an attenuated myocardial oxygenation reserve is associated with myocardial edema, a thicker septum, and diastolic dysfunction. A quantitative comprehensive CMR exam including oxygenation-sensitive-CMR allows for comprehensive imaging-based phenotyping of heart failure with preserved ejection fraction.



Circ Heart Fail: 17 Jan 2022:CIRCHEARTFAILURE121008903; epub ahead of print
Fischer K, Guensch DP, Jung B, King I, ... Eberle B, Friedrich MG
Circ Heart Fail: 17 Jan 2022:CIRCHEARTFAILURE121008903; epub ahead of print | PMID: 35038887
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Impact:
Abstract

Ratio of Mixed Venous Oxygen Saturation-to-Pulmonary Capillary Wedge Pressure: Insights From the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program.

Hillerson D, Charnigo R, Moon Kim S, Iyengar A, ... Gurley JC, Booth DC
Background
Hemodynamic values from right heart catheterization aid diagnosis and clinical decision-making but may not predict outcomes. Mixed venous oxygen saturation percentage and pulmonary capillary wedge pressure relate to cardiac output and congestion, respectively. We theorized that a novel, simple ratio of these measurements could estimate cardiovascular prognosis.
Methods
We queried Veterans Affairs\' databases for clinical, hemodynamic, and outcome data. Using the index right heart catheterization between 2010 and 2016, we calculated the ratio of mixed venous oxygen saturation-to-pulmonary capillary wedge pressure, termed ratio of saturation-to-wedge (RSW). The primary outcome was time to all-cause mortality; secondary outcome was 1-year urgent heart failure presentation. Patients were stratified into quartiles of RSW, Fick cardiac index (CI), thermodilution CI, and pulmonary capillary wedge pressure alone. Kaplan-Meier curves and Cox proportional hazards models related comparators with outcomes.
Results
Of 12 019 patients meeting inclusion criteria, 9826 had values to calculate RSW (median 4.00, interquartile range, 2.67-6.05). Kaplan-Meier curves showed early, sustained separation by RSW strata. Cox modeling estimated that increasing RSW by 50% decreases mortality hazard by 19% (estimated hazard ratio, 0.81 [95% CI, 0.79-0.83], P<0.001) and secondary outcome hazard by 28% (hazard ratio, 0.72 [95% CI, 0.70-0.74], P<0.001). Among the 3793 patients with data for all comparators, Cox models showed RSW best associated with outcomes (by both C statistics and Bayes factors). Furthermore, pulmonary capillary wedge pressure was superior to thermodilution CI and Fick CI. Multivariable adjustment attenuated without eliminating the association of RSW with outcomes.
Conclusions
In a large national database, RSW was superior to conventional right heart catheterization indices at assessing risk of mortality and urgent heart failure presentation. This simple calculation with routine data may contribute to clinical decision-making in this population.



Circ Heart Fail: 13 Jan 2022:CIRCHEARTFAILURE121008838; epub ahead of print
Hillerson D, Charnigo R, Moon Kim S, Iyengar A, ... Gurley JC, Booth DC
Circ Heart Fail: 13 Jan 2022:CIRCHEARTFAILURE121008838; epub ahead of print | PMID: 35026961
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Impact:
Abstract

Intermittent Occlusion of the Superior Vena Cava to Improve Hemodynamics in Patients With Acutely Decompensated Heart Failure: The VENUS-HF Early Feasibility Study.

Kapur NK, Kiernan MS, Gorgoshvili I, Yousefzai R, ... Burkhoff D, Karas RH
Background
Reducing congestion remains a primary target of therapy for acutely decompensated heart failure. The VENUS-HF EFS (VENUS-Heart Failure Early Feasibility Study) is the first clinical trial testing intermittent occlusion of the superior vena cava with the preCARDIA system, a catheter mounted balloon and pump console, to improve decongestion in acutely decompensated heart failure.
Methods
In a multicenter, prospective, single-arm exploratory safety and feasibility trial, 30 patients with acutely decompensated heart failure were assigned to preCARDIA therapy for 12 or 24 hours. The primary safety outcome was a composite of major adverse cardiovascular and cerebrovascular events through 30 days. Secondary end points included technical success defined as successful preCARDIA placement, treatment, and removal and reduction in right atrial and pulmonary capillary wedge pressure. Other efficacy measures included urine output and patient-reported symptoms.
Results
Thirty patients were enrolled and assigned to receive the preCARDIA system. Freedom from device- or procedure-related major adverse events was observed in 100% (n=30/30) of patients. The system was successfully placed, activated and removed after 12 (n=6) or 24 hours (n=23) in 97% (n=29/30) of patients. Compared with baseline values, right atrial pressure decreased by 34% (17±4 versus 11±5 mm Hg, P<0.001) and pulmonary capillary wedge pressure decreased by 27% (31±8 versus 22±9 mm Hg, P<0.001). Compared with pretreatment values, urine output and net fluid balance increased by 130% and 156%, respectively, with up to 24 hours of treatment (P<0.01).
Conclusions
We report the first-in-human experience of intermittent superior vena cava occlusion using the preCARDIA system to reduce congestion in acutely decompensated heart failure. PreCARDIA treatment for up to 24 hours was well tolerated without device- or procedure-related serious or major adverse events and associated with reduced filling pressures and increased urine output. These results support future studies characterizing the clinical utility of the preCARDIA system.
Registration
URL: https://www.clinicaltrials.gov; Unique identifier: NCT03836079.



Circ Heart Fail: 09 Jan 2022:CIRCHEARTFAILURE121008934; epub ahead of print
Kapur NK, Kiernan MS, Gorgoshvili I, Yousefzai R, ... Burkhoff D, Karas RH
Circ Heart Fail: 09 Jan 2022:CIRCHEARTFAILURE121008934; epub ahead of print | PMID: 35000420
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Impact:
Abstract

MiR-150 Attenuates Maladaptive Cardiac Remodeling Mediated by Long Noncoding RNA MIAT and Directly Represses Profibrotic .

Aonuma T, Moukette B, Kawaguchi S, Barupala NP, ... Nakagawa S, Kim IM
Background
MicroRNA-150 (miR-150) plays a protective role in heart failure (HF). Long noncoding RNA, myocardial infarction-associated transcript (MIAT) regulates miR-150 function in vitro by direct interaction. Concurrent with miR-150 downregulation, MIAT is upregulated in failing hearts, and gain-of-function single-nucleotide polymorphisms in MIAT are associated with increased risk of myocardial infarction (MI) in humans. Despite the correlative relationship between MIAT and miR-150 in HF, their in vivo functional relationship has never been established, and molecular mechanisms by which these 2 noncoding RNAs regulate cardiac protection remain elusive.
Methods
We use MIAT KO (knockout), Hoxa4 (homeobox a4) KO, MIAT TG (transgenic), and miR-150 TG mice. We also develop DTG (double TG) mice overexpressing MIAT and miR-150. We then use a mouse model of MI followed by cardiac functional, structural, and mechanistic studies by echocardiography, immunohistochemistry, transcriptome profiling, Western blotting, and quantitative real-time reverse transcription-polymerase chain reaction. Moreover, we perform expression analyses in hearts from patients with HF. Lastly, we investigate cardiac fibroblast activation using primary adult human cardiac fibroblasts and in vitro assays to define the conserved MIAT/miR-150/HOXA4 axis.
Results
Using novel mouse models, we demonstrate that genetic overexpression of MIAT worsens cardiac remodeling, while genetic deletion of MIAT protects hearts against MI. Importantly, miR-150 overexpression attenuates the detrimental post-MI effects caused by MIAT. Genome-wide transcriptomic analysis of MIAT null mouse hearts identifies Hoxa4 as a novel downstream target of the MIAT/miR-150 axis. Hoxa4 is upregulated in cardiac fibroblasts isolated from ischemic myocardium and subjected to hypoxia/reoxygenation. HOXA4 is also upregulated in patients with HF. Moreover, Hoxa4 deficiency in mice protects the heart from MI. Lastly, protective actions of cardiac fibroblast miR-150 are partially attributed to the direct and functional repression of profibrotic Hoxa4.
Conclusions
Our findings delineate a pivotal functional interaction among MIAT, miR-150, and Hoxa4 as a novel regulatory mechanism pertinent to ischemic HF.



Circ Heart Fail: 09 Jan 2022:CIRCHEARTFAILURE121008686; epub ahead of print
Aonuma T, Moukette B, Kawaguchi S, Barupala NP, ... Nakagawa S, Kim IM
Circ Heart Fail: 09 Jan 2022:CIRCHEARTFAILURE121008686; epub ahead of print | PMID: 35000421
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Impact:
Abstract

Heart Failure Spending Function: An Investment Framework for Sequencing and Intensification of Guideline-Directed Medical Therapies.

Allen LA, Teerlink JR, Gottlieb SS, Ahmad T, Lam CSP, Psotka MA
Heart failure with reduced ejection fraction is managed with increasing numbers of guideline-directed medical therapies (GDMT). Benefits tend to be additive. Burdens can also be additive. We propose a heart failure spending function as a conceptual framework for tailored intensification of GDMT that maximizes therapeutic opportunity while limiting adverse events and patient burden. Each patient is conceptualized to have reserve in physiological and psychosocial domains, which can be spent for a future return on investment. Key domains are blood pressure, heart rate, serum creatinine, potassium, and out-of-pocket costs. For each patient, GDMT should be initiated and intensified in a sequence that prioritizes medications with the greatest expected cardiac benefit while drawing on areas where the patient has ample reserves. When reserve is underspent, patients fail to gain the full benefit of GDMT. Conversely, when a reserve is fully spent, addition of new drugs or higher doses that draw upon a domain will lead to patient harm. The benefit of multiple agents drawing upon varied physiological domains should be balanced against cost and complexity. Thresholds for overspending are explored, as are mechanisms for implementing these concepts into routine care, but further health care delivery research is needed to validate and refine clinical use of the spending function. The heart failure spending function also suggests how newer therapies may be considered in terms of relative value, prioritizing agents that draw on different spending domains from existing GDMT.



Circ Heart Fail: 09 Jan 2022:CIRCHEARTFAILURE121008594; epub ahead of print
Allen LA, Teerlink JR, Gottlieb SS, Ahmad T, Lam CSP, Psotka MA
Circ Heart Fail: 09 Jan 2022:CIRCHEARTFAILURE121008594; epub ahead of print | PMID: 35000432
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Impact:
Abstract

Quantifying Benefit-Risk Preferences for Heart Failure Devices: A Stated-Preference Study.

Reed SD, Yang JC, Rickert T, Johnson FR, ... Tarver ME, Bruhn-Ding D
Background
Regulatory and clinical decisions involving health technologies require judgements about relative importance of their expected benefits and risks. We sought to quantify heart-failure patients\' acceptance of therapeutic risks in exchange for improved effectiveness with implantable devices.
Methods
Individuals with heart failure recruited from a national web panel or academic medical center completed a web-based discrete-choice experiment survey in which they were randomized to one of 40 blocks of 8 experimentally controlled choice questions comprised of 2 device scenarios and a no-device scenario. Device scenarios offered an additional year of physical functioning equivalent to New York Heart Association class III or a year with improved (ie, class II) symptoms, or both, with 30-day mortality risks ranging from 0% to 15%, in-hospital complication risks ranging from 0% to 40%, and a remote adjustment device feature. Logit-based regression models fit participants\' choices as a function of health outcomes, risks and remote adjustment.
Results
Latent-class analysis of 613 participants (mean age, 65; 49% female) revealed that two-thirds were best represented by a pro-device, more risk-tolerant class, accepting up to 9% (95% CI, 7%-11%) absolute risk of device-associated mortality for a one-year gain in improved functioning (New York Heart Association class II). Approximately 20% were best represented by a less risk-tolerant class, accepting a maximum device-associated mortality risk of 3% (95% CI, 1%-4%) for the same benefit. The remaining class had strong antidevice preferences, thus maximum-acceptable risk was not calculated.
Conclusions
Quantitative evidence on benefit-risk tradeoffs for implantable heart-failure device profiles may facilitate incorporating patients\' views during product development, regulatory decision-making, and clinical practice.



Circ Heart Fail: 30 Dec 2021; 15:e008797
Reed SD, Yang JC, Rickert T, Johnson FR, ... Tarver ME, Bruhn-Ding D
Circ Heart Fail: 30 Dec 2021; 15:e008797 | PMID: 34937393
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Impact:
Abstract

Inflammatory Glycoprotein 130 Signaling Links Changes in Microtubules and Junctophilin-2 to Altered Mitochondrial Metabolism and Right Ventricular Contractility.

Prisco SZ, Hartweck LM, Rose L, Lima PDA, ... Archer SL, Prins KW
Background
Right ventricular dysfunction (RVD) is the leading cause of death in pulmonary arterial hypertension (PAH), but no RV-specific therapy exists. We showed microtubule-mediated junctophilin-2 dysregulation (MT-JPH2 pathway) causes t-tubule disruption and RVD in rodent PAH, but the druggable regulators of this critical pathway are unknown. GP130 (glycoprotein 130) activation induces cardiomyocyte microtubule remodeling in vitro; however, the effects of GP130 signaling on the MT-JPH2 pathway and RVD resulting from PAH are undefined.
Methods
Immunoblots quantified protein abundance, quantitative proteomics defined RV microtubule-interacting proteins (MT-interactome), metabolomics evaluated the RV metabolic signature, and transmission electron microscopy assessed RV cardiomyocyte mitochondrial morphology in control, monocrotaline, and monocrotaline-SC-144 (GP130 antagonist) rats. Echocardiography and pressure-volume loops defined the effects of SC-144 on RV-pulmonary artery coupling in monocrotaline rats (8-16 rats per group). In 73 patients with PAH, the relationship between interleukin-6, a GP130 ligand, and RVD was evaluated.
Results
SC-144 decreased GP130 activation, which normalized MT-JPH2 protein expression and t-tubule structure in the monocrotaline RV. Proteomics analysis revealed SC-144 restored RV MT-interactome regulation. Ingenuity pathway analysis of dysregulated MT-interacting proteins identified a link between microtubules and mitochondrial function. Specifically, SC-144 prevented dysregulation of electron transport chain, Krebs cycle, and the fatty acid oxidation pathway proteins. Metabolomics profiling suggested SC-144 reduced glycolytic dependence, glutaminolysis induction, and enhanced fatty acid metabolism. Transmission electron microscopy and immunoblots indicated increased mitochondrial fission in the monocrotaline RV, which SC-144 mitigated. GP130 antagonism reduced RV hypertrophy and fibrosis and augmented RV-pulmonary artery coupling without altering PAH severity. In patients with PAH, higher interleukin-6 levels were associated with more severe RVD (RV fractional area change 23±12% versus 30±10%, P=0.002).
Conclusions
GP130 antagonism reduces MT-JPH2 dysregulation, corrects metabolic derangements in the RV, and improves RVD in monocrotaline rats.



Circ Heart Fail: 30 Dec 2021; 15:e008574
Prisco SZ, Hartweck LM, Rose L, Lima PDA, ... Archer SL, Prins KW
Circ Heart Fail: 30 Dec 2021; 15:e008574 | PMID: 34923829
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Impact:
Abstract

Long-Term Survival With Tafamidis in Patients With Transthyretin Amyloid Cardiomyopathy.

Elliott P, Drachman BM, Gottlieb SS, Hoffman JE, ... Sultan MB, Shah SJ
Background
Tafamidis is approved in many countries for the treatment of transthyretin amyloid cardiomyopathy. This study reports data on the long-term efficacy of tafamidis from an ongoing long-term extension (LTE) to the pivotal ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial).
Methods
Patients with transthyretin amyloid cardiomyopathy who completed ATTR-ACT could enroll in an LTE, continuing with the same tafamidis dose or, if previously treated with placebo, randomized (2:1) to tafamidis meglumine 80 or 20 mg. All patients in the LTE transitioned to tafamidis free acid 61 mg (bioequivalent to tafamidis meglumine 80 mg) following a protocol amendment. In this interim analysis, all-cause mortality was assessed in patients treated with tafamidis meglumine 80 mg in ATTR-ACT continuing in the LTE, compared with those receiving placebo in ATTR-ACT transitioning to tafamidis in the LTE.
Results
Median follow-up was 58.5 months in the continuous tafamidis group (n=176) and 57.1 months in the placebo to tafamidis group (n=177). There were 79 (44.9%) deaths with continuous tafamidis and 111 (62.7%) with placebo to tafamidis (hazard ratio, 0.59 [95% CI, 0.44-0.79]; P<0.001). Mortality was also reduced in the continuous tafamidis (versus placebo to tafamidis) subgroups of: variant transthyretin amyloidosis (0.57 [0.33-0.99]; P=0.05) and wild-type transthyretin amyloidosis (0.61 [0.43-0.87]; P=0.006); and baseline New York Heart Association class I and II (0.56 [0.38-0.82]; P=0.003) and class III (0.65 [0.41-1.01]; P=0.06).
Conclusions
In the LTE, patients initially treated with tafamidis in ATTR-ACT had substantially better survival than those first treated with placebo, highlighting the importance of early diagnosis and treatment in transthyretin amyloid cardiomyopathy. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01994889 and NCT02791230.



Circ Heart Fail: 30 Dec 2021; 15:e008193
Elliott P, Drachman BM, Gottlieb SS, Hoffman JE, ... Sultan MB, Shah SJ
Circ Heart Fail: 30 Dec 2021; 15:e008193 | PMID: 34923848
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Impact:
Abstract

Invasive Right Ventricular Pressure-Volume Analysis: Basic Principles, Clinical Applications, and Practical Recommendations.

Brener MI, Masoumi A, Ng VG, Tello K, ... Uriel N, Burkhoff D
Right ventricular pressure-volume (PV) analysis characterizes ventricular systolic and diastolic properties independent of loading conditions like volume status and afterload. While long-considered the gold-standard method for quantifying myocardial chamber performance, it was traditionally only performed in highly specialized research settings. With recent advances in catheter technology and more sophisticated approaches to analyze PV data, it is now more commonly used in a variety of clinical and research settings. Herein, we review the basic techniques for PV loop measurement, analysis, and interpretation with the aim of providing readers with a deeper understanding of the strengths and limitations of PV analysis. In the second half of the review, we detail key scenarios in which right ventricular PV analysis has influenced our understanding of clinically relevant topics and where the technique can be applied to resolve additional areas of uncertainty. All told, PV analysis has an important role in advancing our understanding of right ventricular physiology and its contribution to cardiovascular function in health and disease.



Circ Heart Fail: 30 Dec 2021; 15:e009101
Brener MI, Masoumi A, Ng VG, Tello K, ... Uriel N, Burkhoff D
Circ Heart Fail: 30 Dec 2021; 15:e009101 | PMID: 34963308
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Impact:
Abstract

Social Determinants of Health and 30-Day Readmissions Among Adults Hospitalized for Heart Failure in the REGARDS Study.

Sterling MR, Ringel JB, Pinheiro LC, Safford MM, ... Nguyen OK, Goyal P
Background
It is not known which social determinants of health (SDOH) impact 30-day readmission after a heart failure (HF) hospitalization among older adults. We examined the association of 9 individual SDOH with 30-day readmission after an HF hospitalization.
Methods and results
Using the REGARDS study (Reasons for Geographic and Racial Differences in Stroke), we included Medicare beneficiaries who were discharged alive after an HF hospitalization between 2003 and 2014. We assessed 9 SDOH based on the Healthy People 2030 Framework: race, education, income, social isolation, social network, residential poverty, Health Professional Shortage Area, rural residence, and state public health infrastructure. The primary outcome was 30-day all-cause readmission. For each SDOH, we calculated incidence per 1000 person-years and multivariable-adjusted hazard ratios of readmission. Among 690 participants, the median age was 76 years at hospitalization (interquartile range, 71-82), 44.3% were women, 35.5% were Black, 23.5% had low educational attainment, 63.0% had low income, 21.0% had zip code-level poverty, 43.5% resided in Health Professional Shortage Areas, 39.3% lived in states with poor public health infrastructure, 13.1% were socially isolated, 13.3% had poor social networks, and 10.2% lived in rural areas. The 30-day readmission rate was 22.4%. In an unadjusted analysis, only Health Professional Shortage Area was significantly associated with 30-day readmission; in a fully adjusted analysis, none of the 9 SDOH were individually associated with 30-day readmission.
Conclusions
In this modestly sized national cohort, although prevalent, none of the SDOH were associated with 30-day readmission after an HF hospitalization. Policies or interventions that only target individual SDOH to reduce readmissions after HF hospitalizations may not be sufficient to prevent readmission among older adults.



Circ Heart Fail: 30 Dec 2021; 15:e008409
Sterling MR, Ringel JB, Pinheiro LC, Safford MM, ... Nguyen OK, Goyal P
Circ Heart Fail: 30 Dec 2021; 15:e008409 | PMID: 34865525
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Impact:
Abstract

Detection of Left Atrial Myopathy Using Artificial Intelligence-Enabled Electrocardiography.

Verbrugge FH, Reddy YNV, Attia ZI, Friedman PA, ... Kapa S, Borlaug BA
Background
Left atrial (LA) myopathy is common in patients with heart failure and preserved ejection fraction and leads to the development of atrial fibrillation (AF). We investigated whether the likelihood of LA remodeling, LA dysfunction, altered hemodynamics, and risk for incident AF could be identified from a single 12-lead ECG using a novel artificial intelligence (AI)-enabled ECG analysis.
Methods
Patients with heart failure and preserved ejection fraction (n=613) underwent AI-enabled ECG analysis, echocardiography, and cardiac catheterization. Individuals were grouped by AI-enabled ECG probability of contemporaneous AF, taken as an indicator of underlying LA myopathy.
Results
Structural heart disease was more severe in patients with higher AI-probability of AF, with more left ventricular hypertrophy, larger LA volumes, and lower LA reservoir and booster strain. Cardiac filling pressures and pulmonary artery pressures were higher in patients with higher AI-probability, while cardiac output reserve was more impaired during exercise. Among patients with sinus rhythm and no prior AF, each 10% increase in AI-probability was associated with a 31% greater risk of developing new-onset AF (hazard ratio, 1.31 [95% CI, 1.20-1.42]; P<0.001). In the population as a whole, each 10% increase in AI-probability was associated with a 12% greater risk of death (hazard ratio, 1.12 [95% CI, 1.08-1.17]; P<0.001) during long-term follow-up, which was no longer significant after adjustments for baseline characteristics.
Conclusions
A novel AI-enabled score derived from a single 12-lead ECG identifies the presence of underlying LA myopathy in patients with heart failure and preserved ejection fraction as evidenced by structural, functional, and hemodynamic abnormalities, as well as long-term risk for incident AF. Further research is required to determine the role of the AI-enabled ECG in the evaluation and care of patients with heart failure and preserved ejection fraction.



Circ Heart Fail: 30 Dec 2021; 15:e008176
Verbrugge FH, Reddy YNV, Attia ZI, Friedman PA, ... Kapa S, Borlaug BA
Circ Heart Fail: 30 Dec 2021; 15:e008176 | PMID: 34911362
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Impact:
Abstract

Use of Extracorporeal Membrane Oxygenation as Bridge to Replacement Therapies in Cardiogenic Shock: Insights From the Extracorporeal Life Support Organization.

Mastoris I, Tonna JE, Hu J, Sauer AJ, ... Fang JC, Shah Z
Background
There has been increasing use of extracorporeal membrane oxygenation (ECMO) as bridge to heart transplant (orthotopic heart transplant [OHT]) or left ventricular assist device (LVAD) over the last decade. We aimed to provide insights on the population, outcomes, and predictors for the selection of each therapy.
Methods
Using the Extracorporeal Life Support Organization Registry between 2010 and 2019, we compared in-hospital mortality and length of stay, predictors of OHT versus LVAD, and predictors of in-hospital mortality for patients with cardiogenic shock that were bridged with ECMO to OHT or LVAD. One hundred sixty-seven patients underwent LVAD versus 234 patients who underwent OHT.
Results
The overall use of ECMO has increased from 1.7% in 2010 to 22.2% in 2019. Mortality was similar between groups (LVAD: 28.7% versus OHT: 29.1%) while length of stay was longer for OHT (LVAD: 49.6 versus OHT: 59.5 days, P=0.05). Factors associated with OHT included prior transplant (odds ratio [OR]=31.26 [CI, 3.84-780.5]), use of a temporary pacemaker (OR=6.5 [CI, 1.39-50.15]), and increased use of inotropes on ECMO (OR=3.77 [CI, 1.39-11.07]), whereas LVAD use was associated with weight (OR=0.98 [CI, 0.97-0.99]), cardiogenic shock presentation (OR=0.40 [CI, 0.21-0.78]), previous LVAD (OR=0.01 [CI, 0.0001-0.22]), respiratory failure (OR=0.28 [CI, 0.11-0.70]), and milrinone infusion (OR=0.32 [CI, 0.15-0.67]). Older age (OR=1.07 [CI, 1.02-1.12]), cannulation bleeding (OR=26.1 [CI, 4.32-221.3]), and surgical bleeding (OR=6.7 [CI, 1.26-39.9]) in patients receiving LVAD and respiratory failure (OR=5 [CI, 1.17-23.1]) and continuous renal replacement therapy (OR=3.82 [CI, 1.28-11.9]) in patients receiving OHT were associated with increased mortality.
Conclusions
ECMO use as a bridge to advanced therapies has increased over time, with more patients undergoing LVAD than OHT. Mortality was equal between the 2 groups while length of stay was longer for OHT.



Circ Heart Fail: 30 Dec 2021; 15:e008777
Mastoris I, Tonna JE, Hu J, Sauer AJ, ... Fang JC, Shah Z
Circ Heart Fail: 30 Dec 2021; 15:e008777 | PMID: 34879706
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Impact:
Abstract

Machine Learning-Based Prediction of Myocardial Recovery in Patients With Left Ventricular Assist Device Support.

Topkara VK, Elias P, Jain R, Sayer G, Burkhoff D, Uriel N
Background
Prospective studies demonstrate that aggressive pharmacological therapy combined with pump speed optimization may result in myocardial recovery in larger numbers of patients supported with left ventricular assist device (LVAD). This study sought to determine whether the use of machine learning (ML) based models predict LVAD patients with myocardial recovery resulting in pump explant.
Methods
A total of 20 270 adult patients with a durable continuous-flow LVAD in the INTERMACS registry (Interagency Registry for Mechanically Assisted Circulatory Support) were included in the study. Ninety-eight raw clinical variables were screened using the least absolute shrinkage and selection operator for selection of features associated with LVAD-induced myocardial recovery. ML models were developed in the training data set (70%) and were assessed in the validation data set (30%) by receiver operating curve and Kaplan-Meier analysis.
Results
Least absolute shrinkage and selection operator identified 28 unique clinical features associated with LVAD-induced myocardial recovery, including age, cause of heart failure, psychosocial risk factors, laboratory values, cardiac rate and rhythm, and echocardiographic indices. ML models achieved area under the receiver operating curve of 0.813 to 0.824 in the validation data set outperforming logistic regression-based new INTERMACS recovery risk score (area under the receiver operating curve of 0.796) and previously established LVAD recovery risk scores (INTERMACS Cardiac Recovery Score and INTERMACS Recovery Score by Topkara et al) with area under the receiver operating curve of 0.744 and 0.748 (P<0.05). Patients who were predicted to recover by ML models demonstrated a significantly higher incidence of myocardial recovery resulting in LVAD explant in the validation cohort compared with those who were not predicted to recover (18.8% versus 2.6% at 4 years of pump support).
Conclusions
ML can be a valuable tool to identify subsets of LVAD patients who may be more likely to respond to myocardial recovery protocols.



Circ Heart Fail: 30 Dec 2021; 15:e008711
Topkara VK, Elias P, Jain R, Sayer G, Burkhoff D, Uriel N
Circ Heart Fail: 30 Dec 2021; 15:e008711 | PMID: 34949101
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Impact:
Abstract

Right Ventricular and Right Atrial Function Are Less Compromised in Pulmonary Hypertension Secondary to Heart Failure With Preserved Ejection Fraction: A Comparison With Pulmonary Arterial Hypertension With Similar Pressure Overload.

van Wezenbeek J, Kianzad A, van de Bovenkamp A, Wessels J, ... Handoko ML, de Man FS
Background
Heart failure with preserved ejection fraction (HFpEF) is a prevalent disorder for which no effective treatment yet exists. Pulmonary hypertension (PH) and right atrial (RA) and ventricular (RV) dysfunction are frequently observed. The question remains whether the PH with the associated RV/RA dysfunction in HFpEF are markers of disease severity.
Methods
To obtain insight in the relative importance of pressure-overload and left-to-right interaction, we compared RA and RV function in 3 groups: 1. HFpEF (n=13); 2. HFpEF-PH (n=33), and; 3. pulmonary arterial hypertension (PAH) matched to pulmonary artery pressures of HFpEF-PH (PH limited to mPAP ≥30 and ≤50 mmHg) (n=47). Patients underwent right heart catheterization and cardiac magnetic resonance imaging.
Results
The right ventricle in HFpEF-PH was less dilated and hypertrophied than in PAH. In addition, RV ejection fraction was more preserved (HFpEF-PH: 52±11 versus PAH: 36±12%). RV filling patterns differed: vena cava backflow during RA contraction was observed in PAH only. In HFpEF-PH, RA pressure was elevated throughout the cardiac cycle (HFpEF-PH: 10 [8-14] versus PAH: 7 [5-10] mm Hg), while RA volume was smaller, reflecting excessive RA stiffness (HFpEF-PH: 0.14 [0.10-0.17] versus PAH: 0.08 [0.06-0.11] mm Hg/mL). RA stiffness was associated with an increased eccentricity index (HFpEF-PH: 1.3±0.2 versus PAH: 1.2±0.1) and interatrial pressure gradient (9 [5 to 12] versus 2 [-2 to 5] mm Hg).
Conclusions
RV/RA function was less compromised in HFpEF-PH than in PAH, despite similar pressure-overload. Increased RA pressure and stiffness in HFpEF-PH were explained by left atrial/RA-interaction. Therefore, our results indicate that increased RA pressure is not a sign of overt RV failure but rather a reflection of HFpEF-severity.



Circ Heart Fail: 22 Dec 2021:CIRCHEARTFAILURE121008726; epub ahead of print
van Wezenbeek J, Kianzad A, van de Bovenkamp A, Wessels J, ... Handoko ML, de Man FS
Circ Heart Fail: 22 Dec 2021:CIRCHEARTFAILURE121008726; epub ahead of print | PMID: 34937392
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Impact:
Abstract

Epicardial Adipose Tissue and Outcome in Heart Failure With Mid-Range and Preserved Ejection Fraction.

van Woerden G, van Veldhuisen DJ, Manintveld OC, van Empel VPM, ... Westenbrink BD, Gorter TM
Background
Epicardial adipose tissue (EAT) accumulation is thought to play a role in the pathophysiology of heart failure (HF) with mid-range and preserved ejection fraction, but its effect on outcome is unknown. We evaluated the prognostic value of EAT volume measured with cardiac magnetic resonance in patients with HF with mid-range ejection fraction and HF with preserved ejection fraction.
Methods
Patients enrolled in a prospective multicenter study that investigated the value of implantable loop-recorders in HF with mid-range ejection fraction and HF with preserved ejection fraction were analyzed. EAT volume was quantified with cardiac magnetic resonance. Main outcome was the composite of all-cause mortality and first HF hospitalizations. Hazard ratios (HR) and 95% CI are described per SD increase in EAT.
Results
We studied 105 patients (mean age 72±8 years, 50% women, and mean left ventricular ejection fraction 53±8%). During median follow-up of 24 (17-25) months, 31 patients (30%) died or were hospitalized for HF. In univariable analysis, EAT was significantly associated with a higher risk of the composite outcome (HR, 1.76 [95% CI, 1.24-2.50], P=0.001), and EAT remained associated with outcome after adjustment for age, sex, and body mass index (HR, 1.61 [95% CI, 1.13-2.31], P=0.009), and after adjustment for New York Heart Association functional class and N-terminal of pro-brain natriuretic peptide (HR, 1.53 [95% CI, 1.04-2.24], P=0.03). Furthermore, EAT was associated with all-cause mortality alone (HR, 2.06 [95% CI, 1.26-3.37], P=0.004) and HF hospitalizations alone (HR, 1.54 [95% CI, 1.04-2.30], P=0.03).
Conclusions
EAT accumulation is associated with adverse prognosis in patients with HF with mid-range ejection fraction and HF with preserved ejection fraction. This finding supports the importance of EAT in these patients with HF.
Registration
URL: https://www.clinicaltrials.gov; Unique identifier: NCT01989299.



Circ Heart Fail: 21 Dec 2021:CIRCHEARTFAILURE121009238; epub ahead of print
van Woerden G, van Veldhuisen DJ, Manintveld OC, van Empel VPM, ... Westenbrink BD, Gorter TM
Circ Heart Fail: 21 Dec 2021:CIRCHEARTFAILURE121009238; epub ahead of print | PMID: 34935412
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Impact:
Abstract

Exercise Training Protects Against Heart Failure Via Expansion of Myeloid-Derived Suppressor Cells Through Regulating IL-10/STAT3/S100A9 Pathway.

Feng L, Li G, An J, Liu C, ... Yang L, Qi Z
Background
Exercise training (ET) has a protective effect on the progression of heart failure, however, the specific mechanism has not been fully explored. Myeloid-derived suppressor cells (MDSCs) are a group of myeloid-derived immunosuppressive cells, which showed a protective effect in the progression of heart failure. Thus, we hypothesized that the protective effect of ET on heart failure may be related to the infiltration of MDSCs.
Methods
C57BL/6 mice were made to run on a treadmill 6× a week for 4 weeks followed by isoproterenol injection from third week. Heart function was evaluated by echocardiography and the proportion of MDSCs was detected by flow cytometry. Hypertrophic markers, cardiac fibrosis, and inflammatory factors were detected by real-time PCR, ELISA, histological staining, and Western blot.
Results
ET treatment in isoproterenol-induced heart failure mice (n=7) enhanced cardiac function (57% increase in FS%, P=0.002) and improved morphological changes compared with isoproterenol mice (n=17). ET further caused 79% increasing in cardiac MDSCs in isoproterenol mice (P<0.001). In addition, depletion of MDSCs by 5-Fluorouracil blunted the cardio-protective effect of ET. T-cell proliferation assay showed that ET did not affect the suppressive activity of MDSCs. Furthermore, we found that ET activated the secretion of IL (interleukin)-10 by macrophages in isoproterenol mice. MDSCs expansion and cardio protection was not present in tamoxifen-inducible macrophage-specific IL-10 knockout mice. Western blot results confirmed that IL-10 regulated the differentiation of MDSCs through the translocation of p-STAT3 (signal transducer and activator of transcription 3)/S100A9 (S100 calcium-binding protein A9) to the nucleus.
Conclusions
ET could increase MDSCs by stimulating the secretion of IL-10 from macrophage, which was through IL-10/STAT3/S100A9 signaling pathway, thereby achieving the role of heart protection.



Circ Heart Fail: 15 Dec 2021:CIRCHEARTFAILURE121008550; epub ahead of print
Feng L, Li G, An J, Liu C, ... Yang L, Qi Z
Circ Heart Fail: 15 Dec 2021:CIRCHEARTFAILURE121008550; epub ahead of print | PMID: 34911348
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Impact:
Abstract

Factors Associated With Racial and Ethnic Diversity Among Heart Failure Trial Participants: A Systematic Bibliometric Review.

Wei S, Le N, Zhu JW, Breathett K, ... Zannad F, Van Spall HGC
Background
Heart failure has a disproportionate burden on patients who are Black, Indigenous, and people of color (BIPOC), but not much is known about representation of these groups in randomized controlled trials (RCTs). We explored temporal trends in and RCT factors associated with the reporting of race and ethnicity data and the enrollment of BIPOC in heart failure RCTs.
Methods
We searched MEDLINE, EMBASE, and CINAHL for heart failure RCTs published in journals with an impact factor ≥10 between January 1, 2000 and June 17, 2020. We used the Cochran-Armitage and Jonchkeere-Terpstra tests to examine temporal trends, and multivariable regression to assess the association between trial characteristics and outcomes.
Results
Of 414 RCTs meeting inclusion criteria, only 157 (37.9% [95% CI, 33.2%-2.8%]) reported race and ethnicity data. Among 158 200 participants in these 157 RCTs, 29 512 (18.7% [95% CI, 18.5%-18.9%]) were BIPOC. There was a temporal increase in reporting of race and ethnicity data (29.5% in 2000-2003 to 54.7% in 2016-2020, P<0.001) and in enrollment of BIPOC (14.4% in 2000-2003 to 22.2% in 2016-2020, P=0.038). Trial leadership by a woman was independently associated with twice the odds of reporting race and ethnicity data (odds ratio, 2.0 [95% CI, 1.1-3.8]; P=0.028) and an 8.4% increase (95% CI, 1.9%-15.0%; P=0.013) in BIPOC enrollment.
Conclusions
A minority of heart failure RCTs reported race and ethnicity data, and among these, BIPOC were under-enrolled relative to disease distribution. Both reporting of race and ethnicity as well as enrollment of BIPOC increased between 2000 and 2020. After multivariable adjustment, trials led by women had greater odds of reporting race and ethnicity and enrolling BIPOC.
Registration
URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42021237497.



Circ Heart Fail: 15 Dec 2021:CIRCHEARTFAILURE121008685; epub ahead of print
Wei S, Le N, Zhu JW, Breathett K, ... Zannad F, Van Spall HGC
Circ Heart Fail: 15 Dec 2021:CIRCHEARTFAILURE121008685; epub ahead of print | PMID: 34911363
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Impact:
Abstract

FGF21 (Fibroblast Growth Factor 21) Defines a Potential Cardiohepatic Signaling Circuit in End-Stage Heart Failure.

Sommakia S, Almaw NH, Lee SH, Ramadurai DKA, ... Drakos SG, Chaudhuri D
Background
Extrinsic control of cardiomyocyte metabolism is poorly understood in heart failure (HF). FGF21 (Fibroblast growth factor 21), a hormonal regulator of metabolism produced mainly in the liver and adipose tissue, is a prime candidate for such signaling.
Methods
To investigate this further, we examined blood and tissue obtained from human subjects with end-stage HF with reduced ejection fraction at the time of left ventricular assist device implantation and correlated serum FGF21 levels with cardiac gene expression, immunohistochemistry, and clinical parameters.
Results
Circulating FGF21 levels were substantially elevated in HF with reduced ejection fraction, compared with healthy subjects (HF with reduced ejection fraction: 834.4 [95% CI, 628.4-1040.3] pg/mL, n=40; controls: 146.0 [86.3-205.7] pg/mL, n=20, P=1.9×10-5). There was clear FGF21 staining in diseased cardiomyocytes, and circulating FGF21 levels negatively correlated with the expression of cardiac genes involved in ketone metabolism, consistent with cardiac FGF21 signaling. FGF21 gene expression was very low in failing and nonfailing hearts, suggesting extracardiac production of the circulating hormone. Circulating FGF21 levels were correlated with BNP (B-type natriuretic peptide) and total bilirubin, markers of chronic cardiac and hepatic congestion.
Conclusions
Circulating FGF21 levels are elevated in HF with reduced ejection fraction and appear to bind to the heart. The liver is likely the main extracardiac source. This supports a model of hepatic FGF21 communication to diseased cardiomyocytes, defining a potential cardiohepatic signaling circuit in human HF.



Circ Heart Fail: 05 Dec 2021:CIRCHEARTFAILURE121008910; epub ahead of print
Sommakia S, Almaw NH, Lee SH, Ramadurai DKA, ... Drakos SG, Chaudhuri D
Circ Heart Fail: 05 Dec 2021:CIRCHEARTFAILURE121008910; epub ahead of print | PMID: 34865514
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Impact:
Abstract

A Novel Small Molecule Troponin Activator Increases Cardiac Contractile Function Without Negative Impact on Energetics.

He H, Baka T, Balschi J, Motani AS, ... Reagan JD, Luptak I
Background: Current heart failure (HF) therapies unload the failing heart without targeting the underlying problem of reduced cardiac contractility. Traditional inotropes (i.e. calcitropes) stimulate contractility via energetically costly augmentation of calcium cycling and worsen patient survival. A new class of agents - myotropes - activate the sarcomere directly, independent of calcium. We hypothesize that a novel myotrope TA1 increases contractility without the deleterious myocardial energetic impact of a calcitrope dobutamine.
Methods:
We determined the effect of TA1 in bovine cardiac myofibrils and human cardiac microtissues, ex vivo in mouse cardiac fibers and in vivo in anesthetized normal rats. Effects of increasing concentrations of TA1 or dobutamine on contractile function, phosphocreatine (PCr) and ATP concentrations and ATP production were assessed by 31P NMR spectroscopy on isolated perfused rat hearts.
Results:
TA1 increased the rate of myosin ATPase activity in isolated bovine myofibrils and calcium sensitivity in intact mouse papillary fibers. Contractility increased dose dependently in human cardiac microtissues and in vivo in rats as assessed by echocardiography. In isolated rat hearts, TA1 and dobutamine similarly increased rate pressure product (RPP). Dobutamine increased both developed pressure (DevP) and heart rate (HR) accompanied by decreased PCr to ATP ratio and decreased free energy of ATP hydrolysis (ΔG~ATP) and elevated left ventricular end-diastolic pressure (LVEDP). In contrast, the TA1 increased DevP without any effect on HR, LVEDP, PCr/ATP ratio or ΔG~ATP. Conclusions: Novel myotrope, TA1, increased myocardial contractility by sensitizing the sarcomere to calcium without impairing diastolic function or depleting the cardiac energy reserve. Since energetic depletion negatively correlates with long term survival, myotropes may represent a superior alternative to traditional inotropes in heart failure management.




Circ Heart Fail: 07 Nov 2021; epub ahead of print
He H, Baka T, Balschi J, Motani AS, ... Reagan JD, Luptak I
Circ Heart Fail: 07 Nov 2021; epub ahead of print | PMID: 34743528
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Impact:
Abstract

Effect of Empagliflozin on Blood Volume Redistribution in Patients With Chronic Heart Failure and Reduced Ejection Fraction: An Analysis from the Empire HF Randomized Clinical Trial.

Omar M, Jensen J, Burkhoff D, Frederiksen PH, ... Schou M, Møller JE
Background: Stressed blood volume (SBV) is a major determinant of systemic and pulmonary venous pressures which, in turn, determine left and right ventricular fillings and regulates cardiac output via the Frank-Starling mechanism. It is not known whether inhibition of the sodium-glucose cotransporter-2 (SGLT2) favorably affects SBV. We investigated the effect of empagliflozin on estimated stressed blood volume (eSBV) in patients with heart failure andreduced ejection fraction (HFrEF) compared to placebo.
Methods:
This was a post-hoc analysis of an investigator-initiated, double-blinded, placebo controlled, randomized trial. Seventy patients were assigned to empagliflozin 10 mg or matching placebo once-daily for 12 weeks. Patients underwent right heart catheterization at rest and during exercise at baseline and follow-up. The outcome was change in eSBV after 12 weeks of empagliflozin treatment over the full range of exercise, determined using a recently introduced analytical approach based on invasive hemodynamic assessment.
Results:
Patients with HFrEF, mean age, 57 years and mean ejection fraction 27 %, with 47 patients (71%) receiving diuretics were randomized. The effect of empagliflozin on eSBV over the full range of exercise loads showed a statistically significant reduction compared with placebo (-198.4 mL, 95%CI: -317.4; -79.3, p=0.001), a 9% decrease. The decrease in eSBV by empagliflozin was significantly correlated with the decrease in PCWP ((R= ̶ 0.33, p<0.0001). The effect of empagliflozin was consistent across subgroup analysis. Conclusions: Empagliflozin treatment significantly reduced stressed blood volume compared with placebo after 12 weeks of treatment in patients with stable chronic HFrEF during sub maximal exercise. Registration: URL: https://www.clinicaltrials.gov, Unique identifier: NCT03198585.




Circ Heart Fail: 07 Nov 2021; epub ahead of print
Omar M, Jensen J, Burkhoff D, Frederiksen PH, ... Schou M, Møller JE
Circ Heart Fail: 07 Nov 2021; epub ahead of print | PMID: 34743533
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Impact:

This program is still in alpha version.