Progressive Left Ventricular Dilatation Research Articles

Non-ischemic etiology is a better prognostic factor of reverse left ventricular remodeling in patients with heart failure reduced ejection fraction

Abstract Background and Purpose Even though the similar guideline directed standard care of heart failure (HF) is applied, clinical outcomes may differ in case by case. Since progressive left ventricular (LV) dilation makes the worse outcome, we investigate the prognostic factor of LV reverse remodeling and functional recovery in patients with heart failure reduced ejection fraction (HFrEF). Methods More than 1000 HFrEF who were followed from 2018 to 2023, 438 patients (61.1±15.2 years, 284 male) with consecutive echocardiography at 1-year intervals and treated by the guideline directed medical therapy including angiotensin receptor neprilysin inhibitor were enrolled. We compared clinical, laboratory, echocardiographic parameters according to LV reverse remodeling. LV reverse remodeling was defined as the normalized LV end-systolic volume index and LV functional recovery was defined as LV EF ≥ 50% on 1-year follow up echocardiography. Results Baseline clinical and echocardiographic characteristics including LV EF were not different between the groups. Non-ischemic etiology was significantly frequent in LV reverse remodeling group compared with non-reverse group (96.4% vs.88.6, p=0.005). During 5 years of clinical follow up, death was developed in 25 patients (5.7%), most of death was in non-reverse group (1.5% vs. 9.0%). Non-ischemic etiology was an independent predictor for LV reverse remodeling (OR 3.329, CI 1.253-8.846, p=0.012) and LV functional recovery (OR 4.210, CI 1.459-12.151, p=0.008) in patients with HFrEF. In Kaplan Meier analysis, non-ischemic etiology showed better outcome than ischemic etiology (Log Rank p=0.001). Ischemic etiology was an independent predictor of mortality in patients with HFrEF (OR 5.569, CI 2.127-14.582, p<0.001). Conclusions LV reverse remodeling was more common and clinical outcomes were better in non-ischemic etiology as compared to those of ischemic etiology, even after standard medication in patients with HFrEF. This etiologic difference of clinical outcomes should be considered in the management of HF.

CD14 blockade preserves left ventricular structure and systolic function in a murine model of ST-elevation myocardial infarction

Abstract Background Cluster of differentiation-14 (CD14) facilitates the excessive pro-inflammatory monocyte-macrophage response to myocardial injury. Both acute and chronic infiltration of pro-inflammatory macrophages are implicated in the immunological progression of ischemic heart failure. However, investigation of clinically practicable strategies of CD14 blockade are yet to be reported. Purpose This fully blinded and randomised preclinical study evaluated the efficacy of a neutralising anti-CD14 antibody given at reperfusion in a murine model of reperfused ST-elevation myocardial infarction (STEMI) with key clinical features. Methods Large anterior STEMI was induced in 48 adult mice by left anterior descending coronary artery occlusion for 1 h prior to reperfusion and randomisation to receive anti-CD14 antibody, isotype control (IgG2a) or saline weekly for four weeks (independently blinded). Outcome measures included functional assessments by 9.4T cardiac magnetic resonance (CMR) imaging and ultra-high-resolution echocardiography at 21- and 28-days post-STEMI, respectively. Results Multi-plane short axis CMR at 21-days post-STEMI revealed greater left ventricular (LV) ejection fraction in the anti-CD14 antibody-treated group compared with saline- and isotype-treated controls (30±1 vs 19±1 and 20±1 %, respectively, p<0.001; Figure 1A). CMR also revealed reduced LV dilatation with anti-CD14-treatment compared to control groups (76±5 vs 102±8 and 107±7 µl EDV in saline- and isotype-treated controls, respectively, p<0.05). Parasternal long axis echocardiography at 28 days post-STEMI confirmed that anti-CD14 antibody treatment was associated with greater LV systolic function compared to saline and isotype controls (30±1 vs 24±1 and 25±2 % EF, respectively, p<0.05; Figure 1B). Preservation of LV end-diastolic (86±4 vs 111±6 and 101±5 µl, p<0.01) and end-systolic (61±3 vs 84±5 and 77±5 µl, p<0.01) volumes was also observed with anti-CD14 treatment. Global longitudinal strain (GLS) of the LV was also significantly greater at 28 days post-STEMI with anti-CD14 treatment relative to saline and isotype controls (-8.5±0.4 vs -6.8±0.3 and -6.6±0.4 %, respectively, p<0.05). Conclusion(s) The findings of this fully blinded and randomised preclinical study provide evidence of a clinically practicable strategy of CD14 blockade initiated at reperfusion to mitigate progressive LV systolic dysfunction and dilatation post-STEMI.Figure 1.Functional outcome measures

Abstract Tu075: Cardiac macrophages expressing CD206 and IL-4Ra are required for adverse LV remodeling in HF

Cardiac macrophages significantly expand in chronic heart failure (HF). We tested the hypothesis that CD206 + macrophages expressing interleukin (IL)-4Ra in the failing heart are key drivers of left ventricular (LV) remodeling and ischemic cardiomyopathy. Cardiac macrophages were profiled using flow cytometry in adult male C57BL/6 (WT) mice following non-reperfused myocardial infarction (MI) to induce HF or sham operation. CD206 + macrophages progressively expanded in post-MI hearts during the progression of LV remodeling and comprised ~85% of macrophages at 8 w. These macrophages were exclusively proliferative and predominantly C-C motif chemokine receptor (CCR2) – and major histocompatibility complex (MHC)II hi in failing hearts, with the majority (92%) of CD206 + CCR2 – macrophages expressing LYVE-1, an embryonically-derived resident macrophage marker. Nearly half of cardiac CD206 + macrophages expressed IL-4Ra; the abundance of CD206 + IL-4Ra + directly correlated with LV dysfunction and fibrosis. Intramyocardial adoptive transfer of IL-4-polarized bone marrow derived CD206 + macrophages induced progressive LV dilation, dysfunction and fibrosis over 4 w in naïve recipient mice. To evaluate the role of CD206 + IL-4Ra + macrophages in LV remodeling, we used male and female LysM CreERT2 ;IL-4Ra F/F mice that allow for inducible myeloid-specific IL-4Ra gene deletion. Administration of tamoxifen from at 4 to 10 w post-MI (in established HF), effectively deleted IL-4Ra in cardiac macrophages and significantly reduced CD206 + macrophage abundance and proliferation in the remodeling heart. Myeloid-specific IL-4Ra deletion further prevented LV remodeling progression, improved fibrosis and neovascularization, and alleviated LV systolic dysfunction, while suppressing expansion of cardiac immune cells and blood Ly6C high monocytosis. We conclude that an expanded and proliferative population of CD206 + IL-4Ra + macrophages primarily derived from resident macrophages are key mediators of pathological LV remodeling and fibrosis. Inhibition of CD206 + macrophage IL-4Ra signaling may be a fruitful therapeutic approach to alleviate disease progression in HF.

Progressive Left Ventricular Remodeling for Predicting Mortality in Children With Dilated Cardiomyopathy: The Pediatric Cardiomyopathy Registry.

Pediatric dilated cardiomyopathy often leads to death or cardiac transplantation. We sought to determine whether changes in left ventricular (LV) end-diastolic dimension (LVEDD), LV end-diastolic posterior wall thickness, and LV fractional shortening (LVFS) over time may help predict adverse outcomes. We studied children up to 18 years old with dilated cardiomyopathy, enrolled between 1990 and 2009 in the Pediatric Cardiomyopathy Registry. Changes in LVFS, LVEDD, LV end-diastolic posterior wall thickness, and the LV end-diastolic posterior wall thickness:LVEDD ratio between baseline and follow-up echocardiograms acquired ≈1 year after diagnosis were determined for children who, at the 1-year follow-up had died, received a heart transplant, or were alive and transplant-free. Within 1 year after diagnosis, 40 (5.0%) of the 794 eligible children had died, 117 (14.7%) had undergone cardiac transplantation, and 585 (73.7%) had survived without transplantation. At diagnosis, survivors had higher median LVFS and lower median LVEDD Z scores. Median LVFS and LVEDD Z scores improved among survivors (Z score changes of +2.6 and -1.1, respectively) but remained stable or worsened in the other 2 groups. The LV end-diastolic posterior wall thickness:LVEDD ratio increased in survivors only, suggesting beneficial reverse LV remodeling. The risk for death or cardiac transplantation up to 7 years later was lower when LVFS was improved at 1 year (hazard ratio [HR], 0.83; P=0.004) but was higher in those with progressive LV dilation (HR, 1.45; P<0.001). Progressive deterioration in LV contractile function and increasing LV dilation are associated with both early and continuing mortality in children with dilated cardiomyopathy. Serial echocardiographic monitoring of these children is therefore indicated. URL: https://www.clinicaltrials.gov; Unique identifier: NCT00005391.

Veno-Venous Coiling as A Strategy to Wean Extracorporeal Membrane Oxygenator Post Adult Fontan Completion

We discuss a case of veno-venous collaterals in a patient with Fontan circulation post complex redo-surgery, which impeded veno-venous extracorporeal membrane oxygenation (VV-ECMO) weaning. A 31-year-old male, born with complex congenital heart disease (D-transposition of the great vessels, tricuspid atresia, aortic coarctation, ventricular septal defect, and hypoplastic right ventricle) with single ventricle physiology. The patient underwent multiple cardiac surgeries leading to Fontan completion. He subsequently developed significant aortic regurgitation with progressive left ventricular dilatation requiring multiple readmissions for congestive heart failure. Despite maximal medical optimisation he remained symptomatic and was offered further surgery. Complex 6th redo-operation with aortic valve replacement, modification to intracardiac fenestrated Fontan and insertion of intra-aortic balloon pump was performed. At 72 hours postoperative, VV-ECMO was required for refractory hypoxia. Right heart catheterisation was performed with coiling of two large fistulous venous connections. Post-coiling saturations improved from 92% to 98%. The patient was successfully weaned from VV-ECMO and decannulated the following day. This case demonstrates successful embolisation for veno-venous collaterals causing significant right to left shunt and hypoxia, in a patient with Fontan circulation.

Abstract GS.102: Cd206 + Il-4rα + Macrophages Are Drivers Of Adverse Cardiac Remodeling In Ischemic Cardiomyopathy

Background: Cardiac macrophages are significantly expanded in chronic heart failure (HF); however, their role is unclear. We tested the hypothesis that CD206 + macrophages expressing interleukin (IL)-4Rα in the failing heart are key drivers of adverse left ventricular (LV) remodeling and ischemic cardiomyopathy. Methods and Results: Adult male C57BL/6 (WT) mice underwent non-reperfused myocardial infarction (MI) to induce HF, or sham operation, and cardiac macrophages were profiled using flow cytometry. As compared to sham hearts, both the frequency and absolute number of CD206 + macrophages steadily increased in post-MI hearts during the progression of LV remodeling and HF, such that at 8 w post-MI they comprised ~85% of macrophages. These macrophages were exclusively proliferative and predominantly C-C motif chemokine receptor (CCR2) - with nearly half expressing IL-4Rα, and correlated with LV dysfunction and fibrosis. IL-4-polarized bone marrow derived CD206 + macrophages exhibited marked upregulation of found in inflammatory zone (FIZZ)1 and induced FIZZ1-dependent myofibroblast differentiation of cardiac mesenchymal stem cells (cMSCs), in part related to DLL-4/Jagged1-Notch1 signaling. Intramyocardial adoptive transfer of M[IL-4], but not M[IL-10], macrophages induced progressive LV dilation and dysfunction and augmented cardiac fibrosis over 4 weeks in naïve mice. In vivo IL-4Rα gene silencing in mice with established HF effectively depleted cardiac CD206 + IL-4Rα + macrophages and induced reverse LV remodeling, improving fibrosis, neovascularization, and dysfunction, and suppressing local and systemic inflammation. Lastly, alternatively activated CD206 + and CD163 + macrophages were significantly expanded in human failing hearts and correlated with cardiac fibrosis, with the majority of CD163 + macrophages expressing IL-4Rα and FIZZ3, the human homolog of FIZZ1. Conclusion: CD206 + IL-4Rα + macrophages proliferate and expand in the failing heart and are key mediators of pathological remodeling and fibrosis, in part through the secretion of FIZZ1. Inhibition of CD206 + macrophage IL-4Rα signaling may be a fruitful therapeutic approach for alleviating LV remodeling in HF.

A Mouse Model of Dilated Cardiomyopathy Produced by Isoproterenol Acute Exposure Followed by 5-Fluorouracil Administration.

Appropriate dilated cardiomyopathy (DCM) animal models are highly desirable considering the pathophysiological and clinical heterogeneity of DCM. Genetically modified mice are the most widely and intensively utilized research animals for DCM. However, to translate discoveries from basic science into new and personalized medical applications, research in non-genetically based DCM models remains a key issue. Here, we characterized a mouse model of non-ischemic DCM induced by a stepwise pharmacologic regime of Isoproterenol (ISO) high dose bolus followed by a low dose systemic injection of the chemotherapy agent, 5-Fluorouracil (5-FU). C57BL/6J mice were injected with ISO and, 3 days after, were randomly assigned to saline or 5-FU. Echocardiography and a strain analysis show that ISO + 5FU in mice induces progressive left ventricular (LV) dilation and reduced systolic function, along with diastolic dysfunction and a persistent global cardiac contractility depression through 56 days. While mice treated with ISO alone recover anatomically and functionally, ISO + 5-FU causes persistent cardiomyocyte death, ensuing in cardiomyocyte hypertrophy through 56 days. ISO + 5-FU-dependent damage was accompanied by significant myocardial disarray and fibrosis along with exaggerated oxidative stress, tissue inflammation and premature cell senescence accumulation. In conclusions, a combination of ISO + 5FU produces anatomical, histological and functional cardiac alterations typical of DCM, representing a widely available, affordable, and reproducible mouse model of this cardiomyopathy.

A novel gene therapy for familial dilated cardiomyopathy based upon disruption of PP2A -- mAKAP-beta signalosomes

Familial Dilated Cardiomyopathy (DCM) is a common inherited cause of heart failure characterized by progressive left ventricular dilatation and systolic dysfunction. Despite the discovery of novel genetic mutations causing DCM, the downstream mechanisms resulting in heart failure are still unclear, and there remains a great unmet clinical need. Contributing to the phenotype of ventricular dilatation in DCM is the lengthening of cardiac myocytes, which exhibit increased overall length to width ratio. We have shown that increasing the phosphorylation of the transcription factor serine response factor (SRF) at serine residue 103 by displacement of protein phosphatase 2A (PP2A) from the perinuclear scaffold protein muscle A-kinase anchoring protein β (mAKAPβ) can inhibit myocyte lengthening and improve cardiac function following myocardial infarction. Notably, SRF S103 phosphorylation is decreased in both human heart failure and in the hearts of transgenic mice expressing the human DCM α-tropomyosin Glu54Lys (Tm-E54K) mutant allele. We now show that, accordingly, targeting of mAKAPβ-PP2A signalosomes constitutes a new therapeutic strategy for DCM. A self-complementary serotype 9 adeno-associated virus (AAV9sc) conferring cardiac-specific expression of a mAKAPβ fragment comprising the PP2A binding domain (PBD) was used to target the signalosomes in mice. AAV9sc.PBD administration into neonatal Tm-E54K mice provided long term preservation of cardiac function and prevented ventricular dilatation. At 16 weeks of age, ejection fraction was significantly improved 14%[MK1], and wall thickness was increased for AAV9sc.PBD TM-E54K mice when compared with control AAV9sc.GFP treated TM-E54K mice. Morphometry of acutely dissociated adult mouse myocytes showed that AAV9sc.PBD treatment restored myocyte length to width ratio to that of non-transgenic animals, while western blots showed increased SRF S103 phosphorylation. The results in mice have been corroborated by PBD expression in engineered heart tissues (EHT) generated from an induced pluripotent stem cell (iPSC) line for a DCM phospholamban R14del patient. PBD expression increased SRF S103 phosphorylation and improved tissue contractility. Taken together, this study suggests that increasing SRF S103 phosphorylation by disruption of mAKAPβ-PP2A signalosomes can constitute a novel therapeutic strategy for DCM. Funded by Department of NIH Grant R01HL146111 (Dr. Kapiloff), R01 HL139679 and Leducq Foundation CurePlan (Dr. Karakikes), and the NHLBI Gene Therapy Resource Program. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Left ventricular size and function in patients with systemic lupus erythematosus associate with lupus anticoagulant: An echocardiographic follow-up study

BackgroundSystemic lupus erythematosus (SLE) is a chronic autoimmune disease with increased risk of cardiac dysfunction. The pathophysiological mechanisms are poorly understood, and prognostic markers are warranted. PurposeWe aimed to identify SLE-characteristics associated with measures of cardiac size and function during a five-year follow-up. MethodsWe included 108 patients with SLE: 90% females, mean age 46 ± 13 years, median disease duration 14 (range 7–21) years. We performed blood sampling for potential biomarkers as well as a standard echocardiography at baseline and at a 5-year follow-up. To investigate associations with baseline and prospective 5-year changes in echocardiographic parameters, we performed multivariate regression analyses of SLE-related baseline variables (clinical disease activity, lupus nephritis, chronic kidney disease, anti-cardiolipin and/or anti-beta-2 glycoprotein I antibodies, and lupus anticoagulant (LAC)) and adjusted for traditional risk factors. ResultsDuring follow-up, diastolic function regressed in two out of five echocardiographic measures (E/A ratio 1.4 ± 0.5 vs. 1.3 ± 0.5, p = 0.002; tricuspid regurgitation peak velocity 2.0 ± 0.6 vs. 2.2 ± 0.4 mmHg, p < 0.001). Left ventricular (LV) end-diastolic volume index increased (43.7 ± 13.9 vs. 52.5 ± 15.7 mL/m2, p < 0.001). Left and right ventricular systolic function remained stationary. LAC was associated with inferior diastolic function: lower E/A ratio (p = 0.04) and higher E/e’ ratio at baseline (p = 0.04) and increased left ventricular atrial volume index during follow-up (p = 0.01). LAC was further associated with LV dilatation during follow-up (p = 0.01). ConclusionPresence of LAC was associated with measures of diastolic function as well as progressive LV dilatation during the 5-year follow-up. Thus, LAC might be a predictor of cardiac dysfunction in SLE patients. LAC is known to have implications for the microvascular circulation, but the clinical significance of the present findings is yet to be elucidated.

CDC-like kinase 4 deficiency contributes to pathological cardiac hypertrophy by modulating NEXN phosphorylation

Kinase-catalyzed phosphorylation plays a crucial role in pathological cardiac hypertrophy. Here, we show that CDC-like kinase 4 (CLK4) is a critical regulator of cardiomyocyte hypertrophy and heart failure. Knockdown of Clk4 leads to pathological cardiomyocyte hypertrophy, while overexpression of Clk4 confers resistance to phenylephrine-induced cardiomyocyte hypertrophy. Cardiac-specific Clk4-knockout mice manifest pathological myocardial hypertrophy with progressive left ventricular systolic dysfunction and heart dilation. Further investigation identifies nexilin (NEXN) as the direct substrate of CLK4, and overexpression of a phosphorylation-mimic mutant of NEXN is sufficient to reverse the hypertrophic growth of cardiomyocytes induced by Clk4 knockdown. Importantly, restoring phosphorylation of NEXN ameliorates myocardial hypertrophy in mice with cardiac-specific Clk4 deletion. We conclude that CLK4 regulates cardiac function through phosphorylation of NEXN, and its deficiency may lead to pathological cardiac hypertrophy. CLK4 is a potential intervention target for the prevention and treatment of heart failure.

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

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. RNA-sequencing of cardiac CD4+ T cells and flow cytometric analysis of immune cells was conducted. 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. 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.

Lupus anticoagulant in patients with systemic lupus erythematosus is associated with lower E/A ratio and progressive left ventricular dilatation: a five-year follow-up study

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Copenhagen University Hospital Background Systemic lupus erythematosus (SLE) is an autoimmune disease with increased risk of cardiovascular complications such as coronary artery disease, myocarditis, pericarditis and valvular dysfunction. The pathophysiological mechanisms are poorly understood and clinical, biochemical and/or imaging markers to identify high risk patients are warranted. Purpose We aimed to identify SLE-characteristics that are associated with progressive cardiac dysfunction during a five-year follow-up period in patients with SLE. Methods A total of 147 patients with SLE were included from 2013 to 2014. All patients underwent standard echocardiography at baseline as well as a collection of blood samples, including a selection of biomarkers. Patients were invited to a five-year follow-up with a total of 108 patients (90 % female, mean age 46 ± 13 years, median disease duration of 14 (7-21) years) completing a full echocardiographic, laboratory, and clinical examination. Multivariate regression analyses with eight independent baseline variables of interest (age, sex, disease activity (SLEDAI-2K), lupus nephritis, ischemic heart disease (IHD), antiphospholipid antibodies (IgM and IgG), and lupus anticoagulant(LAC)) were performed as for the association with baseline echocardiographic parameters as well as for changes during follow-up. Only echocardiographic measurements that changed significantly (p &amp;lt; 0.01) during follow-up were selected for the regression analyses. Left ventricular end-diastolic volume index (LVEDVI) and E/A ratio were log-transformed at baseline in the regression analyses due to non-normality. Results During a five-year follow-up period, LVEDVI increased from 43.5 ± 13.9 to 52.5 ± 15.7 ml/m2 (p &amp;lt;0.001), and left ventricular diastolic measures declined (E/A ratio 1.4 ± 0.5 vs. 1.3 ± 0.5, p = 0.002; e’ velocity 12.8 ± 3.8 vs. 12.0 ± 3.7 ms, p = 0.02; mitral valve deceleration time 227.9 vs. 200.8 ms, p &amp;lt; 0.001), except for E/e’ (7.5 ± 3.8 vs. 6.8 ± 3.4, p = 0.02). Left ventricular ejection fraction remained stationary (59.5 ± 6.8 vs. 59.6 ± 6.4 %, p = 0.81). In multivariate regression analyses, presence of LAC was significantly associated with progressive left ventricular dilation during the follow-up period (p = 0.003) but not with higher baseline levels (p = 0.64) (Fig. A1 &amp; A2). LAC was associated with lower E/A ratio at baseline (p = 0.005) but did not predict a decrease of E/A ratio during follow-up (p = 0.24) (Fig. B1 &amp; B2). IHD was associated with higher LVEDVI at baseline (p = 0.004), but not with further progression of dilation (p = 0.07). Conclusion Presence of LAC was associated with lower E/A ratio at baseline as well as progressive left ventricular dilation during a five-year follow-up period. Hence, LAC might be a predictor of progressive cardiac dysfunction in patients with SLE. LAC is known to have implications for the microvascular circulation, but the clinical significance of the present findings is yet to be elucidated. Abstract Figure A Abstract Figure B

IMPACT OF TRUNCAL VALVE REGURGITATION ON LEFT VENTRICULAR FUNCTION AND GEOMETRY IN COMMON ARTERIAL TRUNK: A CASE-MATCH CONTROLLED STUDY

<h3>BACKGROUND</h3> Truncal valve insufficiency (TVI) not only is one of the risk factors for death in neonatal primary repair for common arterial trunk (CAT), but also influences long-term left ventricular performance. This study investigates the functional and survival outcomes of CAT repair in patients based on TVI severity. <h3>METHODS AND RESULTS</h3> In this single-center retrospective case-matched controlled study, 16 consecutive CAT patients from 2000- 2018 with moderate to severe truncal valve regurgitation (TVR2-3) undergoing primary CAT surgery with truncal valve (TrV) repair were matched to 16 CAT patients with none to mild truncal valve regurgitation (TVR1-0). Survival was analyzed using Kaplan-Meier; reintervention using competing risks; paired tests for ventricular function and geometry, and health status. TVR2-3 group had 11 (69%) patients with moderate TVR and 5 (31%) patients with severe TVI, with operative median age of 7(4 – 19) days. The TVR1-0 group had 3 (19%) patients with none/trivial TVI and 13 (81%) patients with mild TVI, with an operative median age of 132(6– 22) days (p = 0.30). There were no significant differences in preoperative variables between the groups and repair technique as shown in Table 1. There was no significant difference between overall survival and modified Ross heart failure score at median length of follow-up of 9.17 (1.40 – 15.12) years. Rate of surgical TrV reintervention at 5 years postoperative was 8% and 67% for TVR0-1 and TVR2-3, respectively (Stratified Gray's p = 0.005). TVR2-3 experienced greater residual TVI at discharge and 1 year post-repair with severity of TrV dysfunction converging between groups as more patients in TVR0-1 developed mild/moderate TVI over time and TVR2-3 patients underwent reintervention. Left ventricular ejection fraction (LVEF) was comparable between groups at all time-points, with the exception of postoperative year 1 [TVR0-1: 69(67 – 74)% vs. TVR2-3: 62(59 – 66)% (p = 0.006) Figure 1]. Although not statistically significant, pronounced left ventricular dilatation was seen in the TVR2-3 group (upper quartile, z-score +6) throughout 1-year post-repair. Increasing left ventricular size in TVR2-3 reached statistical significance at 3 (p = 0.001) and 5 years (p = 0.003), but did not impair LVEF. <h3>CONCLUSION</h3> There was a greater number of surgical TrV reinterventions (i.e. repair or replacement) in the TVR2-3 population, with two deaths associated with critical residual TVI refractory to reintervention. Progressive left ventricular dilatation in the TVR2-3 group due to residual TVI was well tolerated. Ventricular remodeling did not significantly impact left ventricular function or clinical status.

Re-do MitraClip in patients with functional mitral valve regurgitation and advanced heart failure.

AimPercutaneous mitral valve repair (PMVR) via MitraClip implantation is a therapeutic option for severe mitral regurgitation (MR) in advanced stages of heart failure (HF). However, progressive left ventricular dilation in these patients may lead to recurrent MR after PMVR and consequent re‐do MitraClip implantation. Here, we describe the characteristics and outcomes of this clinical scenario.Methods and resultsPatients with systolic HF and functional MR undergoing a re‐do MitraClip procedure were retrospectively analysed. Inclusion criteria were age ≥18 years, technical, device and procedural success at first MitraClip procedure, functional MR and systolic HF with an ejection fraction (EF) of <45%. Seventeen out of 684 patients undergoing PMVR with the MitraClip device at our institution between September 2009 and July 2019 were included. All patients displayed advanced HF with an EF of 20% (±9.9) and highly elevated N‐terminal pro‐brain natriuretic peptide. Technical success of the re‐do MitraClip procedure was 100%, whereas procedural and device success were only achieved in 11 patients (65%). Unsuccessful re‐do procedures were related to lower EF and implantation of more than one clip at initial procedure. However, despite reduction in MR grade and no occurrence of significant mitral stenosis after the procedure, the mortality during 12 months follow‐up remained high (8 of 17; 47%).ConclusionsIn a cohort of patients with advanced HF undergoing PMVR, re‐do MitraClip procedure was feasible, but procedural success was unsatisfactory and morbidity and mortality remained high, possibly reflecting the advanced stage of HF in these patients.

Recurrence of Functional Versus Organic Mitral Regurgitation After Transcatheter Mitral Valve Repair: Implications from Three-Dimensional Echocardiographic Analysis of Mitral Valve Geometry and Left Ventricular Dilation for a Point of No Return

MitraClip implantation has become the standard transcatheter mitral valve repair (TMVR) technique for severe mitral regurgitation (MR). However, approximately one third of patients have poor outcomes, with MR recurrence at follow-up. The aim of this study was to investigate whether quantitative analysis of mitral valve (MV) geometry on three-dimensional (3D) echocardiography can identify geometric parameters associated with the recurrence of severe functional MR (FMR) versus organic MR (OMR) at 6-month follow-up after TMVR using the MitraClip. Sixty-one patients with severe FMR (n=45) or OMR (n=16) who underwent transesophageal 3D echocardiography before and 6months after TMVR were retrospectively analyzed. MV geometry was quantified using 3D echocardiography software. Vena contracta area (VCA) at 6-month follow-up was used to define two outcome groups: patients with good results with VCA<0.6cm2(MR<0.6) and those with MR recurrence with VCA≥0.6cm2(MR≥0.6). MR recurrence was found in 34% of all study patients (21 of 61). In patients with FMR, significant differences between MR<0.6 and MR≥0.6 were found at baseline for tenting index (1.13 vs 1.23, P=.004), tenting volume (2.8 vs 4.0ml, P=.04), indexed left ventricular (LV) end-diastolic volume (68.0 vs 99.9ml/m2, P=.001), and VCA (0.71 vs 1.00cm2, P=.003); no significant parameters of MR recurrence were found in patients with OMR. Multivariate analysis identified indexed LV end-diastolic volume as the strongest independent determinant of MR recurrence. Receiver operating characteristic analysis identified a tenting index of 1.185 (area under the curve 0.79) and indexed LV end-diastolic volume of 88ml/m2 (area under the curve 0.76) to best discriminate between MR<0.6 and MR≥0.6. MR recurrence after TMVR in patients with FMR is associated with advanced LV dilation and MV tenting before TMVR, which provides clinical implications for a point of no return beyond which progressive LV dilation with MV geometry dilation and tethering cannot be effectively prevented by TMVR. In contrast, no significant determinants of MR recurrence and progressive MV annular dilation could be identified in patients with OMR.

Abstract 101: Novel Inhibitors for Temporal Modulation of T-lymphocytes During Chronic Heart Failure

CD4+ T-cells mediate wound-healing post-myocardial infarction (MI) but exacerbate left-ventricular (LV) remodeling during chronic heart failure (HF). Mechanisms that lead to this transition are unknown. Therefore, we hypothesized that as opposed to MI, T-cells activate specific pathological signals to promote LV-remodeling during chronic HF. To identify such signals, we conducted limited cell RNA-sequencing of CD4+ T-cells sorted from the failing hearts (8 weeks post-MI) of male mice and, surprisingly, found activation of estrogen receptor (ER)-α signaling. As ERα effects are antagonized by ERβ, we tested a novel ERβ agonist (OSU-ERB-012) to modulate T-cell activity and LV remodeling. In-vitro assays showed that OSU-ERB-012 dose dependently inhibit activation and proliferation of T-cells isolated from male mice (IC 50 3.4 μM). In-vivo assays (60 mg/kg/day; oral) showed no overt toxicity and a significant reduction in circulating T cells without affecting neutrophils, monocytes, or B-cells indicating specificity against T-cells. Furthermore, this effect was specific to TCR-mediated T-cell activation and the drug did not affect T-cells stimulated with PMA/Ionomycin suggesting preferential inhibition of antigenically-activated T-cells. To test therapeutic efficacy, male 10-12 week old mice underwent coronary ligation or sham operation and at 4 weeks post-MI randomized according to their cardiac function to receive either the vehicle or OSU-ERB-012 (60 mg/kg/day, oral) for the next 4 weeks. Consistently, at 8 weeks we observed a significant reduction in T-cells in the circulation and the spleens of drug-treated mice when compared with the vehicle treatment. As expected, vehicle treated HF mice showed progressive LV dilatation with significantly increased end-diastolic and end-systolic volumes (EDV and ESV, respectively) from 4-8 weeks post-MI. Importantly, treatment with OSU-ERB-012 significantly inhibited these changes and blunted LV remodeling from 4-8 weeks post-MI. Significant reduction in tibia-normalized heart weights supported these results. Our studies indicate that OSU-ERB-012 is a novel orally-active drug molecule that selectively inhibits T-cell activation and blunts pathological LV-remodeling during chronic HF.

Mechanisms of mitral regurgitation after percutaneous mitral valve repair with the MitraClip.

We sought to find the morphological mechanisms of recurrent mitral regurgitation (MR) after MitraClip procedure using 3D transoesophageal echocardiography (TOE). Of 478 consecutive patients treated with the initial MitraClip procedure, 41 patients who underwent repeat mitral valve (MV) transcatheter or surgical intervention for recurrent MR were retrospectively reviewed. Using 3D-TOE, we investigated morphological changes of MV leading to repeat MV intervention. Aetiology of MR at the index intervention was primary in 24 (59%) and secondary in 17 (41%) patients. In the primary MR group, worsening leaflet prolapse at the clip site caused recurrent MR in 12 (50%) patients, while 7 (29%) patients had a leaflet tear at the clip site. Acute single leaflet device detachment was seen in four patients and one patient had recurrent MR between the plug and the clip. In secondary MR, left ventricular (LV)/left atrial dilation caused recurrent MR in 13 (76%) patients. Significant increase in the LV end-diastolic volume and tenting height were observed from post-index procedure to repeat intervention (LV end-diastolic volume; from 205 to 237 ml, P < 0.001, tenting height; from 0.8 to 1.3 cm, P < 0.001). New emergent leaflet prolapse/flail was seen in 3 (18%) patients, suggesting iatrogenic MR. Mechanisms of recurrent MR after MitraClip procedure varied and depended on the underlying MV pathology: in primary MR, worsening mitral leaflet prolapse and in secondary MR, progressive LV dilation with worsening tenting were the main causes of recurrent MR.

P3804Left ventricular wall thickness measured with computed tomography predicts mitral regurgitation improvement in patients implanted with cardiac resynchronization therapy

Abstract Background Secondary mitral regurgitation (MR) is common in heart failure (HF) patients and results in progressive left ventricular (LV) dilatation, papillary muscle (PM) displacement and mitral valve leaflet tethering. In selected HF patients, cardiac resynchronization therapy (CRT) has been proved to reduce MR by LV reverse remodeling, resynchronization of PM insertion site contraction and reduction in MV tenting area and inter PM distance. However, data regarding the impact of LV wall thickness (WT) on MR improvement are scarce. Methods In this prospective study, a total 54 patients scheduled for CRT, underwent pre procedural CT. Reduced LV WT was defined as WT&lt;6mm and was quantified as a percentage of total LV area. LV was segmented in 17 segments to assess the number of LV segments with reduced WT. End point was 6-month echocardiographic MR improvement by ≥1 class. For this analysis, we focused on patient with mild (class 2) to severe (class 4) MR. Results Among the 54 patients, 38 (70.4%) had mild to severe MR at baseline and a total of 16 (42.1%) experienced MR improvement by ≥1 class at 6 months. there was no difference regarding the co-morbidities, electrocardiogram and echocardiographic parameters between patients with or without MR improvement. However, patients without MR improvement had significant higher NT-pro BNP level at baseline. Interestingly, patients without MR improvement had larger LVWT &lt;6mm area (41.541.5±19.4 vs. 22.4±16.1%, p=0.003) associated with higher number of papillary muscle (PM) inserted in reduced LV WT area. In multivariate analysis, an area ≥25% of LVWT&lt;6mm including at least 1 PM insertion was the only predictor of no MR improvement at 6 months (HR 18.4 (1.25–271.75), p=0.034). Lastly, patients with MR improvement had significant lower rate of basal segments with reduced WT, especially in the lateral location. Of note, patients with MR improvement exhibited fewer rate of postero-lateral WT &lt;6mm segments. Left ventriculat segmentation Conclusion LV WT evaluated using CT is a strong predictor of no MR improvement in HF patients with mild to severe MR and who scheduled for CRT implantation.

Glucagonoma-associated dilated cardiomyopathy refractory to somatostatin analogue therapy.

SummaryA 67-year-old woman presented with a generalised rash associated with weight loss and resting tachycardia. She had a recent diagnosis of diabetes mellitus. Biochemical evaluation revealed elevated levels of circulating glucagon and chromogranin B. Cross-sectional imaging demonstrated a pancreatic lesion and liver metastases, which were octreotide-avid. Biopsy of the liver lesion confirmed a diagnosis of well-differentiated grade 2 pancreatic neuroendocrine tumour, consistent with metastatic glucagonoma. Serial echocardiography commenced 4 years before this diagnosis demonstrated a progressive left ventricular dilatation and dysfunction in the absence of ischaemia, suggestive of glucagonoma-associated dilated cardiomyopathy. Given the severity of the cardiac impairment, surgical management was considered inappropriate and somatostatin analogue therapy was initiated, affecting clinical and biochemical improvement. Serial cross-sectional imaging demonstrated stable disease 2 years after diagnosis. Left ventricular dysfunction persisted, however, despite somatostatin analogue therapy and optimal medical management of cardiac failure. In contrast to previous reports, the case we describe demonstrates that chronic hyperglucagonaemia may lead to irreversible left ventricular compromise. Management of glucagonoma therefore requires careful and serial evaluation of cardiac status.Learning points:In rare cases, glucagonoma may present with cardiac failure as the dominant feature. Significant cardiac impairment may occur in the absence of other features of glucagonoma syndrome due to subclinical chronic hyperglucagonaemia.A diagnosis of glucagonoma should be considered in patients with non-ischaemic cardiomyopathy, particularly those with other features of glucagonoma syndrome.Cardiac impairment due to glucagonoma may not respond to somatostatin analogue therapy, even in the context of biochemical improvement.All patients with a new diagnosis of glucagonoma should be assessed clinically for evidence of cardiac failure and, if present, a baseline transthoracic echocardiogram should be performed. In the presence of cardiac impairment these patients should be managed by an experienced cardiologist.

Reverse, stationary and progressive left ventricular dilatation in dilated and nondilated ventricles on admission following first anterior STEMI

The relationship between admission left ventricular (LV) volumes, regional contractility and persistent ST elevation in first anterior ST elevation myocardial infarction (STEMI) with evolution of LV volumes at 12 months remains inconclusive. Thus possible differences among patients with reverse dilatation (RD), stationary dilatation (SD) or progressive dilatation (PD) at 12 months based on left ventricle end-systolic volume (LVESV) index changes were investigated. ECG and echocardiographic features of 394 1-year survivors of anterior STEMI were analyzed at admission, 6 and 12 months in those with RD (≥15% reduction of LVESV index, at 12 months n=141), SD (<15% reduction or increase, n=123) or PD (≥15% increase, n=130). Long-term outcome was also evaluated. Admission LVESV values in tertiles and incidence of moderate-severe mitral regurgitation were similar in three groups. In patients with RD, LVESV decreased at 6 months (P<0.001) and further at 12 months (P=0.003), whereas in PD, it increased at 6 months (P<0.001) and further at 12 months (P=0.016). Contractility score in PD was higher on admission (P=0.050) than in the other groups, but it involved the same segments. At 12 months, it improved in each of the six most affected in RD (P<0.001) and SD (P=0.025-0.001) but not in PD group (P=0.452-1.00). Persistent ST elevation at 24 h and peak troponin I were the only independent predictors for RD (odds ratio: 0.900, 95% confidence interval: 0.840-0.905, P=0.003; 0.996, 0.986-0.994, P<0.001) and PD (1.143, 1.001-1.304, P=0.048; 1.004, 1.002-1.006, P<0.001), respectively. During an 8-year follow-up, 77 (19.5%) patients died and although the total mortality was comparable in the three groups, cardiac death or hospitalization for heart failure was higher in the PD (16/130, 14%) than in the other two groups (14/250, 5.6%, P=0.014). Admission normal or enlarged LV volumes may evolve towards RD, SD or PD at 12 months following first anterior STEMI mainly depending in part on infarct size. Importantly, relevant changes occur at not only 6 months but also between 6 and 12 months.