Improvement In Cardiac Function Research Articles

Dynamic Electrocardiogram under P Wave Detection Algorithm Combined with Low-Dose Betaloc in Diagnosis and Treatment of Patients with Arrhythmia after Hepatocarcinoma Resection.

This work aimed to study the diagnostic value of dynamic electrocardiogram (ECG) based on P wave detection algorithm for arrhythmia after hepatectomy in patients with primary liver cancer, and to compare the therapeutic effect of different doses of Betaloc. P wave detection algorithm was introduced for ECG automatic detection and analysis, which can be used for early diagnosis of arrhythmia. Sixty patients with arrhythmia after hepatectomy for primary liver cancer were selected as the research objects. They were randomly divided into control group, SD group, MD group, and HD group, with 15 cases in each group. No Betaloc, low-dose (≤47.5 mg), medium-dose (47.5–95 mg), and high-dose (142.5–190 mg) Betaloc were used for treatment. As a result, P wave detection algorithms can mark P waves that may be submerged in strong interference. P waves from arrhythmia database were used to verify the performance of the proposed algorithm. The prediction precision (Pp) of ventricular arrhythmia and atrial arrhythmia was 98.53% and 98.76%, respectively. Systolic blood pressure (117.35 ± 7.33, 126.44 ± 9.38, and 116.02 ± 8.2) mmHg in SD group, MD group, and HD group was significantly lower than that in control group (140.3 ± 7.21) mmHg after two weeks of treatment. Moreover, those of SD group and HD group were significantly lower than MD group (P < 0.05). The effective rate of cardiac function improvement in SD group (72.35 ± 1.21%) was significantly higher than that in control group, MD group, and HD group (38.2 ± 0.98%, 65.12 ± 1.33%, and 60.43 ± 1.25%; P < 0.05). In short, dynamic ECG based on P wave detection algorithm had high diagnostic value for arrhythmia after hepatectomy in patients with primary liver cancer. It was safe and effective for patients to choose small dose of Betaloc.

The cardioprotective effect of intralipid in decreasing the ischemic insults during off-pump coronary artery revascularization

BackgroundOff pump coronary artery revascularization (OPCAB) surgeries have benefits over the conventional on pump cardiac surgery, because it avoids the trauma caused by cardiopulmonary bypass (CPB) and minimize aortic manipulation. However, some disadvantages of OPCAB include the concern of ineffective coronary revascularization. Some drugs have shown the ability to protect the myocardium in different studies, by different methods. The usage of intralipid has been shown to make a better functional recovery of the cardiac muscles and help to decrease the myocardial infarct size, it shortens the action potential time, which show polyunsaturated fatty acids diets mechanism as an antiarrhythmic drug, and are associated with low incidence of coronary artery disease.MethodsWe divided patients into two groups according to the randomization envelopes: intralipid group (group A) received 1.5 ml/kg intralipid 20% through central venous line after sternotomy over 1 h and during infusion, blood pressure, heart rate, and temperature were monitored all through the infusion time. Control group (group B) received normal saline 0.9% in the same volume over the same duration.ResultsThis study showed that infusion of 1.5 ml/kg intralipid after sternotomy in off pump coronary artery revascularization given as preconditioning agent improve the myocardial ischemia reperfusion injury, decrease the need for high doses of nor adrenaline infusion after revascularization, earlier normalization in troponin levels starting 24 h after surgery and higher values of cardiac index were measured in ICU using PICCO.ConclusionsThis study showed the benefits of infusion of 1.5 ml/kg of intralipid after sternotomy, in preconditioning during OPCABG. Preconditioning with intralipid proved to decrease reperfusion injury in myocardium expressed by improvement in cardiac functions (EF and cardiac index) and normalization of specific cardiac marker (cardiac troponin I).

Levosimendan versus dobutamine for sepsis-induced cardiac dysfunction: a systematic review and meta-analysis

Levosimendan and dobutamine are extensively used to treat sepsis-associated cardiovascular failure in ICU. Nevertheless, the role and mechanism of levosimendan in patients with sepsis-induced cardiomyopathy remains unclear. Moreover, previous studies on whether levosimendan is superior to dobutamine are still controversial. More importantly, these studies did not take changes (before-after comparison to the baseline) in quantitative parameters such as ejection fraction into account with the baseline level. Here, we aimed to determine the pros and cons of the two medicines by assessing the changes in cardiac function and blood lactate, mortality, with the standardized mean difference used as a summary statistic. Relevant studies were obtained by a thorough and disciplined literature search in several notable academic databases, including Google Scholar, PubMed, Cochrane Library and Embase until November 2020. Outcomes included changes in cardiac function, lactic acid, mortality and length of hospital stay. A total of 6 randomized controlled trials were included in this study, including 192 patients. Compared with dobutamine, patients treated with levosimendan had a greater improvement of cardiac index (ΔCI) (random effects, SMD = 0.90 [0.20,1.60]; I2 = 76%, P < 0.01) and left ventricular stroke work index (ΔLVSWI) (random effects, SMD = 1.56 [0.90,2.21]; I2 = 65%, P = 0.04), a significant decrease of blood lactate (Δblood lactate) (random effects, MD = − 0.79 [− 1.33, − 0.25]; I2 = 68%, P < 0.01) at 24-h after drug intervention, respectively. There was no significant difference between levosimendan and dobutamine on all-cause mortality in ICU (fixed effect, OR = 0.72 [0.39,1.33]; I2 = 0%, P = 0.99). We combine effect sizes related to different measurement parameters to evaluate cardiac function, which implied that septic patients with myocardial dysfunction might have a better improvement of cardiac function by levosimendan than dobutamine (random effects, SMD = 1.05 [0.69,1.41]; I2 = 67%, P < 0.01). This study suggested a significant improvement of CI, LVSWI, and decrease of blood lactate in septic patients with myocardial dysfunction in ICU after 24-h administration of levosimendan than dobutamine. However, the administration of levosimendan has neither an impact on mortality nor LVEF. Septic patients with myocardial dysfunction may partly benefit from levosimendan than dobutamine, mainly embodied in cardiac function improvement.

Changes in cMRI parameters following a switch to riociguat from phosphodiesterase type 5 inhibitors (PDE5i) in patients with pulmonary arterial hypertension: a REPLACE substudy

Abstract Background The REPLACE study investigated the effect of switching to riociguat (RIO) in patients with pulmonary arterial hypertension receiving PDE5i but still at intermediate risk. The centrally adjudicated composite primary endpoint was clinical improvement in the absence of clinical worsening, where clinical improvement was defined as meeting at least two of the following criteria: 6-minute walk distance (6MWD), increase by ≥10% or ≥30 m from baseline (BL) to Wk 24; World Health Organization functional class (WHO FC) I or II at Wk 24; or N-terminal prohormone of brain natriuretic peptide reduction of ≥30% from BL to Wk 24. Twice as many patients switching to RIO (45/111, 41%) met the primary endpoint compared with those remaining on PDE5i (23/113, 20%); odds ratio (OR): 2.78 (95% confidence interval [CI] 1.53–5.06); p=0.0007. Purpose Assess changes in right and left ventricular (RV; LV) function using cardiac magnetic resonance imaging (cMRI) in a subgroup of patients participating in REPLACE. Methods REPLACE was a randomised, open-label, 24-week, Phase 4 study (NCT02891850). Patients in WHO FC III, with 6MWD 165–440 m, were randomised to switch to RIO 2.5 mg–max tid or remain on PDE5i. Background endothelin receptor antagonist therapy was permitted in both arms. cMRI was performed on a subset of patients from the full analysis set as an exploratory substudy. The following parameters were measured at BL and Wk 24: RV and LV end-diastolic and end-systolic volumes (RVEDV; RVESV; LVEDV; LVESV), RV stroke volume and stroke volume index (RVSV; RVSVI), LV stroke volume (LVSV), RV ejection fraction (RVEF), and pericardial effusion. Results Twenty-seven patients participated in the cMRI substudy. This comprised 11/111 (10%) patients in the RIO arm (mean [standard deviation {SD}] 40.0 [12.4] years), and 16/113 (14%) patients (mean 44.5 [17.6] years) in the PDE5i arm. Like the main population, the treatment response in the cMRI subpopulation favoured RIO versus PDE5i (OR: 6.11 [95% CI 0.90–41.60]). From BL to Wk 24, RVEDV and RVESV decreased in the RIO treatment arm but increased in the PDE5i treatment arm (Table 1). Similar, but less pronounced, changes were observed for the left ventricle (LVESV, LVEDV). RVSV and RVEF levels were close to normal at BL and did not increase in either arm at Wk 24 (Table 1). Pericardial effusion, which was present in 5 patients in each group at BL, decreased in 1 patient in the RIO arm and no patients in the PDE5i arm. Conclusions Decreases in RVEDV and RVESV suggest improvements in cardiac function in the RIO arm compared with the PDE5i arm. Values for RVEF and RVSVI were close to normal at BL and did not change at Wk 24. Improvements in cMRI parameters were in line with the clinical improvement observed in patients switching to RIO in the overall population. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): The REPLACE study was co-funded by Bayer AG (Berlin, Germany) and Merck Sharp &amp; Dohme Corp., a subsidiary of Merck &amp; Co., Inc. (Kenilworth, NJ, USA)

Sex differences in cardio-oncology: utilizing a genetic variant as a therapeutic target doxorubicin-induced cardiomyopathy

Abstract Introduction Doxorubicin is an anthracycline used as a chemotherapeutic drug for the treatment of a wide range of adult and pediatric cancers. Doxorubicin is associated with an increased risk of cardiomyopathy and heart failure with up to 10% of patients developing cardiac complications. A GWAS conducted of 1,191 patients from the N9831 clinical trial identified that cardiac gene expression and genetic variants of TRPC6 were associated with a decline in left ventricular ejection fraction (LVEF) (p=0.005 and p=1.6x10–6, respectively). TRPC6 is a non-selective cation channel expressed in heart and vascular tissue. TRPC6 participates in the pathogenesis of cardiac hypertrophy as a pathological response to chronic mechanical stress. Chronic activation has been found to promote cardiac fibrosis leading to heart failure. Purpose TRPC6 variants could be associated with increased risk of doxorubicin-induced cardiotoxicity. Data/tests to determine which patients may progress to cardiomyopathy and heart failure are currently lacking and there are no targeted treatments to prevent cardiomyopathy in these patients. Methods In preliminary in vivo data, B6.129 wild-type mice or TRPC6 knockout mice were treated with either 6x intraperitoneal saline or 4mg/kg doxorubicin injections (cumulative dose of 24mg/kg). Results We found doxorubicin increased cardiac vacuolation (male, p≤0.001 and female, p≤0.05) in WT mice compared to controls. Higher HW/BW ratio was observed in male TRPC6 knock out mice compared to wild-type mice when both were treated with doxorubicin (males, p=0.005 and females, p=0.19). Additionally, we found that doxorubicin-induced cardiac injury was significantly reduced in TRPC6 knock-out mice compared to wild-type mice based on reduced vacuolation (p=0.0004 males, p=0.03 females), with the effect being greater in male mice than female mice. Furthermore, a significant decrease in stroke volume (p=0.007), diastolic volume (p=0.01) and cardiac output (p=0.004) in wild-type male mice treated with doxorubicin compared to control and TRPC6 knock-out mice. Our in vitro preliminary data show that inhibition of TRPC6 using the TRPC6 inhibitor GsMTx-4 in human iPSC-derived cardiomyocytes significantly reduced doxorubicin-induced apoptosis (p&amp;lt;0.0001). Further we treated male mice with the TRPC6 inhibitor, GsMTx4, and found that they had less global longitudinal cardiac strain (p=0.04) and higher ejection fraction (p=0.01) compared to mice who were only treated with doxorubicin. Histologically we found that mice given the TRPC6 inhibitor had less fibrosis as measured by Trichrome stained heart sections (p=0.004) which could account for improvements in cardiac function. Conclusion TRPC6 could be a novel therapeutic target in the prevention of chemotherapy-induced cardiomyopathy and heart failure. Additionally genetic mapping of TRCP6 functional variants may provide a new screening tool to determine increased risk of developing heart failure. Funding Acknowledgement Type of funding sources: Private hospital(s). Main funding source(s): Mayo Clinic

Quantitative and qualitative composition of the innate immune response are equally important in wound healing after myocardial infarction

Abstract Background Emergency hematopoiesis (EH) serves as the foundation of monocyte-derived and macrophage (Mφ) driven efferocytosis and ventricular remodeling after myocardial infarction (MI). Excessive myelopoiesis, however, can stipulate maladaptive wound healing and its therapeutic reduction may be a novel approach to preserve cardiac function. All-trans retinoic acid (ATRA) is a pleiotropic modulator of EH and innate immunity shielding hematopoietic stem cells from activation and driving survival and differentiation of myeloid cells. Purpose This study aimed to investigate this intriguing interplay of ATRA in wound healing after MI. Methods MI was induced by permanent coronary ligation in C57BL/6 mice and treated with daily injections of either ATRA (30mg/kg) or DMSO (vehicle) up to five days, starting 24h after ligation. Flow cytometry (FACS) was used for cell cycle analysis and immunophenotyping of leukocytes in bone marrow (BM), blood and heart. Immunohistochemistry (IH), masson trichrome (MT) staining and echocardiography evaluated inflammatory-fibrotic and functional development. Cytokine expression was analyzed by qPCR in bulk infarct and isolated, polarized Mφ-populations of BM-derived and cardiac resident origin. Results On day 2 after MI, EH was significantly reduced in ATRA-treated mice as compared to vehicle controls by means of cell cycle activity (n=6–13 per group; p&amp;lt;0,01) and myeloid cells in BM, blood and infarct tissue (n=5–13; p&amp;lt;0,05). Consequently, mRNA-expression of key inflammatory cytokines, IL-1β and TNFα, was diminished in the infarct tissue in this early phase (n=5–12; p&amp;lt;0,05). These changes, however, failed to preserve cardiac function and ventricular remodeling, 21 days after MI (n=10–11; not significant). By qPCR, non-canonical activation of recruited ATRA-primed monocyte-derived Mφ, was found to propagate a pro-inflammatory phenotype with higher expression of MMP2 and MMP9 in sorted cardiac Mφ (n=4–5; p&amp;lt;0,001). Furthermore, prominent IL-1β-expression in M2-polarized BM-derived Mφ indicated an impaired anti-inflammatory phenotype after ATRA treatment (n=4–6; p&amp;lt;0,05). Strikingly, these changes also occurred in remote myocardium where IH revealed a 2-fold increase of CD11b - positive myeloid cells accompanied by increased expression of TNFα and TGFβ (n=9; p&amp;lt;0,001). MT-staining, performed 21 days after MI, demonstrated an almost 3-fold increase in collagen deposition in remote myocardium of ATRA treated mice in contrast to vehicle controls (n=4–6; p&amp;lt;0,0001). Conclusion Despite a beneficial reduction of EH after MI, short-term treatment with ATRA induced profound and persisting changes in the cytokine expression of monocyte-derived Mφ, which significantly altered their function and thus prevented improvements in cardiac function. Our data provide evidence that quantitative and qualitative changes in innate immunity are equally important for cardiac remodeling after MI. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Deutsche Forschungsgemeinschaft

Efficacy of left bundle branch area pacing in patients with indication for cardiac resynchronization therapy

Abstract Background Cardiac resynchronization therapy (CRT) with biventricular pacing has demonstrated clinical benefits in heart failure patients with left bundle branch block (LBBB) and ventricular dysfunction. Left bundle branch area pacing (LBBAP) results in a relatively short QRS duration (QRSd) with fast left ventricular activation and could be considered as an alternative to conventional CRT. Purpose The aim of the present study was to evaluate the feasibility and outcomes of LBBAP in patients with indications for CRT. Methods Consecutive patients with indications for CRT were included. LBBAP was performed via transventricular septal approach (1–3). We aimed to achieve a paced QRS with right bundle branch conduction delay morphology, a stimulus to peak left ventricular activation time (S-LVAT) &amp;lt;100ms and/or a QRSd ≤130ms. AV delay programming was individualized in patients in sinus rhythm, taking consideration of the AV conduction, programming the one that generated the shortest QRSd at rest. Rate adaptive AV was also activated in these patients. Pacing electrical and echocardiographic parameters were recorded at baseline and during follow-up. Results LBBAP was achieved in 19 of 21 (90.5%) patients with indication for CRT. Indications were heart failure with LBBB and left ventricular ejection fraction (LVEF) ≤35% in 8 (42%), AV node ablation or AV block with LVEF &amp;lt;50% and high expected RV pacing burden in 9 (47%), 1 pacing-induced cardiomyopathy and 1 patient with biventricular pacemaker malfunction (high LV capture threshold). The mean follow-up was 4.6±1.7 months and the percentage of ventricular pacing was 93.4±13.9%. There were no device-related complications during this period. LBBA capture threshold was 0.6±0.3V at 0.4ms at the implantation, and remained stable (0.7±0.1 V, p=0.17). The lead impedance and R-wave amplitude at implantation were 636±106 ohms and 13.4±6.8 mV, and 541±88 ohms and 13.0±5.1 mV during the follow-up (p&amp;lt;0.001 and p=0.27, respectively). Mean S-LVAT was 85.5±13.9 ms, and mean QRSd was 122±9 ms, that remained stable during follow-up (122 vs 124 ms, p=0.21). In patients with LBBB, a significant narrowing of paced QRSd was achieved (160.9±16.7 vs. 123.9±9.7 ms, p&amp;lt;0.001). Mean LVEF increased by 15.9%, from 35.4±8.9% at baseline to 51.3±9.8% at follow-up (p&amp;lt;0.001) in the overall population, and 14.5% (from 32.7±4.8% to 47.2±10.7%, p=0.001) in patients with LBBB. After one month, estimated time for elective replacement was 11.9±0.4 years. Conclusions LBBPA was successfully achieved in 90.5% of the patients with indication for CRT, with good and stable pacing electrical parameters, long estimated battery longevity and relatively narrow QRS, and was associated with improvement in cardiac function. LBBAP may be considered as a first-line option for patients with indications for CRT. Funding Acknowledgement Type of funding sources: None.

Uptake of [68Ga]-NODAGA-E[(cRGDyK)]2 is related to improvement in pump function in rats with chronic ischemic cardiomyopathy treated with cell therapy

Abstract Background An increasing number of patients living with chronic ischemic cardiomyopathy (ICM) are potential candidates for cell therapy, including adipose tissue-derived mesenchymal stromal cells (ASC). However, proper assessment of clinical effects in relation to cellular effector mechanisms, such as angiogenesis, is currently lacking. Purpose To investigate the prognostic value of assessing angiogenesis non-invasively using novel PET imaging in terms of functional outcome after cell therapy in a homologous animal model of ICM. Methods Myocardial infarction was induced by permanent ligation of the left anterior descending coronary artery. Four weeks after infarction, the rats were scanned with [18F]-FDG and echocardiography, and based on left ventricular ejection fraction (LVEF) and infarct size randomized to allogeneic ASC treatment (n=14) or saline (n=9). Animals were treated using echo-guided trans-thoracic intramyocardial injections. Follow-up echocardiography was performed four weeks after treatment. Angiogenesis was assessed non-invasively using the [68Ga]-NODAGA-E[(cRGDyK)]2 (RGD) PET-tracer before treatment and two weeks after the treatment (Figure). The output was RGD-uptake by maximum standardized uptake value (SUVmax). Results RGD-uptake in the infarct area significantly decreased in the saline group (p=0.04), while this decline was not significant in the ASC group (p=0.58). There was no effect on LVEF of the cell therapy in this study (p=0.70). When the rats were grouped by RGD-uptake post treatment, the high RGD-uptake group (n=8) improved LVEF compared to the rats with medium or low RGD-uptake (n=15, p=0.04) irrespective of the treatment. This could indicate that non-invasive detection of a high degree of myocardial angiogenesis measured using RGD is predictive of improvement in cardiac pump function in ICM. Conclusions Following injection of ASC or saline, a high RGD-uptake precluded improvement in pump function. This is the first evidence of how uptake of the novel RGD tracer relates to changes in pump function in ICM and the results could affect the design of future clinical trials using regenerative therapy for ICM patients. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Aase and Ejnar Danielsens FondDoctor Sofus Carl Emil Friis and wife Olga Doris Friis' Scholarship Study design, RGD-uptake, and results

Circulating microRNA-122-5p correlates with improvement in left-ventricular function after transcatheter aortic valve replacement and regulates viability of cardiomyocytes via extracellular vesicles

Abstract Transcatheter aortic valve replacement (TAVR) is a well-established treatment option for high- and intermediate-risk patients with severe symptomatic aortic valve stenosis (AVS). However, a specific role for circulating microRNAs (miRNAs) in the improvement of cardiac function for patients after TAVR has not yet been investigated. Herein, we generally explored the differential expression of miRNAs in circulating extracellular vesicles (EV-miRNAs) in patients after TAVR and, in particular, the novel role of circulating miR-122-5p in cardiomyocytes. Circulating EV-associated miRNAs were investigated by using an unbiased Taqman-based human miR array. Several EV-miRNAs (miR-122-5p, miR-26a, miR-192, miR-483-5p, miR-720, miR-885-5p, and miR-1274) were significantly deregulated in aortic stenosis patients at day seven after TAVR in comparison to the pre-procedural levels in patients without LVEF-improvement. The higher levels of miR-122 were negatively correlated with LVEF improvement at both day seven (r=−0.264 and p=0.015) and at six months (r=−0.328 and p=0.0018) after TAVR. At the three-year follow-up, patients with a higher level of miR-122-5p displayed significantly increased cardiovascular mortality (p=0.03). By utilization of patient-derived samples and a murine aortic-stenosis model, we observed that the expression of miR-122-5p correlates negatively with cardiac function, which is associated with LVEF. Graded wire-injury-induced aortic-valve-stenotic mice demonstrated a higher level of miR-122-5p, which was related to cardiomyocyte dysfunction. Murine ex vivo experiments revealed that miR-122-5p is highly enriched in endothelial cells in comparison to cardiomyocytes. Co-culture experiments with endothelial cells and cardiomyocytes, copy-number analysis, fluorescence microscopy with Cy3-labeled miR-122-5p demonstrated that miR-122-5p can be shuttled via large extracellular vesicles from endothelial cells into cardiomyocytes. Gain- and loss-of-function experiments suggested that EV-mediated shuttling of miR-122-5p increases the level of miR-122-5p in recipient cardiomyocytes and regulates viability of the cardiomyocytes. In silico prediction and mass spectrometry were used to search for binding partners of miR-122-5p. Mechanistically, miR pulldown, electrophoretic mobility shift assay, and RNA immunoprecipitation confirmed that miR-122-5p interacts with an RNA-binding protein, hnRNPU, in a sequence-specific manner to encapsulate miR-122-5p into large EVs. Upon shuttling into recipient cells, miR-122-5p negatively regulates the expression of the anti-apoptotic gene BCL2, by binding to its 3' untranslated region to regulate its translation, and thereby decreasing the viability of target cardiomyocytes. Increased levels of circulating pro-apoptotic EV-incorporated miR-122-5p is associated with reduced LVEF after TAVR. Extracellular vesicular shuttling of miR-122-5p regulates the viability and apoptosis of cardiomyocytes in a Bcl2-dependent manner. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): German Research Foundation (DFG); German Society of Cardiology (DGK)

Novel antisense therapy targeting microRNA-132 in patients with heart failure

Abstract Background Cardiac microRNA-132-3p (miR-132) levels are increased in patients with heart failure (HF) and mechanistically drive cardiac remodelling processes. CDR132L, a specific antisense oligonucleotide, is a first-in-class miR-132 inhibitor that attenuates and even reverses HF in preclinical models. Purpose The aim of the current clinical Phase 1b study was to assess safety, pharmacokinetics, target engagement, and exploratory pharmacodynamic effects of CDR132L in patients on standard-of-care therapy for chronic ischaemic HF in a randomized, placebo-controlled, double-blind, dose-escalation study. Methods Patients had left ventricular ejection fraction between ≥30% and &amp;lt;50% or amino terminal fragment of pro-brain natriuretic peptide (NT-proBNP) &amp;gt;125 ng/L at screening. Twenty-eight patients were randomized to receive CDR132L (0.32, 1, 3, and 10 mg/kg body weight) or placebo (0.9% saline) in two intravenous infusions, 4 weeks apart in four cohorts of seven (five verum and two placebo) patients each. Results CDR132L was safe and well tolerated, without apparent dose-limiting toxicity. A pharmacokinetic/pharmacodynamic dose modelling approach suggested an effective dose level at ≥1 mg/kg CDR132L. CDR132L treatment resulted in a dose-dependent, sustained miR-132 reduction in plasma. Patients given CDR132L ≥1 mg/kg displayed median 23.3% NT-proBNP reduction, vs. 0.9% median increase in the control group. CDR132L treatment induced significant QRS narrowing and positive trends for cardiac fibrosis biomarkers. Conclusions This study is the first clinical trial of an antisense drug in HF patients. CDR132L was safe and well tolerated, confirmed linear plasma pharmacokinetics with no signs of accumulation, and suggests cardiac functional improvements. The indicative efficacy of this drug is very encouraging justifying additional clinical studies to confirm the beneficial CDR132L pharmacodynamic effects for the treatment of HF. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Cardior Pharmaceuticals GmbH

Novel Mechanisms of Exosome-Mediated Phagocytosis of Dead Cells in Injured Heart.

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Association between ethnicity and degree of improvement in cardiac function following initiation of sacubitril/valsartan.

The aim of this study was to determine the degree of short-term improvement in left ventricular ejection fraction (LVEF), haemodynamics, NT-proBNP and quality of life following initiation of sacubitril/valsartan in black patients when compared with white patients. This was a retrospective, observational, single-centre, hypothesis-generating study of patients with symptomatic heart failure and reduced ejection fraction (HFrEF) treated with guideline recommended therapy, who were transitioned from an ACE inhibitor (ACE-I) or angiotensin receptor blocker (ARB) to sacubitril/valsartan. Our analysis included 83 patients (mean age 57 years) with echocardiography performed before and after transition from ACE-I/ARB to sacubitril/valsartan, after excluding patients with concomitant Cardiac resynchronization therapy implantation. Overall, sacubitril/valsartan was associated with LVEF improvement from 28.8% ± 0.7 to 32.0% ± 1.1% (P = 0.0002), but no reverse remodelling was observed. The association with LVEF improvement was only observed in white patients (n = 46, P = 0.0006), but not in black patients (n = 37, P = 0.1728), and appeared to be associated with reduced blood pressure (baseline vs. 2-week blood pressure 116.5 ± 13.9 vs. 109.4 ± 14.3 mmHg, respectively, in white patients, P = 0.0449). Fifteen patients (18.1%) became ineligible for primary prevention Implantable cardioverter defibrillator implantation. Sacubitril/valsartan was associated with improved LVEF, NT-proBNP concentrations and quality of life in patients with symptomatic HFrEF on guideline recommended therapy. However, in our cohort, improvement of LVEF and quality of life might be attenuated in black patients, which warrants further investigation.

Bone Morphogenetic Protein 7 Gene Delivery Improves Cardiac Structure and Function in a Murine Model of Diabetic Cardiomyopathy.

Diabetes is a major contributor to the increasing burden of heart failure prevalence globally, at least in part due to a disease process termed diabetic cardiomyopathy. Diabetic cardiomyopathy is characterised by cardiac structural changes that are caused by chronic exposure to the diabetic milieu. These structural changes are a major cause of left ventricular (LV) wall stiffness and the development of LV dysfunction. In the current study, we investigated the therapeutic potential of a cardiac-targeted bone morphogenetic protein 7 (BMP7) gene therapy, administered once diastolic dysfunction was present, mimicking the timeframe in which clinical management of the cardiomyopathy would likely be desired. Following 18 weeks of untreated diabetes, mice were administered with a single tail-vein injection of recombinant adeno-associated viral vector (AAV), containing the BMP7 gene, or null vector. Our data demonstrated, after 8 weeks of treatment, that rAAV6-BMP7 treatment exerted beneficial effects on LV functional and structural changes. Importantly, diabetes-induced LV dysfunction was significantly attenuated by a single administration of rAAV6-BMP7. This was associated with a reduction in cardiac fibrosis, cardiomyocyte hypertrophy and cardiomyocyte apoptosis. In conclusion, BMP7 gene therapy limited pathological remodelling in the diabetic heart, conferring an improvement in cardiac function. These findings provide insight for the potential development of treatment strategies urgently needed to delay or reverse LV pathological remodelling in the diabetic heart.

Inorganic nitrate attenuates cardiac dysfunction: roles for xanthine oxidoreductase and nitric oxide.

NO is a vasodilator and independent modulator of cardiac remodelling. Commonly, in cardiac disease (e.g., heart failure), endothelial dysfunction (synonymous with NO deficiency) has been implicated in increased BP, cardiac hypertrophy and fibrosis. Currently, no effective therapies replacing NO have succeeded in the clinic. Inorganic nitrate (NO3 - ), through chemical reduction to nitrite and then to NO, exerts potent BP lowering, but whether it might be useful in treating undesirable cardiac remodelling is not known. We analysed demographics in a nested age- and sex-matched case-control study of hypertensive patients with or without left ventricular hypertrophy (NCT03088514) and assessed the effects of dietary nitrate in mouse models of cardiac dysfunction. Lower plasma nitrite concentrations and vascular dysfunction accompanied cardiac hypertrophy and fibrosis in patients. In mouse models of cardiac remodelling, restoration of circulating nitrite levels using dietary nitrate improved endothelial dysfunction through targeting the xanthine oxidoreductase-driven increase in levels of H2 O2 and superoxide, and decreased cardiac fibrosis through NO-mediated block of SMAD phosphorylation leading to improvements in cardiac structure and function. Dietary nitrate offers easily translatable therapeutic options for delivery of NO and thereby treatment of cardiac dysfunction.

Empagliflozin Treatment Is Associated With Improvements in Cardiac Energetics and Function and Reductions in Myocardial Cellular Volume in Patients With Type 2 Diabetes.

Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of major adverse cardiovascular (CV) events and hospitalization for heart failure (HF) in patients with type 2 diabetes (T2D). Using CV MRI (CMR) and 31P-MRS in a longitudinal cohort study, we aimed to investigate the effects of the selective SGLT2 inhibitor empagliflozin on myocardial energetics and cellular volume, function, and perfusion. Eighteen patients with T2D underwent CMR and 31P-MRS scans before and after 12 weeks’ empagliflozin treatment. Plasma N-terminal prohormone B-type natriuretic peptide (NT-proBNP) levels were measured. Ten volunteers with normal glycemic control underwent an identical scan protocol at a single visit. Empagliflozin treatment was associated with significant improvements in phosphocreatine-to-ATP ratio (1.52 to 1.76, P = 0.009). This was accompanied by a 7% absolute increase in the mean left ventricular ejection fraction (P = 0.001), 3% absolute increase in the mean global longitudinal strain (P = 0.01), 8 mL/m2 absolute reduction in the mean myocardial cell volume (P = 0.04), and 61% relative reduction in the mean NT-proBNP (P = 0.05) from baseline measurements. No significant change in myocardial blood flow or diastolic strain was detected. Empagliflozin thus ameliorates the “cardiac energy-deficient” state, regresses adverse myocardial cellular remodeling, and improves cardiac function, offering therapeutic opportunities to prevent or modulate HF in T2D.

Circulating and Myocardial Cytokines Predict Cardiac Structural and Functional Improvement in Patients With Heart Failure Undergoing Mechanical Circulatory Support.

BackgroundRecent prospective multicenter data from patients with advanced heart failure demonstrated that left ventricular assist device (LVAD) support combined with standard heart failure medications, induced significant cardiac structural and functional improvement, leading to high rates of LVAD weaning in selected patients. We investigated whether preintervention myocardial and systemic inflammatory burden could help identify the subset of patients with advanced heart failure prone to LVAD‐mediated cardiac improvement to guide patient selection, treatment, and monitoring.Methods and ResultsNinety‐three patients requiring durable LVAD were prospectively enrolled. Myocardial tissue and blood were acquired during LVAD implantation, for measurement of inflammatory markers. Cardiac structural and functional improvement was prospectively assessed via serial echocardiography. Eleven percent of the patients showed significant reverse remodeling following LVAD support (ie, responders). Circulating tumor necrosis factor alpha, interleukin (IL)‐4, IL‐5, IL‐6, IL‐7, IL‐13, and interferon gamma were lower in responders, compared with nonresponders (P<0.05, all comparisons). The myocardial tissue signal transducer and activator of transcription‐3, an inflammatory response regulator, was less activated in responders (P=0.037). Guided by our tissue studies and a multivariable dichotomous regression analysis, we identified that low levels of circulating interferon gamma (odds ratio [OR], 0.06; 95% CI, 0.01–0.35) and tumor necrosis factor alpha (OR, 0.05; 95% CI, 0.00–0.43), independently predict cardiac improvement, creating a 2‐cytokine model effectively predicting responders (area under the curve, 0.903; P<0.0001).ConclusionsBaseline myocardial and systemic inflammatory burden inversely correlates with cardiac improvement following LVAD support. A circulating 2‐cytokine model predicting significant reverse remodeling was identified, warranting further investigation as a practical preintervention tool in identifying patients prone to LVAD‐mediated cardiac improvement and device weaning.

RATE VS RHYTHM CONTROL IN A PATIENT WITH PULMONARY ARTERIAL HYPERTENSION AND ATRIAL FLUTTER: USE OF DIRECT HEMODYNAMIC MEASUREMENTS

TOPIC: Pulmonary Vascular Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Atrial arrhythmias in patients with pulmonary arterial hypertension (PAH) are generally felt to be poorly tolerated hemodynamically [1]. Although this observation has driven expert recommendations to attempt rhythm control first, there is no high-quality evidence to support this approach in rate-controlled arrhythmias. We present a case in which management in a patient with PAH and rate-controlled atrial flutter was informed by invasive hemodynamic measurements performed before and after cardioversion. CASE PRESENTATION: A 45-year-old female with history of PAH, treated with subcutaneous treprostinil and macitentan, and atrial flutter, was admitted for decompensated right heart failure and rate-controlled atrial flutter. Atrial flutter was recurrent after prior cardioversion, prompting consideration of ablation.As the patient was rate-controlled and given the potential risk of anesthesia and an invasive procedure, we measured hemodynamics before and immediately after electrical cardioversion. Hemodynamics are summarized in Table 1. Initial hemodynamics showed significant pulmonary hypertension, with evidence of both pre-capillary and post-capillary components and a reduced cardiac index. Cardioversion to sinus rhythm did not result in a significant change in hemodynamics. Given no hemodynamic improvement with restoration of sinus rhythm, ablation was not pursued. DISCUSSION: Attempting rhythm control in patients with rate-controlled atrial arrhythmias and PAH is the currently accepted practice, although the evidence to support this approach is insufficient. Improvement in cardiac function in heart failure with reduced ejection fraction can be seen immediately after electrical cardioversion, with significant improvement in stroke volume, even in rate-controlled populations[2]. In our case, hemodynamic measurements showed no improvement in cardiac performance or pulmonary pressures after cardioversion. This suggests that some patients with PAH and rate-controlled atrial arrhythmias merit an assessment of the potential benefit of a rhythm control strategy. Understanding the benefit of rhythm-control is particularly important in patients with PAH given the high-risk nature of anti-arrhythmic medications and cardiac ablation. Patients with PAH more often have atypical ablative targets leading to longer procedures, time under anesthesia, and more detrimental consequences if an iatrogenic ASD occurs[1]. CONCLUSIONS: While a rhythm control strategy may be beneficial for some PAH patients, hemodynamic evaluation may help inform the management strategy for rate-controlled atrial arrhythmias in this population. REFERENCE #1: Wanamaker, B., et al., Atrial Arrhythmias in Pulmonary Hypertension: Pathogenesis, Prognosis and Management. Arrhythm Electrophysiol Rev, 2018. 7(1): p. 43-48. REFERENCE #2: Fumagalli, S., et al., External Cardioversion of Atrial Fibrillation Causes an Early Improvement of Cardiac Performance: A Longitudinal Strain Analysis Study. J Cardiovasc Echogr, 2014. 24(1): p. 10-17. DISCLOSURES: No relevant relationships by Hana Bakalli, source=Web Response No relevant relationships by Aron Bender, source=Web Response No relevant relationships by Jessica Channick, source=Web Response Advisory Committee Member relationship with Actelion Please note: $5001 - $20000 by Richard Channick, source=Web Response, value=Consulting fee Consultant relationship with Actelion Please note: $5001 - $20000 by Richard Channick, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Arena Please note: $5001 - $20000 by Richard Channick, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Bayer Please note: $5001 - $20000 by Richard Channick, source=Web Response, value=Consulting fee Advisory Committee Member relationship with United Therapeutics Please note: $5001 - $20000 by Richard Channick, source=Web Response, value=Consulting fee No relevant relationships by Sonia Jasuja, source=Web Response No relevant relationships by Rajan Saggar, source=Web Response No relevant relationships by Alexander Sherman, source=Web Response

ACUTE RIGHT VENTRICULAR DYSFUNCTION FIXED IN A HEARTBEAT

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Acute right ventricular (RV) dilation is often associated with acute pulmonary embolism (PE) or right-sided myocardial ischemia. Acute RV dilation can lead to RV failure, in which the RV doesn't maintain sufficient blood flow through the pulmonary circulation. Common causes of RV failure include pulmonary arterial hypertension (PAH), COPD, and massive PE. In the ICU, pulmonary vascular disease complicated by insufficient myocardial contractility as well as derangements in excessive preload or afterload can result in changes in cardiopulmonary physiology. Determining the cause of RV decompensation and reversing it is integral in the initial management of RV failure. CASE PRESENTATION: 82-year-old female with no known medical history was admitted to medical service for sepsis secondary to cholecystitis requiring percutaneous cholecystectomy tube placement. She received IV fluids and appropriate antibiotics. On day two of hospitalization, a rapid response was called due to hypoxemia and increased work of breathing. Vital signs were afebrile, BP 88/56, HR 110, RR 26. She was placed on BIPAP and transferred to the ICU. Physical examination findings were significant for decreased breath sounds and 2+ edema in both lower extremities. Laboratory values were significant for elevated troponin 0.242 and BNP 1,000. No evidence of ischemia on EKG. CT angiography (CTA) showed bilateral pleural effusions but did not show evidence of PE. Bedside transthoracic echocardiogram (TTE) showed septal bounce and mild left atrial dilation and hypokinesis. Repeat TTE two days later showed a newly developed severely dilated RV with a severe reduction in systolic function, severely dilated right atrium and dyssynergic ventricular septal motion. Right heart cardiac catheterization confirmed elevated pulmonary artery pressures to 60-65 mmHg. Fluids were stopped, Lasix was given and sepsis was treated. TTE two days later showed marked improvement and near normalization of the RV systolic function. DISCUSSION: The patient's first TTE showed septal bounce consistent with pre-existing RV pressure overload. Acute severe RV dilation combined with hypotension likely represented an acute pulmonary hypertension crisis. The lack of a large PE on CTA ruled out thromboembolic disease for the cause of the acute dilation. RV infarct was unlikely as this would not cause elevated pulmonary artery pressures and elevated pulmonary vascular resistance. RV systolic function was restored once her sepsis was treated and fluids were stopped. It is likely that she had pre-existing primary pathology, such as chronic PAH, which was tipped over by her sepsis. CONCLUSIONS: Our patient manifested with acute RV failure in the setting of her septic physiology. Most cases of RV failure have gradual recovery; however, our case demonstrates an instance of varying RV function with significant rapid improvement in cardiac function. REFERENCE #1: Ventetuolo CE, Klinger JR. Management of acute right ventricular failure in the intensive care unit. Ann Am Thorac Soc. 2014;11(5):811-822. doi:10.1513/AnnalsATS.201312-446FR REFERENCE #2: Acute decompensated pulmonary hypertensionLaurent Savale, Jason Weatherald, Xavier Jaïs, Constance Vuillard, Athénaïs Boucly, Mitja Jevnikar, David Montani, Olaf Mercier, Gerald Simonneau, Elie Fadel, Olivier Sitbon, Marc HumbertEuropean Respiratory Review Dec 2017, 26 (146) 170092; DOI: 10.1183/16000617.0092-2017 REFERENCE #3: Matthews JC, McLaughlin V. Acute right ventricular failure in the setting of acute pulmonary embolism or chronic pulmonary hypertension: a detailed review of the pathophysiology, diagnosis, and management. Curr Cardiol Rev. 2008;4(1):49-59. doi:10.2174/157340308783565384 DISCLOSURES: No relevant relationships by Joseph Bahgat, source=Web Response No relevant relationships by Frantz Hastrup, source=Web Response

IT'S NOT THE HEART

TOPIC: Pulmonary Vascular Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: HOHF is suspected when patients present with clinical symptoms of CHF but have an elevated CI typically above 4L/min/m2 [1]. These patients can exhibit signs and symptoms of CHF and have PH as a result of elevated blood flows through the pulmonary vasculature. CASE PRESENTATION: A 56 year-old male kidney transplant recipient (KTR) presented with shortness of breath, lower extremity edema 3-months after cadaveric renal transplantation. He had a history of chronic mild systolic cardiac dysfunction (EF 50%), pulmonary hypertension (WSPH group II), and diabetes mellitus type 2 prior to kidney transplantation. Physical exam was significant for +3 pitting edema of bilateral lower extremities, crackles at lung bases and a right brachiocephalic AVF with palpable thrill. Serum creatinine was 3.5mg/dL (baseline 2.0mg/dL) and Chest X ray showed pulmonary edema. Diuresis improved the edema and shortness of breath, but worsened renal function. Renal biopsy was negative for rejection. Echocardiography (TTE) revealed an elevated right ventricular systolic pressure (RVSP) and severely dilated right atrium (RA) and ventricle (RV). Right heart catheterization demonstrated elevated right and left sided filling pressures with moderate pulmonary hypertension (PH) and an elevated cardiac output/index (CO/CI). An AVF occlusion in the cath lab resulted in a significant reduction in CO 7.75 L/min and CI 3.10 L/min/m2 by thermodilution. Findings were consistent with PH secondary to high output heart failure (HOHF), likely related to AV fistula. He underwent an AVF revision with improvement of symptoms and renal function. DISCUSSION: PH is common in patients with ESRD undergoing HD via an AVF [2] and HOHF could be an easily addressable cause of PH in ESRD. HOHF can be difficult to diagnose based on echocardiography alone. RHC typically shows an elevated CO (> 8L/min, CI>4L/min/m2), AVF/G flow > 1.5L/min, and a cardiopulmonary recirculation ratio (CPR) > 0.3 [3]. Furthermore, PH prior to transplantation appears to have an adverse impact on allograft function in kidney transplant recipients (KTR) [4]. In a retrospective analysis of KTRs in a single institution, 29/113 (26%) of patients required closure of their AVF due to symptomatic CHF. The mean AVF flow rate was significantly elevated in patients requiring AVF closure compared to those managed conservatively (2197 ml/min vs. 851 ml/min) [5]. High flow rates due to increased arterial blood shunted from left to right circulation increased the preload and stroke volume and resulted in ventricular hypertrophy leading to subsequent heart failure [6]. CONCLUSIONS: In our patient, HOHF and PH secondary to an aneurysmal AVF resulted in acute cardio-renal syndrome type 1(CRS - 1) in the transplanted kidney. The improvement in both cardiac and renal function following the revision of AVF confirmed the diagnosis of cardiorenal injury due to an aneurysmal AVF. REFERENCE #1: Reddy YN, Obokata M, Dean PG, Melenovsky V, Nath KA, Borlaug BA. Long-term cardiovascular changes following creation of arteriovenous fistula in patients with end stage renal disease. Eur Heart J. 2017 Mar 6. REFERENCE #2: Schoenberg NC, Argula RG, Klings ES, Wilson KC, Farber HW. Prevalence and Mortality of Pulmonary Hypertension in ESRD: A Systematic Review and Meta-analysis. Lung. 2020 Jun;198(3):535-45. REFERENCE #3: Wijnen E, Keuter XH, Planken NR, van der Sande FM, Tordoir JH, Leunissen KM, et al. The relation between vascular access flow and different types of vascular access with systemic hemodynamics in hemodialysis patients. Artif Organs. 2005 Dec;29(12):960-4. DISCLOSURES: Advisory Committee Member relationship with Janssen pharmaceutical Please note: 4/2020 - 4/2021 Added 04/27/2021 by Rahul Argula, source=Web Response, value=Consulting fee Advisory Committee Member relationship with United Therapeutics Please note: 2019-2021 Added 04/27/2021 by Rahul Argula, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Breathe Technologies Please note: 2019 Added 04/27/2021 by Rahul Argula, source=Web Response, value=Consulting feeeducational grant relationship with Reata pharmaceuticals Please note: 2018-2019 Added 04/27/2021 by Rahul Argula, source=Web Response, value=Grant/Research Consultant relationship with Accordant health / CVS Please note: 2020 - 2021 Added 04/27/2021 by Rahul Argula, source=Web Response, value=Consulting fee no disclosure on file for mona haj; No relevant relationships by Elena Vlachos, source=Web Response

Effect Of Comprehensive Assessment of Nursing Mode on The Care Ability of Family Members and Quality of Life of Patients with Acute Heart Failure

Objective To explore the effect of comprehensive assessment of nursing mode on the care ability of family members and quality of life of patients with acute heart failure. Methods 118 patients with acute heart failure treated in our hospital were randomly divided into two groups: control group (n = 59) treated with routine nursing intervention and study group (n = 59) treated with comprehensive nursing mode intervention. Care was initiated at the time of admission until discharge. Family care, changes in cardiac function, quality of life, compliance, satisfaction, and self-management, 6-minute walk test (6MWT), and New York Heart Association (NYHA) classification were compared between the two groups. Results The scores of family care ability in the study group were lower than those in the control group (P=0.000). After nursing intervention, the levels of CO and LVEF in the study group and the control group were higher than those before intervention (P&lt;0.05), and the levels of LVEDD and HR in the study group were lower than those in the control group (P=0.000). The scores of qualities of life in the study group were higher than those in the control group (P=0.000). The compliance rate in the study group was higher than that in the control group (P=0.002). The satisfaction degree in the study group was higher than that in the control group (P&lt;0.05). The score of self-management in study group was higher than that in control group (P=0.000). The 6MWT level at discharge in the study group was higher than that in the control group after intervention. The odds of NYHA functional class II in the study group were higher than that in the control group. The odds of classes III and IV were lower than that in the control group, but the difference had no statistical significance (P=0.087). Conclusion: Comprehensive assessment of nursing mode intervention in patients with acute heart failure is beneficial to the improvement of the patient’s family’s nursing ability and quality of life, as well as the improvement of cardiac function, the improvement of the patient’s compliance, satisfaction, the level of 6MWT and NYHA functional classification.