Serial Echocardiography Research Articles

Intervening to Preserve Function in Ischemic Cardiomyopathy with a Porous Hydrogel and Extracellular Matrix Composite in a Rat Myocardial Infarction Model.

Multiple hydrogels are developed for injection therapy after myocardial infarction, with some incorporating substances promoting tissue regeneration and others emphasizing mechanical effects. In this study, porosity and extracellular matrix-derived digest (ECM) are incorporated, into a mechanically optimized, thermoresponsive, degradable hydrogel (poly(N-isopropylacrylamide-co-N-vinylpyrrolidone-co-MAPLA)) and evaluate whether this biomaterial injectate can abrogate adverse remodeling in rat ischemic cardiomyopathy. After myocardial infarction, rats are divided into four groups: NP (non-porous hydrogel) without either ECM or porosity, PM (porous hydrogel) from the same synthetic copolymer with mannitol beads as porogens, and PME with porosity and ECM digest added to the synthetic copolymer. PBS injection alone is a control group. Intramyocardial injections occurred 3 days after myocardial infarction followed by serial echocardiography and histological assessments 8 weeks after infarction. Echocardiographic function and neovascularization improved in the PME group compared to the other hydrogels and PBS injection. The PME group also demonstrated improved LV geometry and macrophage polarization (toward M2) compared to PBS, whereas differences are not observed in the NP or PM groups versus control. These results demonstrate further functional improvement may be achieved in hydrogel injection therapy for ischemic cardiomyopathy by incorporating porosity and ECM digest, representing combined mechanical and biological effects.

USP20 deletion promotes eccentric cardiac remodeling in response to pressure overload and increases mortality.

Left ventricular hypertrophy (LVH) caused by chronic pressure overload with subsequent pathological remodeling is a major cardiovascular risk factor for heart failure and mortality. The role of deubiquitinases in LVH has not been well characterized. To define whether the deubiquitinase ubiquitin-specific peptidase 20 (USP20) regulates LVH, we subjected USP20 knockout (KO) and cognate wild-type (WT) mice to chronic pressure overload by transverse aortic constriction (TAC) and measured changes in cardiac function by serial echocardiography followed by histological and biochemical evaluations. USP20-KO mice showed severe deterioration of systolic function within 4 wk of TAC compared with WT cohorts. Both USP20-KO TAC and WT-TAC cohorts presented cardiac hypertrophy following pressure overload. However, USP20-KO-TAC mice showed an increase in cardiomyocyte length and developed maladaptive eccentric hypertrophy, a phenotype generally observed with volume overload states and decompensated heart failure. In contrast, WT-TAC mice displayed an increase in cardiomyocyte width, producing concentric remodeling that is characteristic of pressure overload. In addition, cardiomyocyte apoptosis, interstitial fibrosis, and mouse mortality were augmented in USP20-KO-TAC compared with WT-TAC mice. Quantitative mass spectrometry of LV tissue revealed that the expression of sarcomeric myosin heavy chain 7 (MYH7), a fetal gene normally upregulated during cardiac remodeling, was significantly reduced in USP20-KO after TAC. Mechanistically, we identified increased degradative lysine-48 polyubiquitination of MYH7 in USP20-KO hearts, indicating that USP20-mediated deubiquitination likely prevents protein degradation of MYH7 during pressure overload. Our findings suggest that USP20-dependent signaling pathways regulate the layering pattern of sarcomeres to suppress maladaptive remodeling during chronic pressure overload and prevent cardiac failure.NEW & NOTEWORTHY We identify ubiquitin-specific peptidase 20 (USP20) as an important enzyme that is required for cardiac homeostasis and function, particularly during myocardial pressure overload. USP20 regulates protein stability of cardiac MYH7, an essential molecular motor protein expressed in sarcomeres; loss-of-function mutations of MYH7 are associated with human hypertrophic cardiomyopathy, cardiac failure, and sudden death. Enhancing USP20 activity could be a potential therapeutic approach to prevent the development of maladaptive state of eccentric hypertrophy and heart failure.

Cardiovascular effects of BRAF and MEK inhibitors in patients with melanoma: a prospective study incorporating risk scores, cardiac biomarkers and cardiovascular magnetic resonance imaging

Abstract Background BRAF and MEK inhibitors have revolutionised treatment for patients with BRAF-mutated melanoma. Unfortunately, they are associated with cardiovascular adverse effects including hypertension and cancer-therapy related cardiac dysfunction (CTRCD). The ‘real world’ incidence and risk factors for these adverse effects are poorly described. Purpose To characterise the incidence and risk factors for BRAF and MEK inhibitor-associated hypertension and CTRCD in a prospective ‘real world’ setting. Methods Prospective, observational, cohort study of patients with melanoma treated with BRAF and MEK inhibitors at a regional cancer hospital network (March 2021 - May 2023). Comprehensive assessment was performed at baseline, 4, 12 and 24 weeks following start of treatment, including home and clinic blood pressure assessment, serial echocardiography, stress-perfusion cardiovascular magnetic resonance imaging (CMR) and humoral biomarkers (Figure 1). CTRCD was defined as mild, moderate or severe in line with International Cardio-Oncology Society (IC-OS) definitions. Hypertension was defined as 7 day average home blood pressure of ≥135/85 mmHg or the initiation or escalation of anti-hypertensive therapy. Baseline cardiotoxicity risk stratification was performed using the ESC Cardio-Oncology guideline-recommended tool. Results 61 participants were enrolled. 48% developed BRAF/MEK inhibitor associated hypertension. 46% of participants developed CTRCD and, of these, 24 (86%) were classified as mild, 3 (11%) moderate and 1 (3%) severe. Left ventricular ejection fraction (LVEF) during follow up is shown in Figure 2. All participants with moderate and severe CTRCD also had BRAF/MEK inhibitor associated hypertension. After stratification with the baseline risk assessment tool, no patient in the ‘low risk’ group developed moderate or severe CTRCD. Baseline elevated NT-proBNP (>125pg/mL), history of left ventricular systolic dysfunction and atrial fibrillation were associated with the development of CTRCD. 20 participants underwent stress perfusion CMR at baseline, 4 and 24 weeks. 25% had a drop in LVEF to <50% but only 5% had a co-existing LVEF ≥10% from baseline to fulfil criteria for the diagnosis of moderate CTRCD. Conclusion BRAF and MEK inhibitor-associated hypertension and CTRCD is common, with a higher incidence in this ‘real world’ prospective cohort than observed in clinical trials. The majority of CTRCD was ‘mild’ and the long term sequalae of this remains unknown. No patients considered to be at low baseline risk for CTRCD using the ESC-recommended risk stratification tool developed moderate or severe CTRCD. These findings support the use of routine blood pressure surveillance in this group as well as baseline risk stratification to guide appropriate imaging surveillance of cardiac function.Figure 1.Schedule of study visitsFigure 2.LV function/CTRCD over time

Study design of the CARDIO-TTRansform cardiac magnetic resonance imaging substudy

Abstract Background Cardiac magnetic resonance (CMR) with extracellular volume (ECV) mapping can track treatment response in patients with cardiac amyloidosis by assessing changes in cardiac amyloid burden along with associated changes in structure and function. The CARDIO-TTRansform trial is a phase 3, multicentre, double-blind, randomised, placebo-controlled trial designed to assess the efficacy and safety of eplontersen in transthyretin amyloid cardiomyopathy (ATTR-CM). Eplontersen is a ligand-conjugated antisense oligonucleotide designed to reduce hepatic production of transthyretin protein, the amyloid fibril precursor protein in ATTR-CM. Patients with hereditary or wild-type ATTR-CM on available standard of care were randomized 1:1 to receive 45 mg of eplontersen or placebo via subcutaneous injection every 4 weeks. Patients in the main study with no contraindication to CMR were invited to participate in this sub-study. Purpose The primary objective is to measure the change in amyloid burden (defined as % change in ECV from baseline) over time in patients receiving eplontersen versus placebo. Methods Participants will undergo CMR with ECV mapping at baseline, 25, 49, 97 and 140 weeks (Figure 1). Images will be acquired under a standardized protocol comprising cine imaging with steady state free precession sequence, late gadolinium enhancement imaging (LGE) and T1 mapping. T1 mapping will be performed before the administration of contrast and will be repeated 15 minutes post-contrast using the same slice locations, to produce ECV maps. Results In the main study, 1432 patients were randomized from 120 sites across 20 countries. Of these patients, 157 patients were enrolled in the CMR sub-study, from 6 centers across 4 countries. Images will be read centrally at the end of the study. All participants in the study will also receive serial transthoracic echocardiography with strain analysis to correlate findings with conventional imaging techniques, and a subset of patients from the CMR substudy will be co-enrolled in a scintigraphy substudy for further characterization of amyloid deposition in their heart. Conclusion The CARDIO-TTRansform CMR substudy represents the largest CMR study of ATTR-CM. The CMR sub-study has enrolled a broad global population of patients with hereditary and wild-type ATTR-CM and will provide key information on the impact of eplontersen on the cardiac amyloid load and the associated change in structure and function.

Longitudinal echocardiographic parameters for evaluation of pulmonary hypertension in preterm infants with very low birth weight.

Echocardiography is essential for the evaluation of pulmonary hypertension. We determined the feasible quantitative parameter for screening and monitoring pulmonary hypertension in preterm infants. This secondary analysis of a prospective cohort single-centre study was conducted between August 2019 and September 2020. Serial echocardiography was performed 7 and 28 days after birth and at 36 weeks postmenstrual age. The data of infants who developed pulmonary hypertension at 36 weeks postmenstrual age were compared with those without pulmonary hypertension. We also modelled the parameters' trend and performed an interaction test using multi-level Gaussian regression. Out of 30 infants enrolled in the study, 79 echocardiograms were analysed. Left ventricular eccentric index was obtainable in all infants, while tricuspid jet velocity was measurable in 44.1%. Left ventricular eccentric index correlated well with tricuspid regurgitation jet velocity (r = 0.77, P < 0.001). Six infants were diagnosed with newly developed or persistent pulmonary hypertension at 36 weeks postmenstrual age. Serial left ventricular eccentric index showed a significantly different increasing trend in the pulmonary hypertension group (change per day: +0.004; P = 0.090) from the decreasing trend among a non-pulmonary hypertension group (change per day: -0.001; P = 0.041) (P for interaction = 0.007). Right ventricular systolic function and right ventricular isovolumic systolic velocity revealed a reducing trend in the pulmonary hypertension group, which was different from the improving trend in non-pulmonary hypertension infants. Infants with low current weight, low postmenstrual age, and requiring high-flow oxygen therapy at day 28 of life trended to increase the risk of late pulmonary hypertension. Left ventricular eccentric index and right ventricular isovolumic systolic velocity were feasible for assessing pulmonary hypertension and should be incorporated into pulmonary hypertension evaluation. Serial left ventricular eccentric index and right ventricular isovolumic systolic velocity may help predict late pulmonary hypertension and early detection of right ventricular dysfunction.

The Combination of Valsartan and Spironolactone Mitigated Mitral Regurgitation-Induced Cardiac Dysfunction in a Novel Rat Model.

Despite its high prevalence, effective treatment for degenerative mitral regurgitation (MR) remains elusive. Although the mineralocorticoid-receptor antagonist spironolactone, in conjunction with renin-angiotensin-aldosterone system inhibitors, has been shown to reduce mortality in patients with heart failure with reduced ejection fraction, its efficacy in managing degenerative MR is uncertain. In this study, we aimed to compare the effectiveness of valsartan (a renin-angiotensin system inhibitor), spironolactone, and combination therapy in mitigating MR-induced myocardial dysfunction. Using a mini-invasive model of degenerative MR, we administered valsartan (31 mg/kg/d), spironolactone (80 mg/kg/d), or a combination of both to rats over a 4-week period. Serial echocardiography and pressure-volume loops were utilized to assess cardiac function and hemodynamics. Rats with degenerative MR treated with valsartan or spironolactone alone did not show significant improvement in myocardial dysfunction. In contrast, combination therapy resulted in significant improvement. Similarly, the pressure-volume relationship was significantly improved in rats treated with the combination therapy compared with that in rats treated with a single therapy. Mechanistically, combination therapy effectively suppressed circulating and cardiac expression of aldosterone- and apoptosis-associated proteins. Overall, combination treatment with valsartan and spironolactone significantly attenuated the degenerative MR-induced myocardial stress and dysfunction, suggesting a potential therapeutic avenue for managing degenerative MR-induced heart failure.

Aortic regurgitation in left ventricular assist device patients - Does aortic root dilatation contribute to valve incompetence?

Aortic regurgitation (AR) is a known complication after left ventricular assist device (LVAD) implantation potentially leading to recurrent heart failure. Possible pathomechanisms include valvular pathologies and aortic root dilatation. We assessed aortic root dimensions in a group of consecutive LVAD patients who received HeartMate 3. Since 11/2015, we identified 68 patients with no or mild AR at the time of HeartMate 3 implantation who underwent serial echocardiography to assess AR and aortic root dimensions (annulus, sinus, and sinotubular junction). Median follow-up was 40 months (2-94 months). Results were correlated with clinical outcomes. Patients were 60 ± 10 years old, predominantly male (88%) and 35% presented in preoperative critical condition as defined by INTERMACS levels 1 and 2. During follow-up, 23 patients developed AR ≥ II (34%). Actuarial incidence was 8% at 1 year, 29% at 3 years and 41% at 5 years. Echocardiography revealed practically stable root dimensions at the latest follow-up compared to the preoperative state (annulus: 23 ± 3 mm vs. 23 ± 2 mm, sinus: 32 ± 4 mm vs. 33 ± 3 mm, sinotubular junction: 27 ± 3 mm vs. 28 ± 3 mm), irrespective of the development of AR. Serial CT angiograms were performed in 13 patients to confirm echocardiographic findings. Twenty-one patients died during LVAD support leading to a 5-year survival of 71%, showing no difference between patients with and without AR ≥ II (p = 0.573). At least moderate AR develops over time in a substantial fraction of patients (one-third over 3 years). The mechanism does not seem to be related to dilatation of the aortic annulus or root.

Intestinal fatty acid binding protein is associated with infarct size and cardiac function in acute heart failure following myocardial infarction

BackgroundIn acute heart failure (HF), reduced cardiac output, vasoconstriction and congestion may damage the intestinal mucosa and disrupt its barrier function. This could facilitate the leakage of bacterial products into...

Abstract We143: MED12 Dysregulation Disrupts Transcriptional Programs Leading to Dilated Cardiomyopathy

The Mediator complex serves as a bridge to link transcriptional machinery and transcription factors (TFs) to control transcription, but detailed molecular mechanisms of transcriptional regulation by Mediator are not well-understood. Mediator is comprised of the head, middle, and tail submodules that make up the core Mediator, and the transiently associating kinase submodule. The CDK8 kinase submodule acts to regulate Mediator-RNA Polymerase II interaction. MED12 is an essential Mediator component within the kinase submodule and is required for CDK8 kinase activity. In aging models, dysregulated levels of Med12 mRNA are detected in both atria and ventricles by qRT-PCR. MED12 protein levels are also increased in human heart failure biopsies and in the mouse heart after transverse aortic constriction (TAC)-induced heart failure[KB1] . To test the hypothesis that increased levels of MED12 contribute to development of heart failure we generated cardiac-specific Med12 transgenic mice (cTg) by driving increased MED12 expression in cardiomyocytes using the αMHC promoter. Med12 overexpression leads to a progressive decrease in fractional shortening by serial echocardiography. Decreased cardiac function was accompanied by increased cardiac chamber size and dilation, without cardiac fibrosis. RNA sequencing of cardiomyocytes from cTg and control mice revealed that increased levels of MED12 leads to early changes in gene expression programs. Using ingenuity pathway analysis we identified MED12-regulated gene programs including those involved in calcium cycling. MED12 is a transcriptional regulator but does not directly bind DNA. To determine how MED12 regulates gene expression we screened for TFs that interact with MED12. We performed immunoprecipitation of MED12 and by mass spectrometry and determined that MED12 interacts with the TFs MEF2, CREB, and SRF. In follow-up experiments we demonstrated that MED12 interacts with the transcription factor (TF) MEF2 to regulate calcium handling genes. Current studies are focused on determining how MED12 binding coordinates gene expression through multiple TFs in cardiomyocytes. Collectively, our data demonstrate that increased MED12 expression leads to the development of heart failure, in part by dysregulation of gene expression. Therefore, precise regulation of MED12 levels is important to maintain normal cardiac function. [KB1]What about aging?

Abstract We118: Phosphoglycerate Dehydrogenase Gene Therapy for Dilated Cardiomyopathy

Introduction: Dilated cardiomyopathy (DCM) is a multifaceted cardiac disorder affecting approximately 1 in 250 to 2000 individuals and stands as a predominant cause of heart failure. Despite advancements in identifying genetic mutations associated with DCM, the precise mechanisms driving its pathogenesis are unknown, translating to the lack of disease-modifying interventions. Hypothesis: Modulating serine biosynthesis and one-carbon metabolism in cardiomyocytes by forced expression of Phosphoglycerate Dehydrogenase ( PHGDH) will ameliorate cardiac dysfunction in DCM and halt the disease progression. Methods: We developed a gene therapy vector expressing the PHGDH gene, controlled by a chicken cardiac-specific promoter (cardiac troponin T, cTnT) (AAV9.cTnT.hPHGDH). We delivered this construct via an AAV-based gene transfer approach using the cardiotropic adeno-associated virus serotype-9 in the TM54 DCM mouse – a well-established transgenic mouse that expresses a mutant tropomyosin cDNA (Tpm1 p. E54K; Tm54) under the control of the cardiac αMHC promoter. At 6 weeks old, when the animals exhibit DCM, they were treated with AAV9.cTnT.hPHGDH or control (AAV9.cTnT.GFP). Serial echocardiography was employed to assess heart function for 10 weeks. Morphometric data including heart weight, body weight, and tibia length were recorded. Subsequently, WGA and picrosirius red staining were performed to evaluate cardiomyocyte size and fibrosis, respectively. Finally, metabolic changes were assessed by untargeted metabolomics. Results: AAV9.cTnT.hPHGDH treatment of DCM TM54 mice improved the systolic function and halted the progression of DCM compared to the control mice. Furthermore, PHGDH treatment prevented the development of interstitial fibrosis and cardiomyocyte hypertrophy. Finally, these functional and structural improvements correlate with metabolic rewiring of the glucose metabolism in the DCM heart. Conclusion: These findings suggest that metabolic rewiring of the glucose metabolism by enhancing serine biosynthesis and one-carbon metabolism in the DCM heart may be cardioprotective. Thus, PHGDH gene therapy may be a novel therapeutic approach for DCM and heart failure.

Abstract Tu049: Stabilization of RyR2 with dantrolene treatment ameliorates left ventricular remodeling and ventricular tachycardia after myocardial infarction

Background: Dantrolene has been reported to suppress diastolic Ca 2+ leakage through the cardiac ryanodine receptor (RyR2) by restoring defective inter-subunit interactions within RyR2 and enhancing the binding affinity of calmodulin (CaM) to RyR2. Here, we investigated whether chronic administration of dantrolene which was started after myocardial infarction (MI) inhibits ventricular tachycardia (VT) and alleviates left ventricular remodeling. Methods: We developed MI model by left anterior descending coronary artery (LAD) ligation in mice. Wild type mice were divided into 4 groups; sham-operated mice (WT-Sham), sham-operated mice treated with dantrolene (WT-Sham-DAN, 20mg/kg/day, i.p.), MI mice (WT-MI) and MI mice treated with dantrolene (WT-MI-DAN). Then, they were followed up for 12 weeks. Results: The 12-week survival rate was significantly higher in MI-DAN group (71 %) than in WT-MI (40%). Serial echocardiography showed that adverse LV remodeling was ameliorated in WT-MI-DAN group compared to WT-MI group (WT-MI 6.3 ± 0.25 mm, WT-MI-DAN 5.5 ± 0.14 mm, P&lt;0.01). VT test by epinephrine (2mg/kg, i.p.) showed that VT was induced in all WT-MI group, although it was significantly inhibited in WT-MI-DAN group. An increase in diastolic Ca 2+ spark frequency and a decrease in sarcoplasmic reticulum Ca 2+ content were observed in isolated cardiomyocytes from WT-MI group whereas both were significantly ameliorated in WT-MI-DAN group. Conclusions: Dantrolene improves the diastolic Ca 2+ leakage from sarcoplasmic reticulum of damaged cardiomyocytes. Chronic administration of dantrolene after MI inhibits VT and ameliorates LV remodeling, leading to improved prognosis after MI. RyR2-targeting therapy could be a novel strategy for the treatment of post MI.

Abstract Tu053: Activin Signaling Inhibition Enhances Cardiac Functional Recovery After Aortic Debanding

Background: Human aortic stenosis (AS) induces adverse cardiac remodeling and heart failure by pressure overload. Reducing pressure overload (e.g., Trans-catheter aortic valve replacement (TAVR) mitigates or reverses adverse remodeling but these benefits are limited in many TAVR patients. Here we established a murine transverse-aortic-constriction (TAC)-debanding model to mimic TAVR and identify ways to enhance reverse remodeling. Methods: 10-week-old wild-type C57BL/6 mice were subjected to TAC surgery and debanding by suture removal, or sham-debanding, between 4 (short duration) and 10 weeks (long duration) after TAC. Echocardiography was performed to assess cardiac function. RNA sequencing (RNAseq) of TAC and debanded hearts demonstrated activation of activin signaling with TAC that was relieved by debanding. Based on this, TAC-debanded animals were treated with an investigational modified activin receptor type IIB ligand trap, RKER-012 (10 mg/kg IP, bi-weekly), to inhibit signaling downstream of activin and related ligands. Results: Serial echocardiography of TAC-debanded animals showed greater dysfunction with longer duration TAC (Fractional shortening [FS]=39.2±3.84 for 4 weeks-TAC vs Sham: 61.2±0.94, p&lt;0.05; FS=18.2±1.80 for 10 weeks-TAC vs Sham-TAC: 64.7±0.43, p&lt;0.05). Cardiac functional recovery was slower and less complete in animals with longer duration TAC (10 weeks after debanding with TAC for 4 weeks, FS=57.8±1.41 vs 46.6±3.4 TAC for 10 weeks). RNAseq analysis of hearts post-debanding (10 weeks TAC+10 weeks debanding) showed a 5.73-fold decrease (p=2.57x10 -16 ) in FSTL3 expression, a biomarker of activin pathway signaling, suggesting a decrease in activin signaling accompanied functional recovery. To assess functional contribution of activin signaling to incomplete recovery and therapeutic potential of pathway inhibitors, we treated debanded animals (debanded 8 weeks post-TAC) with RKER-012 or placebo (TBS) for 4 weeks. RKER-012-treated mice showed significantly increased ejection fraction (54.12±1.50 vs placebo control 42.88±3.21; p=0.001) and reduced heart weight (p=0.01). Conclusions: Debanding after TAC mitigates adverse remodeling that is slower and less complete with longer duration TAC. A ligand trap (RKER-012) that was designed to inhibit signaling downstream of activin enhanced recovery after debanding and warrants further study as a potential therapeutic intervention in patients with incomplete functional recovery after TAVR.

Abstract Tu052: RPN6-Serine14 Phosphorylation by PKA Protects Against Systolic Overload-Induced Cardiac Remodeling and Heart Failure

The ubiquitin-proteasome system is the main proteolytic pathway for quality control (PQC) and regulatory degradation of proteins in living cells. Systolic overload, as seen in hypertension and aortic stenosis, is a leading cause of heart failure (HF). Proteasome functional insufficiency is implicated in HF caused by systolic overload. Previous studies have established that Ser14-RPN6 phosphorylation (pS14-RPN6) mediates the activation of 26S proteasomes by protein kinase A. However, the pathophysiological significance of pS14-RPN6 in systolic overload remains to be established. We hypothesize that pS14-RPN6 helps maintain proteostasis and protects the heart during systolic overload. We observed a significant increase in myocardial pS14-RPN6 and ubiquitin conjugates in human HF of ischemic or non-ischemic etiologies (p=0.020, p=0.034) and similarly in wild type (WT) mice after 2 weeks of transverse aortic constriction (TAC) (p&lt;0.0001, p=0.001). To investigate the role of pS14-RPN6 in vivo, our lab created Rpn6 S14A (S14A) knock-in mice where Ser14-Rpn6 phosphorylation is blocked. Here we have compared the responses to TAC between WT and S14A mice. We found that TAC-induced increases in myocardial proteasome peptidase activities were significantly attenuated, and accumulation of ubiquitin conjugates exacerbated in S14A mice (p&lt;0.0001; p&lt;0.0005). Serial echocardiography revealed that S14A mice displayed significantly greater left ventricular (LV) end-diastolic posterior wall thickness and LV mass to body weight ratios at 1- and 12-week post-TAC (p=0.024, 0.0003; p=0.005, 0.01), and lower ejection fraction at 12-week post-TAC than WT mice (p=0.035). S14A mice also showed greater heart weight to tibial length (TL) and ventricular weight to TL ratios at 1 and 12-week post-TAC (1-week, p=0.043, 0.039; 12-week, p=0.007, 0.006). Wheat germ agglutinin and picrosirius red staining indicated a greater cardiomyocyte cross-sectional area and cardiac fibrosis in 12-week post-TAC S14A mice vs. WT mice (p&lt;0.0001; p=0.005). These novel findings demonstrate compellingly that myocardial pS14-RPN6 helps maintain proteostasis, curtails cardiac hypertrophy and delays heart failure occurrence during systolic overload

Abstract Tu147: Serial measurement of circulating cardiovascular enriched miR-1 and -34a reflects the changes in cardiac function in patients with ischemic heart disease – a five year follow-up study

Background: Patients with ischemic heart disease (IHD) require frequent monitoring, as the transition from stable disease to acute life-threatening events remains largely unpredictable. Currently available tests are either not sensitive enough to detect early changes or not easily incorporated into routine clinical practice. MicroRNAs (miRNAs), small non-coding RNAs involved in both physiological and pathological processes, are released into circulation and remain stable. Research Question: In this study, we aimed to determine if the serial measurement of cardiovascular-enriched circulating miRNAs could reflect changes in cardiac function in patients with IHD. Methods: Fifty-four new IHD patients joined a 5-year study, providing informed consent for regular echocardiography, blood tests and follow-ups at 12-month intervals. Plasma RNA was extracted and RT-PCR analysis used to assess expression of cardiovascular-enriched miR-1, miR-126, miR-132, and miR-34a. Results: Serial echocardiography analysis showed the development of diastolic dysfunction in the participants starting from 48 months (E/e’-10.7±4.3 vs 9.7±3.6 at baseline, P&lt;0.04). RT-PCR analysis revealed significant downregulation of miR-1 and miR-126 starting from 24 months of follow-up (P&lt;0.03 vs. baseline). Associations between each miRNA and each cardiac function measure were examined using linear mixed models without and with adjustment for changes in BMI and HbA1c during the same period. None of the lagged models found statistically significant associations (all p ≥ 0.126). From the concurrent models, two miRNA were associated with cardiac function: miR-1 and MV E Vel in the unadjusted (p = 0.045) and adjusted models (slope = -0.004, 95% CI -0.007 to -0.000, p = 0.026) models and miR-34a and FS(%) in the adjusted model only (slope = -0.151, 95% CI -0.301 to -0.001, p = 0.048). Conclusion: Results from this first-ever five-year follow-up study have identified a link between cardiovascular enriched miRNAs, miR-1 and -34a and cardiac function in patients with IHD, providing a knowledge platform for prognostic tests for IHD and laying the foundation for further studies in larger population size.

Mortality in septic patients treated with esmolol or landiolol: a systematic review and meta-analysis of randomized controlled trials with trial sequential analysis.

The latest meta-analysis indicated potential survival benefits from ultra-short-acting β-blockers in septic patients with persistent tachycardia. However, subsequent multicenter randomized controlled trials (RCTs) have reported conflicting findings, prompting the need for an updated meta-analysis to incorporate these newly published RCTs. Does the use of ultra-short-acting β-blockers (esmolol or landiolol) in septic patients with persistent tachycardia improve mortality? We conducted an updated systematic search till April 2nd, 2024 exploring MEDLINE, Cochrane Central Register of Controlled Trials, and Embase for RCTs reporting mortality in adult septic patients treated with esmolol or landiolol as compared to none or placebo, and published in English. Meta-analyses were conducted with the random effect model. The primary outcome was mortality at the longest follow-up, with subgroup analysis separating single from large multicenter RCTs. Eight RCTs (885 patients) were included in the primary analysis. Ultra-short acting β-blockers did not significantly improve mortality at the longest follow-up (risk ratio [RR] 0.84; 95% confidence interval [CI], 0.68-1.02; p=0.08, I2=51%, very low certainty of the evidence) and 28-day mortality (RR 0.77; 95%CI 0.59-1.00; p=0.05; I2=62%). Subgroup analyses of mortality outcomes pointed towards different results between single-center and multicenter RCTs. Trial sequence analyses (TSAs) showed that both mortality outcomes were not robust. The sensitivity analyses suggested a significant reduction in mortality by adding RCTs published in non-English language. In this updated meta-analysis, the use of esmolol or landiolol did not reduce mortality in septic patients with persistent tachycardia. However, results were not robust and outcomes differed between single-center and multicenter RCTs. Moreover, sensitivity analyses showed the fragility of the primary outcome. Further studies regarding ultra-short-acting β-blockers with advanced cardiac monitoring or serial echocardiography are warranted. The protocol was preventively registered in the PROSPERO database on the 31th January 2024 (Registration number: CRD: 42024503570).

Eighteen-Month Real-World Experience Using Mavacamten for Treatment of Obstructive Hypertrophic Cardiomyopathy in a Racially Diverse Population.

Patients with obstructive hypertrophic cardiomyopathy have increased symptomatic burden. Mavacamten was recently approved for treatment of obstructive hypertrophic cardiomyopathy based on 2 randomized controlled trials. However, its use under real-world conditions and in diverse populations is under-studied. This was a prospective observational cohort study of patients seen at the Johns Hopkins HCM center and prescribed mavacamten for obstructive hypertrophic cardiomyopathy between July 7, 2022 and January 6, 2024. Patients were followed longitudinally, with serial echocardiography and clinical evaluation as mandated by the risk evaluation and mitigation strategy program. Sixty-six patients received mavacamten (mean age 59 years, 47% male, 29% non-White [Black, Hispanic/Latino, Asian, Native Hawaiian or Pacific Islander], 47% obese). Before treatment, all patients had New York Heart Association class II (51.5%) or III (48.5%) heart failure symptoms. Initial maximum peak left ventricular outflow tract gradient was 107±46 mm Hg. Median treatment duration was 9 months. For patients on mavacamten after ≥6 months (n=43), symptoms improved by ≥1 New York Heart Association class in 72% of patients, and peak left ventricular outflow tract gradient decreased by 80±46 mm Hg, eliminating hemodynamically significant left ventricular outflow tract obstruction in 79.1% of patients. Mavacamten was temporarily discontinued in 3 patients due to left ventricular ejection fraction decrease <50%. There were no medication-related adverse events. Effectiveness and safety were similar between White and non-White patients, but symptomatic relief was attenuated in patients with body-mass index ≥35 kg/m2. Mavacamten was effective and safe when used under real-world conditions in a racially diverse population of symptomatic patients with obstructive hypertrophic cardiomyopathy. Patients with comorbid obesity were less likely to experience symptomatic improvement while on mavacamten.

Perinatal Cardiac Functional Adaptation in Hypoplastic Left Heart Syndrome: A Longitudinal Analysis

The perinatal transition is characterized by acute changes in cardiac loading. Compared with normal newborn combined cardiac output (CCO), single right ventricular (RV) output of neonates with hypoplastic left heart syndrome (HLHS) is markedly greater. The aim of this study was to examine the mechanisms of cardiac adaptation that facilitate this perinatal transition from late fetal to early neonatal life in HLHS. Prospectively recruited pregnancies complicated by fetal HLHS (n=35) and healthy control subjects (Ctrl; n=17) underwent serial echocardiography in late gestation (38±1weeks) and 6, 24, and 48hours after birth. Cardiac function was assessed using conventional, Doppler tissue, and speckle-tracking echocardiography. Term fetuses with HLHS had RV output comparable with Ctrl CCO via higher stroke volume. Compared with both left ventricular and RV indices of Ctrl, they exhibited globular and dilated right ventricles with reduced relative wall thickness (0.40±0.08 vs 0.49±0.10, P<.01), increased Tei index' (HLHS vs Ctrl left ventricle/Ctrl right ventricle: sphericity index, 0.9±0.25 vs 0.5±0.10/0.6±0.11; RV area index, 28±6 vs 15±3/17±5cm2/m2; Tei index', 0.65±0.11 vs 0.43±0.07/0.45±0.09; P<.0001 for all). Neonates with HLHS generated elevated RV cardiac output compared with Ctrl CCO via higher heart rate and stroke volume, with further RV dilatation, increased longitudinal systolic strain at 48hours (-17±4% vs -14±3%/14±5%) with reduced circumferential and rotational myocardial deformation and altered diastolic function. Neonates with HLHS also demonstrated right atrial enlargement with increased longitudinal strain: 6hours (33±12% vs 26±6%), 24hours (37±15% vs 26± 13%), and 48hours (38±11% vs 24±13%) (P<.0001). Term fetuses with HLHS exhibit altered RV geometry and RV systolic and diastolic functional parameters. After birth, further alterations in these cardiac parameters likely reflect adaptation to acutely altered RV loading from increasing cardiac output and pulmonary artery flow demands.

Longitudinal Assessment of Left Atrial Remodeling in Patients With Chronic Severe Aortic Regurgitation

BackgroundThere are significant sex and age differences in left ventricular (LV) remodeling that may lead to disparity in outcomes when used to inform the timing of aortic regurgitation (AR) intervention. ObjectivesThe aim of this study was to examine whether left atrial (LA) parameters might represent better criteria than LV parameters to inform the timing of AR intervention. MethodsUsing data on patients with moderate to severe or severe AR with serial echocardiography (2010-2016), the longitudinal trends in left atrial volume index (LAVI) and left atrial reservoir strain (LAr) were evaluated by sex and age. The incremental utility of these parameters in predicting adverse events over LV parameters was also determined. ResultsIn 525 patients (25.7% women) with 1,687 echocardiograms over a median follow-up period of 2.0 years (Q1-Q3: 1.0-3.6 years), there was significant increase in LAVI (1.0 mL/m2 per year [95% CI: 0.76-1.2 mL/m2 per year]) and decrease in LAr (−1.3% per year [95% CI: −1.6% to −0.92%]), without a significant interaction by sex or age category (P for interaction ≥ 0.17). In addition, both LAVI and LAr were significant predictors of adverse events independent of LV parameters. The optimal discriminatory thresholds were 37 mL/m2 for LAVI and 35% for LAr. These thresholds were similar across categories of sex and age. Within the relatively short-term follow-up, surgery was associated with survival benefit among patients with LAVI ≥37 mL/m2 (HR: 0.33 [95% CI: 0.15-0.72]; P = 0.006) but was not statistically significant among patients with LAVI <37 mL/m2 (HR: 0.46 [95% CI: 0.18-1.17]; P = 0.09). Similarly, surgery was associated with survival for the subgroup with LAr ≤35% but not among those with LAr >35%. ConclusionsUnlike LV remodeling, LA remodeling demonstrates a similar rate of progression between categories of sex and age among patients with AR. In addition, LA parameters provide incremental prognostic value over LV parameters.

Serial GLS assessments over time in patients with preserved ejection fraction undergoing permanent cardiac pacemaker placement

Abstract Background Chronic right-ventricular (RV) pacing can exacerbate heart failure in patients with a low ejection fraction (EF), but little is known about pacing-induced cardiomyopathy (PICM) in patients with preserved EF. We aimed to investigate risk factors of PICM in these patients during long-term follow-up. Methods The prospective registry at our University Hospital, South Korea, included de novo patients with preserved EF undergoing transvenous permanent pacemaker (PPM) implantation for atrioventricular blockage from 2018 to 2022. Patients with EF &amp;gt; 50% and expected ventricular pacing &amp;gt; 40% were included. All patients were followed with serial echocardiography (preimplant, post implant, 12 months). All patients enrolled in this study were seen as outpatients every 3–6 months. Composite outcomes were cardiac death (pump failure), hospitalization because of heart failure, PICM, and biventricular pacing (BVP) upgrade. Results 71 patients (28 men, 73.1 ± 9.5 years) were included. After PPM implantation, EF and GLS were significantly decreased. During three years of follow-up, 2 patient died, 6 were hospitalized, 7 suffered PICM, and 3 underwent BVP upgrade. Cox regression analysis identified reduced post-implant global longitudinal strain (GLS) (HR, 1.524; 95% CI, 1.149–2.021; P = 0.003) as independent predictors of PICM. Post-implant GLS showed high predictive accuracy for PICM, with an area under the curve of 0.92 (95% CI 0.829–0.971; P &amp;lt; 0.001) Conclusion Post-implant GLS, rather than pre-implant GLS could help identify individuals at high risk of PICM. After PPM implantation, it is important to measure GLS, and patients with reduced GLS should be monitored more frequently and echocardiographic surveillance, with a view to an upgrade to BVP.Serial EF and GLS assessmentGLS ROC curve

In vivo fluid dynamics of the Ventura interatrial shunt device in patients with heart failure.

Interatrial shunts are under evaluation as a treatment for heart failure (HF); however, their in vivo flow performance has not been quantitatively studied. We aimed to investigate the fluid dynamics properties of the 0.51cm orifice diameter Ventura shunt and assess its lumen integrity with serial transesophageal echocardiography (TEE). Computational fluid dynamics (CFD) and bench flow tests were used to establish the flow-pressure relationship of the shunt. Open-label patients from the RELIEVE-HF trial underwent TEE at shunt implant and at 6 and 12month follow-up. Shunt effective diameter (Deff) was derived from the vena contracta, and flow was determined by the continuity equation. CFD and bench studies independently validated that the shunt's discharge coefficient was 0.88 to 0.89. The device was successfully implanted in all 97 enrolled patients; mean age was 70±11years, 97% were NYHA class III, and 51% had LVEF ≤40%. Patency was confirmed in all instances, except for one stenotic shunt at 6months. Deff remained unchanged from baseline at 12months (0.47±0.01cm, P=0.376), as did the trans-shunt mean pressure gradient (5.1±3.9mmHg, P=0.316) and flow (1137±463mL/min, P=0.384). TEE measured flow versus pressure closely correlated (R2≥0.98) with a fluid dynamics model. At 12months, the pulmonary/systemic flow Qp/Qs ratio was 1.22±0.12. When implanted in patients with advanced HF, this small interatrial shunt demonstrated predictable and durable patency and performance.