Progressive Left Ventricular Dysfunction Research Articles

Association between speckle tracking echocardiography and pressure-volume loops during cardiogenic shock development

BackgroundThe relationship between speckle tracking assessed global longitudinal strain (GLS) and Doppler-based echocardiography with basic physiological markers of cardiac function derived from pressure-volume loops is poorly elucidated.ObjectiveWe aimed to describe...

Alcohol consumption and progression of heart failure in those at risk for or with pre-heart failure.

This study aims to understand the dose-response relationship between alcohol consumption, progression of left ventricular dysfunction (LVD) and/or symptomatic heart failure (HF) in an older European population at risk for HF (stage A) or with pre-HF (stage B). This longitudinal, observational, secondary analysis of the St Vincent's Screening TO-Prevent Heart Failure (STOP-HF) follow-up study, excluded former alcohol drinkers and included patients with documented alcohol intake and echocardiography at baseline and follow up ≥18 months. It evaluated the relationship between alcohol intake and progression of LVD/symptomatic (stage C) HF in those at risk for or with pre-HF. Of 744 patients (mean age 66.5 [SD 9.8] years), 395 (53.1%) were female, and 260 (34.9%) had pre-HF at baseline. Overall, 201 (27.0%) patients reported no alcohol usage, 356 (47.8%) reported ≤70g/wk (low) alcohol intake and 187 (25.1%) reported >70g/wk (moderate-high). Over a median follow up of 5.44 [IQR 4.33;6.73] years, 84 (11.3%) patients had progression of LVD/symptomatic HF. Alcohol usage of >70g/wk was associated with an adjusted 4.9-fold (95% CI 1.7- 15.1, p<0.01) increased risk of HF progression amongst those with pre-HF at baseline. The adverse relationship remained significant when adjusting for age, sex, diabetes, hypertension, body mass index, as well as further models with baseline liver function and alcohol dehydrogenase 1B gene variant rs1229984 status. The association remained when excluding those with high (>140g) weekly alcohol intake. In patients at risk for HF there was no association of alcohol usage with progression of LVD/symptomatic HF. No protective associations of low alcohol usage (≤70g/wk) on progression of HF were found. Moderate to high alcohol (>70g/wk) usage appears to be associated with progression of LVD/symptomatic HF in those with pre-HF and we did not observe protective benefits of low alcohol usage.

Beyond conduction impairment: Unveiling the profound myocardial injury in left bundle branch block

BackgroundLeft bundle branch block (LBBB) represents a frequently encountered conduction system disorder. Despite its widespread occurrence, a continual dilemma persists regarding its intricate association with underlying cardiomyopathy and its pivotal role in the initiation of dilated cardiomyopathy. The pathologic alterations linked to LBBB-induced cardiomyopathy (LBBB-CM) have remained elusive. ObjectiveThis study sought to investigate the chronologic dynamics of LBBB to left ventricular dysfunction and the pathologic mechanism of LBBB-CM. MethodsLBBB model was established through main left bundle branch trunk ablation in 14 canines. All LBBB dogs underwent transesophageal echocardiography and electrocardiography before ablation and at 1 month, 3 months, 6 months, and 12 months after LBBB induction. Single-photon emission computed tomography imaging was performed at 12 months. We then harvested the heart from all LBBB dogs and 14 healthy adult dogs as normal controls for anatomic observation, Purkinje fiber staining, histologic staining, and connexin43 protein expression quantitation. ResultsLBBB induction caused significant fibrotic changes in the endocardium and mid-myocardium. Purkinje fibers exhibited fatty degeneration, vacuolization, and fibrosis along with downregulated connexin43 protein expression. During a 12-month follow-up, left ventricular dysfunction progressively worsened, peaking at the end of the observation period. The association between myocardial dysfunction, hypoperfusion, and fibrosis was observed in the LBBB-afflicted canines. ConclusionLBBB may lead to profound myocardial injury beyond its conduction impairment effects. The temporal progression of left ventricular dysfunction and the pathologic alterations observed shed light on the complex relationship between LBBB and cardiomyopathy. These findings offer insights into potential mechanisms and clinical implications of LBBB-CM.

Association between speckle tracking echocardiography and pressure-volume loop derived parameters at increasing levels of myocardial damage in a porcine model of acute cardiogenic shock

Abstract Background Echocardiography is a diagnostic cornerstone in acute cardiovascular care. However, the relationship between speckle tracking assessed global longitudinal strain (LS) and Doppler-based echocardiography with basic physiological markers of cardiac function derived from pressure-volume loops remains poorly elucidated, especially with increasing levels of myocardial damage. Objectives We aimed to describe the association between LS and Doppler-based echocardiography and direct measurements of central hemodynamic parameters from conductance catheter-based pressure-volume loops in an animal model with increasing left ventricular (LV) dysfunction. Methods Twelve Danish landrace pigs weighing 75-80 kg were used. All instrumentations were performed percutaneously, including placement of a conductance catheter in the LV. Progressive LV dysfunction was induced by stepwise embolization trough the left main coronary artery every three minutes until a 50% reduction in cardiac output or mixed venous saturation, compared to baseline, or a mixed venous saturation &amp;lt;30%. Echocardiography was performed through a subxiphoid midline incision, and was done at baseline and 90 seconds after each injection. Results With progressive LV dysfunction, mean cardiac output decreased from 5.6 l/min (SD: 0.9) to 2.1 l/min (SD: 0.9) and mean mixed venous saturation deteriorated from 61.1%(SD: 7.9) to 35.3% (SD: 6.1). Mean LS and LV outflow tract velocity time integral (LVOT VTI) declined from -13.8% (SD 3.0) to -6.1% (SD: 2.0) and 16.9 cm (SD: 2.6) to 7.8 cm (SD: 1.8), respectively (Figure 1). LS and LVOT VTI showed the strongest correlation to stroke work in unadjusted univariate regression (r2=0.53 and r2=0.49, respectively. p&amp;lt;0.01 for both). LS correlated significantly, but modest, with stroke volume (r2=0.46, p&amp;lt;0.01), end-systolic elastance (r2=0.32, p&amp;lt;0.01), systolic blood pressure (r2=0.37, p&amp;lt;0.01), ventriculo-arterial coupling(r2=0.34, p&amp;lt;0.01), and arterial elastance (r2=0.23, p&amp;lt;0.01) (Figure 2). In a multivariate regression analysis, LS showed significant correlation with stroke work, systolic blood pressure, and end-diastolic wall stress (r2=0.60, p&amp;lt;0.01). Conclusion In an animal model of acute progressive LV dysfunction, echocardiographic and conductance catheter-based measurements changed significantly. LS and LVOT VTI displayed the earliest and the largest alterations with increased myocardial damage and LS showed moderate correlations with contractility, arterial elastance and ventriculo-arterial coupling. This indicates that LS is a marker of overall ventricular performance.Echocardiographic changes from baselineScatter plot of LS and hemodynamics

Abstract 17810: Sustained Natural Heart Regeneration After Myocardial Infarction in One-Week-Old Rats Without Significant Cardiomyocyte Proliferation

Introduction: Newborn mammals are capable of natural heart regeneration after cardiac injury during the first week of life, but whether a decline in cardiomyocyte (CM) proliferation directly leads to the loss of regenerative potential is unknown. We hypothesized that, after myocardial infarction (MI) in neonatal rats, the extent of regeneration is directly correlated with the degree of CM proliferation. Methods: Neonatal Wistar rats, including both males and females, underwent left coronary artery ligation to induce MI on postnatal day 1 (P1, n=12), day 7 (P7, n=14), day 8 (P8, n=14), or day 9 (P9, n=15). Sham surgery was performed at each age (n=14, 13, 12, 16, respectively). CM proliferation was assessed using Ki67 staining in a subset of each age group, sacrificed 1 week after MI (n=4, 3, 5, 4) or sham surgery (n=4, 3, 3, 5). At 9 weeks post-MI, echocardiography was performed, and the hearts were explanted for Masson’s trichome staining. Results: At 9 weeks after surgery, left ventricular (LV) end-diastolic diameter (Fig 1A) and ejection fraction (EF, Fig 1B) were similar for P1 MI vs P1 sham (EF 62.5±5.2% vs 62.4±3.3%, p=0.941), as well as for P7 MI vs P7 sham (EF 61.4±3.3% vs 63.3±3.3%, p=0.210), consistent with robust natural regeneration. Progressive LV remodeling, dysfunction, and scar formation were observed after P8 MI (EF 50.1±2.6% vs 63.5±3.6%, p&lt;0.001) and P9 MI (EF 39.4±3.4% vs 63.1±3.9%, p&lt;0.001), but minimal scar was observed after P1 MI and P7 MI (Fig 1C). While the proportion of Ki67-positive CM was increased after P1 MI vs P1 Sham (4.0±2.0% vs 0.5±0.5%, p=0.013), CM proliferation was not significantly increased after P7 MI (1.0±0.4% vs 0.3±0.4%, p=0.105), or after P8 or P9 MI (Fig 1D). Conclusions: In rats, CM proliferation is not significantly stimulated after P7 MI, but the hearts develop with preserved geometry, normal function, and minimal infarct. Further studies are needed to examine non-CM-related mechanisms influencing the extent of natural heart regeneration.

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

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

Early assessment of cardiomyopathy in Duchenne patients by means of longitudinal strain echocardiography.

The diagnosis of Duchenne-linked cardiomyopathy may be challenging. Conventional echocardiographic measurements typically show deterioration beyond the second decade. Global longitudinal strain has been proposed as an earlier marker than left ventricular ejection fraction. A prospective, observational, cross-sectional, case-control study was carried out. Both Duchenne patients and control subjects underwent transthoracic echocardiogram in order to assess left ventricle function. Bayesian linear regression was the main tool for inference. Age effects were parameterised by means of a spline function because of its simplicity to characterise continuous variables and smooth contributions. The posterior distribution of the marginal age effects was used to assess the earliest age of deterioration of each marker. Sixteen Duchenne patients and twenty-two healthy male subjects were enrolled. On overage, cardiac function measures were found for ejection fraction and longitudinal strain among different groups. Age effects on global longitudinal strain are more reliably found at ages of 6 and above, while ejection fraction starts to deteriorate at an older age. Progressive left ventricular dysfunction in Duchenne patients is one of the key issues and starts at an early age with subtle symptoms. This cross-sectional study provides supporting evidence that global longitudinal strain is an earlier marker of disease progression than ejection fraction in Duchenne patients.

RyR2 inhibition with dantrolene is antiarrhythmic, prevents further pathological remodeling, and improves cardiac function in chronic ischemic heart disease

Diastolic Ca2+ leak due to cardiac ryanodine receptor (RyR2) hyperactivity has been widely documented in chronic ischemic heart disease (CIHD) and may contribute to ventricular tachycardia (VT) risk and progressive left-ventricular (LV) remodeling. Here we test the hypothesis that targeting RyR2 hyperactivity can suppress VT inducibility and progressive heart failure in CIHD by the RyR2 inhibitor dantrolene. Methods and resultsCIHD was induced in C57BL/6 J mice by left coronary artery ligation. Four weeks later, mice were randomized to either acute or chronic (6 weeks via implanted osmotic pump) treatment with dantrolene or vehicle. VT inducibility was assessed by programmed stimulation in vivo and in isolated hearts. Electrical substrate remodeling was assessed by optical mapping. Ca2+ sparks and spontaneous Ca2+ releases were measured in isolated cardiomyocytes. Cardiac remodeling was quantified by histology and qRT-PCR. Cardiac function and contractility were measured using echocardiography. Compared to vehicle, acute dantrolene treatment reduced VT inducibility. Optical mapping demonstrated reentrant VT prevention by dantrolene, which normalized the shortened refractory period (VERP) and prolonged action potential duration (APD), preventing APD alternans. In single CIHD cardiomyocytes, dantrolene normalized RyR2 hyperactivity and prevented spontaneous intracellular Ca2+ release. Chronic dantrolene treatment not only reduced VT inducibility but also reduced peri-infarct fibrosis and prevented further progression of LV dysfunction in CIHD mice. ConclusionsRyR2 hyperactivity plays a mechanistic role for VT risk, post-infarct remodeling, and contractile dysfunction in CIHD mice. Our data provide proof of concept for the anti-arrhythmic and anti-remodeling efficacy of dantrolene in CIHD.

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

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

Arginase Inhibition Mitigates Bortezomib-Exacerbated Cardiotoxicity in Multiple Myeloma.

Multiple myeloma (MM) is associated with increased cardiovascular morbidity and mortality, while MM therapies also result in adverse cardiac effects. Endothelial dysfunction and impaired nitric oxide (NO) pathway is their possible mediator. Since MM is associated with increased arginase expression, resulting in the consumption of ʟ-arginine, precursor for NO synthesis, our aim was to test if cardiotoxicity mediated by MM and MM therapeutic, bortezomib (a proteasome inhibitor), can be ameliorated by an arginase inhibitor through improved endothelial function. We used a mouse Vĸ*MYC model of non-light chain MM. Cardiac function was assessed by echocardiography. MM resulted in progressive left ventricular (LV) systolic dysfunction, and bortezomib exacerbated this effect, leading to significant impairment of LV performance. An arginase inhibitor, OAT-1746, protected the heart against bortezomib- or MM-induced toxicity but did not completely prevent the effects of the MM+bortezomib combination. MM was associated with improved endothelial function (assessed as NO production) vs. healthy controls, while bortezomib did not affect it. OAT-1746 improved endothelial function only in healthy mice. NO plasma concentration was increased by OAT-1746 but was not affected by MM or bortezomib. Bortezomib exacerbates MM-mediated LV systolic dysfunction in a mouse model of MM, while an arginase inhibitor partially prevents it. Endothelium does not mediate either these adverse or beneficial effects. This suggests that proteasome inhibitors should be used with caution in patients with advanced myeloma, where the summation of cardiotoxicity could be expected. Therapies aimed at the NO pathway, in particular arginase inhibitors, could offer promise in the prevention/treatment of cardiotoxicity in MM.

KLF13 Loss-of-Function Mutations Underlying Familial Dilated Cardiomyopathy.

Background Dilated cardiomyopathy (DCM), characterized by progressive left ventricular enlargement and systolic dysfunction, is the most common type of cardiomyopathy and a leading cause of heart failure and cardiac death. Accumulating evidence underscores the critical role of genetic defects in the pathogenesis of DCM, and >250 genes have been implicated in DCM to date. However, DCM is of substantial genetic heterogeneity, and the genetic basis underpinning DCM remains elusive in most cases. Methods and Results By genome-wide scan with microsatellite markers and genetic linkage analysis in a 4-generation family inflicted with autosomal-dominant DCM, a new locus for DCM was mapped on chromosome 15q13.1-q13.3, a 4.77-cM (≈3.43 Mbp) interval between markers D15S1019 and D15S1010, with the largest 2-point logarithm of odds score of 5.1175 for the marker D15S165 at recombination fraction (θ)=0.00. Whole-exome sequencing analyses revealed that within the mapping chromosomal region, only the mutation in the KLF13 gene, c.430G>T (p.E144X), cosegregated with DCM in the family. In addition, sequencing analyses of KLF13 in another cohort of 266 unrelated patients with DCM and their available family members unveiled 2 new mutations, c.580G>T (p.E194X) and c.595T>C (p.C199R), which cosegregated with DCM in 2 families, respectively. The 3 mutations were absent from 418 healthy subjects. Functional assays demonstrated that the 3 mutants had no transactivation on the target genes ACTC1 and MYH7 (2 genes causally linked to DCM), alone or together with GATA4 (another gene contributing to DCM), and a diminished ability to bind the promoters of ACTC1 and MYH7. Add, the E144X-mutant KLF13 showed a defect in intracellular distribution. Conclusions This investigation indicates KLF13 as a new gene predisposing to DCM, which adds novel insight to the molecular pathogenesis underlying DCM, implying potential implications for prenatal prevention and precision treatment of DCM in a subset of patients.

Novel Cardiac Imaging Risk Score for Mortality Prediction in Duchenne Muscular Dystrophy.

Cardiovascular disease is the leading cause of death in patients with Duchenne Muscular Dystrophy (DMD), but there is significant cardiomyopathy phenotypic variability. Some patients demonstrate rapidly progressive disease and die at a young age while others survive into the fourth decade. Criteria to identify DMD subjects at greatest risk for early mortality could allow for increased monitoring and more intensive therapy. A risk score was created describing the onset and progression of left ventricular dysfunction and late gadolinium enhancement in subjects with DMD. DMD subjects prospectively enrolled in ongoing observational studies (which included cardiac magnetic resonance [CMR]) were used to validate the risk score. A total of 69 subjects had calculable scores. During the study period, 12 (17%) died from complications of DMD. The median risk score was 3 (IQR [2,5]; range [0,9]). The overall risk score applied at the most recent imaging age was associated with mortality at a median age of 17years (IQR [16,20]) (HR 2.028, p < 0.001). There were no deaths in subjects with a score of less than two. Scores were stable over time. An imaging-based risk score allows risk stratification of subjects with DMD. This can be quickly calculated during a clinic visit to identify subjects at greatest risk of early death.

Left ventricular non-compaction in childhood: echocardiographic follow-up and prevalence in first-degree relatives

Abstract Introduction Left ventricular non-compaction (LVNC) is characterized by excessive trabeculations of the left ventricular wall. LVNC may be associated with reduced systolic function but is also found in individuals with normal ventricular function. It is debated whether LVNC is only congenital or may develop later in life. The clinical importance and heredity of LVNC with normal systolic function is unclear. Purpose We aimed to describe the echocardiographic development of the left ventricular function and LVNC pattern in children with LVNC, diagnosed at birth, at follow-up at the age of 2–4 years compared to matched controls. Additionally, we aimed to describe the prevalence of LVNC in first-degree relatives. Methods A follow-up transthoracic echocardiography was performed in children at 2–4 years of age, diagnosed with LVNC at birth (&amp;lt;30 days) as part of a large population study of newborns (n&amp;gt;25,000). Cases were matched 1:4 to controls on mother's age at delivery, parity, and age of the child at follow-up. First-degree relatives (parents, siblings and half-siblings) of cases and controls were also offered inclusion. LVNC was defined as a ratio of non-compact to compact myocardium of ≥2 in at least one left ventricular segment measured in end-diastole perpendicular to the left ventricular cavity. Results 13 of the 16 children diagnosed with LVNC at birth (median age 3 (interquartile range (IQR) 3–4) years, 77% male) and 52 children without LVNC at birth (age 4 (IQR 3–4) years, 88% male) was reevaluated as well as 36 first-degree relatives of children with LVNC (age 30 (IQR 4–37) years, 44% male) and 136 first-degree relatives of children without LVNC (age 32 (IQR 10–38) years, 50% male). In probands, the number of segments fulfilling criteria (8% vs. 13%, p=0.4) and systolic function, measured as fractional shortening (FS), were unchanged from birth to follow-up, and within normal range (29% vs. 30%, p=0.34). However, at follow-up, FS was significantly lower in probands compared with matched controls (30% vs. 33%, p&amp;lt;0.001). Criteria of LVNC was fulfilled in 11 out of 36 (31%) first-degree relatives to probands, whereas none of the first-degree relatives of children without LVNC fulfilled criteria of LVNC (p&amp;lt;0.001). FS was significantly lower in first-degree relatives of probands fulfilling criteria of LVNC compared to first-degree relatives of matched controls (30% vs. 32%, p=0.01). Conclusion Children with LVNC diagnosed neonatally as part of a population study still had a reduced systolic function when compared to controls but showed no further progression of left ventricular dysfunction or extent of trabeculation at the age of 2–4 years. One third of first-degree relatives to children diagnosed with LVNC with a preserved systolic function, fulfilled criteria for LVNC and had reduced systolic function compared to controls. These findings strongly support family-screening and clinical follow-up of children with LVNC. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Novo Nordisk FoundationHerlev-Gentofte Hospital Internal Funding

Inflammatory infiltration of the cardiac conduction system in acute lymphocytic myocarditis.

A 53-year-old man with prior history of bone marrow transplant after acute myeloblastic leukaemia was admitted in the acute cardiac care unit due to suspected acute myocarditis. At admission, his electrocardiogram (ECG) showed right bundle branch block and left anterior fascicular block (Panel A). Previously, he had been assessed regularly in a dedicated cardio-oncology clinic, with normal ECG and transthoracic echocardiography (see Supplementary material online, Videos S1 and S2). Despite high-dose pulses of methylprednisolone, he developed both complete atrio-ventricular (AV) block and progressive left ventricular systolic dysfunction (see Supplementary material online, Videos S3 and S4), leading to cardiogenic shock requiring temporary transvenous pacing and mechanical circulatory support with VA-ECMO. However, he died on day 9 due to multiorgan failure. Gross examination of the heart (Panel B) was normal, but histopathology and immunohistochemistry showed significant infiltration of the ventricular myocardium (Panel C), AV node (Panel D) left anterior fascicle (Panel E), and right bundle branch (Panel F) by mononuclear CD3 + T cells, consistent with the diagnosis of lymphocytic myocarditis. High-definition images S1-S8 are included in the Supplementary material online.

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

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

Cardiac remodelling in association with left ventricular dyssynchrony and systolic dysfunction in patients with coronary artery disease.

In patients with coronary artery disease (CAD), ischaemic cardiomyopathy may result in progressive cardiac remodelling and left ventricular (LV) dysfunction. Myocardial perfusion imaging (MPI) can be used to quantify LV size and shape, mechanical dyssynchrony (LVMD) and ejection fraction (EF) as well as myocardial ischaemia and injury extents. We investigated the prevalence of LV remodelling (LVR) in patients with CAD and the relationship between LVR, LVMD and EF. Three hundred twenty-sixpatients with CAD were evaluated. The EF and end-diastolic volume (EDV) were measured using MPI. LVMD was assessed using phase analysis. LVR was characterised according to LV dilatation or increased shape indices (systolic shape index[SIES] anddiastolic shape index [SIED]). LVR were observed in 41% of CAD patients. EDV, SIES and SIED were larger in patients with LVMD or low EF. After adjustment for age, sex and infarct and ischaemia extents, phase histogram bandwidth correlated with EDV (r = 0.218) and SIES (r = 0.266) and EF correlated with EDV (r = -0.535), SIES (r = -0.554) and SIED (r = -0.217, p < 0.001 for all). LVR is frequently seen in patients with CAD and may be detected even before the development of symptomatic heart failure. A large LV volume and a more spherical-shaped LV were associated with LVMD and low EF, highlighting the close relationships between remodelling and systolic dyssynchrony and dysfunction. MPI is useful for assessing LVR by providing information about LV size and shape, which changes from an ellipsoid towards a spherical form in the development of ischaemic cardiomyopathy.

Human-Induced Pluripotent Stem Cell-Derived Cardiomyocyte Model for TNNT2 Δ160E-Induced Cardiomyopathy.

Background:The Δ160E mutation in TNNT2, which encodes troponin T, is a rare pathogenic variant identified in patients with hypertrophic cardiomyopathy and is associated with poor prognosis. Thus, a convenient human model recapitulating the pathological phenotype caused by TNNT2 Δ160E is required for therapeutic development.Methods:We identified a heterozygous in-frame deletion mutation (c.478_480del, p.Δ160E) in TNNT2 in a patient with familial hypertrophic cardiomyopathy showing progressive left ventricular systolic dysfunction, leading to advanced heart failure. To investigate the pathological phenotype caused by Δ160E, we generated a set of isogenic induced pluripotent stem cells carrying the heterozygous Δ160E, homozygously corrected or homozygously introduced Δ160E using genome editing and differentiated them into cardiomyocytes (Hetero-Δ160E-, wild type-, and Homo-Δ160E-induced pluripotent stem cells [iPSC]-derived cardiomyocytes [iPSC-CMs]).Results:Hetero-Δ160E-iPSC-CMs exhibited prolonged calcium decay, relaxation impairment, and hypertrophy compared to wild type-iPSC-CMs. Notably, these phenotypes were further exacerbated in Homo-Δ160E-iPSC-CMs. Overexpression of R-GECO-fused Δ160E mutant troponin T prolonged decay time and time to peak of the myofilament-localized calcium transient in iPSC-CMs, indicating that sarcomeric calcium retention with Δ160E may affect intracellular calcium concentration. High-content imaging analysis detected remarkable nuclear translocation of NFATc1, especially in Homo-Δ160E-iPSC-CMs, indicating that the Δ160E mutation promotes hypertrophic signaling pathway in a dose-dependent manner. Increased phosphorylation of CaMKIIδ (calcium/calmodulin-dependent protein kinase IIδ) and phospholamban at Thr17 was observed in Homo- and Hetero-Δ160E-iPSC-CMs. Epigallocatechin-3-gallate, a calcium desensitizing compound, shortened prolonged calcium decay and relaxation duration in Δ160E-iPSC-CMs.Conclusions:Isogenic iPSC-CMs recapitulate the prolonged calcium decay, relaxation impairment, and subsequent calcium-regulated signaling pathways caused by the TNNT2 Δ160E mutation and can serve as a human model for therapeutic development to prevent hypertrophic cardiomyopathy pathology.

Defining left bundle branch block according to the new 2021 European Society of Cardiology criteria.

Correctly diagnosing left bundle branch block (LBBB) is fundamental, as LBBB occurs frequently in heart failure and may trigger a vicious cycle of progressive left ventricular dysfunction. Moreover, a correct diagnosis of LBBB is pivotal to guide cardiac resynchronisation therapy. Since the LBBB diagnostic criteria were recently updated by the European Society of Cardiology (ESC), we assessed their diagnostic accuracy compared with the previous ESC 2013 definition. We further discuss the complexity of defining LBBB within the context of recent insights into the electromechanical pathophysiology of LBBB.

Predictors of Pacemaker-Induced Cardiomyopathy and Importance of Nutritional Status and Prognostic Nutritional Index.

Long-term right ventricular (RV) pacing may cause progressive left ventricular systolic dysfunction, and malnutrition is related to adverse cardiovascular outcomes in patients with heart failure. We aimed to evaluate the relationship between immunonutritional status and the development of pacing-induced cardiomyopathy (PICMP). This study included 434 patients who underwent permanent pacemaker (PPM) implantation and had preserved left ventricular ejection fraction (LVEF) of > 40%. At six months of follow-up, the patients with LVEF < 40% were defined as having PICMP. Baseline prognostic nutritional index (PNI) was calculated based on serum albumin and lymphocyte count. Overall, 16.5% of the our study patients developed PICMP. The PICMP group had more males (p = 0.013), lower baseline LVEF values (p = 0.014) and lower baseline PNI levels (p < 0.001). RV pacing ratios and paced QRS intervals were higher in the PICMP group (p < 0.001 for both), but the types of implanted pacemakers were similar for all patients (p = 0.709). According to regression analyses, baseline LVEF (p = 0.020), PNI (p < 0.001), C-reactive protein level (p = 0.012), RV pacing ratio (p < 0.001) and paced QRS interval (p = 0.001) were independent predictors of PICMP development. A cut-off PNI value ≤ 43.2 at the time of PPM implantation could predict PICMP development with a sensitivity of 85.5% and specificity of 86.7% (p < 0.001). Identifying poor nutritional status using the PNI may be an important concept to predict PICMP development, and optimizing nutritional status might help to reduce adverse outcomes in these patients.

Measures to improve in-hospital outcomes of patients undergoing surgical repair for anomalous origin of left coronary artery from pulmonary artery.

Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital anomaly leading to progressive left ventricular dysfunction and mitral regurgitation. We conducted this study to investigate various measures to optimize the outcomes of surgical correction for ALCAPA. This was a single-centre, retrospective, observational study including consecutive patients operated for ALCAPA. The main outcomes evaluated were in-hospital mortality, duration of mechanical ventilation, and duration of intensive care unit (ICU) stay. Independent sample t- test and Fisher's exact test were used for the analysis of continuous and categorical variables respectively. 31 patients underwent surgical correction for ALCAPA during the study duration. The median age was 7.3 months with a range of 21 days to 25 months. All patients underwent coronary re-implantation with the coronary button transfer technique. There was no in-hospital mortality, the mean duration of mechanical ventilation and ICU stay was 117.6 hours and 10.7 days respectively. Age at admission, development of acute kidney injury after surgery, lactate levels at 12- and 24-hours post-surgery, and heart rate at ICU admission and 12-hours post-surgery were significantly associated with mechanical ventilation duration longer than 48 hours. Use of a combination of levosimendan and milrinone and elective intermittent nasal continuous positive airway pressure ventilation after extubation in all patients with severe left ventricular dysfunction were helpful in preventing low cardiac output and need for reintubation post-surgery respectively. Surgical correction for ALCAPA by coronary re-implantation has an excellent short-term outcome. Optimal postoperative management is of utmost importance for achieving the best results.