Adulthood adiposity affects cardiac structure and function in later life.

BACKGROUND AND AIMS: Excess adiposity is associated with poorer cardiac function and adverse left ventricular (LV) remodelling. However, its importance over the adult life course on future cardiac structure and systolic and diastolic function is unknown. METHODS: A total of 1690 participants in the National Survey of Health and Development birth cohort underwent repeated adiposity [body mass index (BMI)/waist-to-hip ratio (WHR)] measurements over adulthood and investigation, including echocardiography at age 60-64 years. The relationship between LV structure [LV mass (LVM), relative wall thickness, and LV internal diameter in diastole (LVIDd)] and function (diastolic: E/e', e', and left atrial volume indexed to body surface area; systolic: ejection fraction, S', and myocardial contraction fraction) was investigated using multivariable linear regression models. RESULTS: Increased BMI from age 20 years onwards was associated with greater LVM and LVIDd independent of confounders. Associations remained independent of current BMI for LVIDd and at age 26, 43, and 53 years for LVM. Increased BMI from 43 years onwards was associated with greater relative wall thickness, but not when BMI at age 60-64 years was accounted for. Increased BMI at age 26, 36, and 53 years and at 20 years onwards was associated with lower ejection fraction and myocardial contraction fraction, respectively, but not independently of BMI at 60-64 years. Higher BMI from 20 years onwards was associated with poorer diastolic function independent of confounders. Associations between BMI and left atrial volume indexed to body surface area persisted from 26 years onwards after adjustment for BMI at 60-64 years. Similar relationships were observed for WHR from age 43 years onwards. CONCLUSIONS: Higher adiposity (BMI/WHR) over adulthood is associated with evidence of adverse cardiac structure and function. Some of these associations are independent of adiposity in later life.

Neutrophils are indispensable for adverse cardiac remodeling in heart failure.

Persistent immune activation contributes significantly to left ventricular (LV) dysfunction and adverse remodeling in heart failure (HF). In contrast to their well-known essential role in acute myocardial infarction (MI) as first responders that clear dead cells and facilitate subsequent reparative macrophage polarization, the role of neutrophils in the pathobiology of chronic ischemic HF is poorly defined. To determine the importance of neutrophils in the progression of ischemic cardiomyopathy, we measured their production, levels, and activation in a mouse model of chronic HF 8 weeks after permanent coronary artery ligation and large MI. In HF mice, neutrophils were more abundant both locally in failing myocardium (more in the border zone) and systemically in the blood, spleen, and bone marrow, together with increased BM granulopoiesis. There were heightened stimuli for neutrophil recruitment and trafficking in HF, with increased myocardial expression of the neutrophil chemoattract chemokines CXCL1 and CXCL5, and increased neutrophil chemotactic factors in the circulation. HF neutrophil NETotic activity was increased in vitro with coordinate increases in circulating neutrophil extracellular traps (NETs) in vivo. Neutrophil depletion with either antibody-based or genetic approaches abrogated the progression of LV remodeling and fibrosis at both intermediate and late stages of HF. Moreover, analogous to murine HF, the plasma milieu in human acute decompensated HF strongly promoted neutrophil trafficking. Collectively, these results support a key tissue-injurious role for neutrophils and their associated cytotoxic products in ischemic cardiomyopathy and suggest that neutrophils are potential targets for therapeutic immunomodulation in this disease.

Left ventricular global longitudinal strain is worse in BRCA mutation positive breast cancer patients prior to cancer treatment and premature menopause.

PURPOSE: Breast cancer patients with mutations in human tumor suppressor genes BRCA1 and BRCA2 are at higher risk of cardiovascular disease (CVD) than the general population, as they are frequently exposed to cardiotoxic chemotherapy, anti-estrogen therapy, radiation, and/or oophorectomy for cancer-related treatment and prophylaxis. Animal and cell culture models suggest that BRCA mutations may play an independent role in heart failure. We sought to evaluate cardiac structure and function in female BRCA1 and BRCA2 mutation carriers with breast cancer compared to BRCA wildtype women with breast cancer. METHODS: We performed a 1:2 age- and hypertension-matched retrospective cohort study comparing BRCA1 and BRCA2 mutation carriers (n = 38) versus BRCA wildtype controls (n = 76) with a new diagnosis of breast cancer. Echocardiographic data were obtained within 6 months of breast cancer diagnosis and prior to chemotherapy, anti-estrogen therapy, radiation, or oophorectomy. Left ventricular global longitudinal strain (LV-GLS), a highly sensitive marker of LV function, was measured using QLab 15 (Philips Healthcare). RESULTS: In the total cohort of 114 patients with a new diagnosis of breast cancer, the median age was 45 ± 11 years and the prevalence of hypertension was 8%. There were no differences in traditional cardiovascular disease risk factors between cases and controls. BRCA carriers had lower LV-GLS (- 18.1% ± 4.7% vs. - 20.1% ± 3.8%, p = 0.02) and greater right atrial area (12.9 cm2 ± 2.7 cm2 vs. 11.8 cm2 ± 2.0 cm2, p = 0.04) compared to controls; however, both LV-GLS and right atrial area were within the normal range. Compared to controls, BRCA carriers had a trend toward worse LV posterior wall thickness (0.89 cm ± 0.15 cm vs. 0.83 cm ± 0.16 cm, p = 0.06) although not statistically significant. CONCLUSION: In women with newly diagnosed breast cancer and prior to treatment, LV-GLS was worse in BRCA1 and BRCA2 mutation carriers compared to those with BRCA wildtype. These findings suggest that BRCA mutations may be associated with subtle changes in cardiac function. Whether differences in GLS translate to increased cardiovascular risk in women with BRCA mutations needs to be further characterized.

Lab-in-a-Vial Rapid Test for Internet of Things-Embedded Point-of-Healthcare Protein Biomarker Detection in Bodily Fluids.

Amateurs often struggle with detecting and quantifying protein biomarkers in body fluids due to the high expertise required. This study introduces a Lab-in-a-Vial (LV) rapid diagnostic platform, featuring hydrangea-like platinum nanozymes (PtNH), for rapid, accurate detection and quantification of protein biomarkers on-site within 15 min. This method significantly enhances detection sensitivity for various biomarkers in body fluids, surpassing traditional methods such as enzyme-linked immunosorbent assays (ELISA) and lateral flow assays (LFA) by ≈250 to 1300 times. The LV platform uses a glass vial coated with specific bioreceptors such as antigens or antibodies, enabling rapid in vitro evaluation of disease risk from small fluid samples, similar to a personal ELISA-like point-of-care test (POCT). It overcomes challenges in on-site biomarker detection, allowing both detection and quantification through a portable wireless spectrometer for healthcare internet of things (H-IoT). The platform's effectiveness and adaptability are confirmed using IgG/IgM antibodies from SARS-CoV-2 infected patients and nuclear matrix protein (NMP22) from urothelial carcinoma (UC) patients as biomarkers. These tests demonstrated its accuracy and flexibility. This approach offers vast potential for diverse disease applications, provided that the relevant protein biomarkers in bodily fluids are identified.

Comparison of the stage-dependent mitochondrial changes in response to pressure overload between the diseased right and left ventricle in the rat.

The right ventricle (RV) differs developmentally, anatomically and functionally from the left ventricle (LV). Therefore, characteristics of LV adaptation to chronic pressure overload cannot easily be extrapolated to the RV. Mitochondrial abnormalities are considered a crucial contributor in heart failure (HF), but have never been compared directly between RV and LV tissues and cardiomyocytes. To identify ventricle-specific mitochondrial molecular and functional signatures, we established rat models with two slowly developing disease stages (compensated and decompensated) in response to pulmonary artery banding (PAB) or ascending aortic banding (AOB). Genome-wide transcriptomic and proteomic analyses were used to identify differentially expressed mitochondrial genes and proteins and were accompanied by a detailed characterization of mitochondrial function and morphology. Two clearly distinguishable disease stages, which culminated in a comparable systolic impairment of the respective ventricle, were observed. Mitochondrial respiration was similarly impaired at the decompensated stage, while respiratory chain activity or mitochondrial biogenesis were more severely deteriorated in the failing LV. Bioinformatics analyses of the RNA-seq. and proteomic data sets identified specifically deregulated mitochondrial components and pathways. Although the top regulated mitochondrial genes and proteins differed between the RV and LV, the overall changes in tissue and cardiomyocyte gene expression were highly similar. In conclusion, mitochondrial dysfuntion contributes to disease progression in right and left heart failure. Ventricle-specific differences in mitochondrial gene and protein expression are mostly related to the extent of observed changes, suggesting that despite developmental, anatomical and functional differences mitochondrial adaptations to chronic pressure overload are comparable in both ventricles.

LBBB and heart failure-Relationships among QRS amplitude, duration, height, LV mass, and sex.

BACKGROUND: Height, left ventricular (LV) size, and sex were proposed as additional criteria for patient selection for cardiac resynchronization therapy (CRT) but their connections with the QRS complex in left bundle branch block (LBBB) are little investigated. We evaluated these. METHODS: Among patients with "true" LBBB, QRS duration (QRSd) and amplitude, and LV hypertrophy indices, were correlated with patient's height and LV mass, and compared between sexes. RESULTS: In this study cohort (n = 220; 60 ± 12 years; left ventricular ejection fraction [LVEF] 21 ± 7%; mostly New York Heart Association II-III, QRSd 165 ± 19 ms; 57% female; 70% responders [LVEF increased ≥5%]), LV mass was increased in all patients. QRS amplitude did not correlate with LV mass or height in any individual lead or with Sokolow-Lyon or Cornell-Lyon indices. QRSd did not correlate with height. In contrast, QRSd correlated strongly with LV mass (r = .51). CRT response rate was greater in women versus men (84% vs. 58%, p < .001) despite shorter QRSd [7% shorter (p < .0001)]. QRSd normalized for height resulted in a 2.7% and for LV mass 24% greater index in women. CONCLUSION: True LBBB criteria do not exclude HF patients with increased LV mass. QRS amplitudes do not correlate with height or LV mass. Height does not affect QRSd. However, QRSd correlates with LV size. QRSd normalized for LV mass results in 24% greater value in women in the direction of sex-specific responses. LV mass may be a significant nonelectrical modifier of QRSd for CRT.

Clinical outcomes and predictors of delayed echocardiographic response to cardiac resynchronization therapy.

INTRODUCTION: The clinical outcomes and mechanisms of delayed responses to cardiac resynchronization therapy (CRT) remain unclear. We aimed to investigate the differences in outcomes and gain insight into the mechanisms of early and delayed responses to CRT. METHODS: This retrospective study included 110 patients who underwent CRT implantation. Positive response to CRT was defined as ≥15% reduction of left ventricular (LV) end-systolic volume on echocardiography at 1 year (early phase) and 3 years (delayed phase) after implantation. The latest mechanical activation site (LMAS) of the LV was identified using two-dimensional speckle-tracking radial strain analysis. RESULTS: Seventy-eight (71%) patients exhibited an early response 1 year after CRT implantation. Of 32 non-responders in the early phase, 12 (38%) demonstrated a delayed response, and 20 (62%) were classified as non-responders after 3 years. During the follow-up time of 10.3 ± 0.5 years, the delayed and early responders had a similar prognosis of mortality and heart failure (HF) hospitalization. In contrast, non-responders had a worse prognosis. Multivariate analysis revealed that a longer duration (months) between initial HF hospitalization and CRT (odds ratio [OR]: 1.126; 95% confidence interval [CI]: 1.036-1.222; p = .005), non-exact concordance of LV lead location with LMAS (OR: 32.744; 95% CI: 1.101-973.518; p = .044), and pre-QRS duration (OR: 0.901; 95% CI: 0.827-0.981; p = .016) were independent predictors of delayed response to CRT compared with early response. CONCLUSION: The prognoses were similar regardless of the response time after CRT. A longer history of HF, suboptimal LV lead position, and shorter pre-QRS duration were related to delayed response than early response.

Large animal models to study effectiveness of therapy devices in the treatment of heart failure with preserved ejection fraction (HFpEF).

Our understanding of the complex pathophysiology of Heart failure with preserved ejection fraction (HFpEF) is limited by the lack of a robust in vivo model. Existing in-vivo models attempt to reproduce the four main phenotypes of HFpEF; ageing, obesity, diabetes mellitus and hypertension. To date, there is no in vivo model that represents all the haemodynamic characteristics of HFpEF, and only a few have proven to be reliable for the preclinical evaluation of potentially new therapeutic targets. HFpEF accounts for 50% of all the heart failure cases and its incidence is on the rise, posing a huge economic burden on the health system. Patients with HFpEF have limited therapeutic options available. The inadequate effectiveness of current pharmaceutical therapeutics for HFpEF has prompted the development of device-based treatments that target the hemodynamic changes to reduce the symptoms of HFpEF. However, despite the potential of device-based solutions to treat HFpEF, most of these therapies are still in the developmental stage and a relevant HFpEF in vivo model will surely expedite their development process. This review article outlines the major limitations of the current large in-vivo models in use while discussing how these designs have helped in the development of therapy devices for the treatment of HFpEF.

Remodeling in Aortic Stenosis With Reduced and Preserved Ejection Fraction: Insight on Motion Abnormality Via 3D + Time Personalized LV Modeling in Cardiac MRI.

BACKGROUND: Increased afterload in aortic stenosis (AS) induces left ventricle (LV) remodeling to preserve a normal ejection fraction. This compensatory response can become maladaptive and manifest with motion abnormality. It is a clinical challenge to identify contractile and relaxation dysfunction during early subclinical stage to prevent irreversible deterioration. PURPOSE: To evaluate the changes of regional wall dynamics in 3D + time domain as remodeling progresses in AS. STUDY TYPE: Retrospective. POPULATION: A total of 31 AS patients with reduced and preserved ejection fraction (14 AS_rEF: 7 male, 66.5 [7.8] years old; 17 AS_pEF: 12 male, 67.0 [6.0] years old) and 15 healthy (6 male, 61.0 [7.0] years old). FIELD STRENGTH/SEQUENCE: 1.5 T Magnetic resonance imaging/steady state free precession and late-gadolinium enhancement sequences. ASSESSMENT: Individual LV models were reconstructed in 3D + time domain and motion metrics including wall thickening (TI), dyssynchrony index (DI), contraction rate (CR), and relaxation rate (RR) were automatically extracted and associated with the presence of scarring and remodeling. STATISTICAL TESTS: Shapiro-Wilk: data normality; Kruskal-Wallis: significant difference (P < 0.05); ICC and CV: variability; Mann-Whitney: effect size. RESULTS: AS_rEF group shows distinct deterioration of cardiac motions compared to AS_pEF and healthy groups (TIAS_rEF : 0.92 [0.85] mm, TIAS_pEF : 5.13 [1.99] mm, TIhealthy : 3.61 [1.09] mm, ES: 0.48-0.83; DIAS_rEF : 17.11 [7.89]%, DIAS_pEF : 6.39 [4.04]%, DIhealthy : 5.71 [1.87]%, ES: 0.32-0.85; CRAS_rEF : 8.69 [6.11] mm/second, CRAS_pEF : 16.48 [6.70] mm/second, CRhealthy : 10.82 [4.57] mm/second, ES: 0.29-0.60; RRAS_rEF : 8.45 [4.84] mm/second; RRAS_pEF : 13.49 [8.56] mm/second, RRhealthy : 9.31 [2.48] mm/second, ES: 0.14-0.43). The difference in the motion metrics between healthy and AS_pEF groups were insignificant (P-value = 0.16-0.72). AS_rEF group was dominated by eccentric hypertrophy (47.1%) with concomitant scarring. Conversely, AS_pEF group was dominated by concentric remodeling and hypertrophy (71.4%), which could demonstrate hyperkinesia with slight wall dyssynchrony than healthy. Dysfunction of LV mechanics corresponded to the presence of myocardial scarring (54.9% in AS), which reverted the compensatory mechanisms initiated and performed by LV remodeling. DATA CONCLUSION: The proposed 3D + time modeling technique may distinguish regional motion abnormalities between AS_pEF, AS_rEF, and healthy cohorts, aiding clinical diagnosis and monitoring of AS progression. Subclinical myocardial dysfunction is evident in early AS despite of normal EF. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 1.

Are Sodium-Glucose Cotransporter-2 Inhibitors the Cherry on Top of Cardio-Oncology Care?

The increasing aging of the population combined with improvements in cancer detection and care has significantly improved the survival and quality of life of cancer patients. These benefits are hampered by the increase of cardiovascular diseases being heart failure the most frequent manifestation of cardiotoxicity and becoming the major cause of morbidity and mortality among cancer survivor. Current strategies to prevent cardiotoxicity involves different approaches such as optimal management of CV risk factors, use of statins and/or neurohormonal medications, and, in some cases, even the use of chelating agents. As a class, SGLT2-i have revolutionized the therapeutic horizon of HF patients independently of their ejection fraction or glycemic status. There is an abundance of data from translational and observational clinical studies supporting a potential beneficial role of SGLT2-i in mitigating the cardiotoxic effects of cancer patients receiving anthracyclines. These findings underscore the need for more robust clinical trials to investigate the effect on cardiovascular outcomes of the prophylactic SGLT2-i treatment in patients undergoing cancer treatment.

Clinical utility of ambulatory ECG monitoring and 2D-ventricular strain for evaluation of post-COVID-19 ventricular arrhythmia.

BACKGROUND: A relatively common complication of COVID -19 infection is arrhythmia. There is limited information about myocardial deformation and heart rate variability (HRV) in symptomatic post COVID patients presented by ventricular arrhythmia. AIM OF THE STUDY: Our goal was to assess 2D-ventricular strain and heart rate variability indices (evaluated by ambulatory ECG monitoring) in post-COVID-19 patients suffering from ventricular arrhythmia. METHODS: The current observational case-control study performed on 60 patients one month after they had recovered from the COVID-19 infection. Thirty healthy volunteers served as the control group. Each participant had a full medical history review, blood tests, a 12-lead surface electrocardiogram (ECG), 24-h ambulatory ECG monitoring, and an echo-Doppler examination to evaluate the left ventricular (LV) dimensions, tissue Doppler velocities, and 2D-speckle tracking echocardiography (2D-STE) for both the LV and right ventricular (RV) strain. RESULTS: Symptomatic post-COVID patients with monomorphic premature ventricular contractions (PVCs) showed a substantial impairment of LV/RV systolic and diastolic functions, LV/RV myocardial performance (MPI) with reduced indices of HRV. Patients with higher versus lower ventricular burden had poorer functional status, higher levels of inflammatory biomarkers and reduced parameters of HRV (New York Heart Association (NYHA) class: 2.1 ± 0.9 vs. 1.5 ± 0.6, p < 0.001, C-reactive protein (CRP): 13.3 ± 4.1 vs. 8.3 ± 5.9 mg/L, p < 0.0001, low frequency/high frequency (LF/HF): 3.6 ± 2.4 vs. 2.2 ± 1.2, p < 0.002, the root mean square of the difference between successive normal intervals (rMSSD): 21.8 ± 4.7 vs. 29.3 ± 14.9 ms, p < 0.039 and the standard deviation of the RR interval (SDNN): 69.8 ± 19.1 vs.108.8 ± 37.4 ms, p < 0.0001). The ventricular burden positively correlated with neutrophil/lymphocyte ratio (NLR) (r = 0.33, p < 0.001), CRP (r = 0.60, p < 0.0001), while it negatively correlated with LV-global longitudinal strain (GLS) (r = -0.38, p < 0.0001), and RV-GLS (r = -0.37, p < 0.0001). CONCLUSIONS: Patients with post-COVID symptoms presented by ventricular arrhythmia had poor functional status. Patients with post-COVID symptoms and ventricular arrhythmia had subclinical myocardial damage, evidenced by speckle tracking echocardiography while having apparently preserved LV systolic function. The burden of ventricular arrhythmia in post-COVID patients significantly correlated with increased inflammatory biomarkers and reduced biventricular strain.

Plasma microRNA-143 and microRNA-145 levels are elevated in patients with left ventricular dysfunction.

MicroRNA(miR)-143 and miR-145 are mainly expressed in vascular smooth muscle cells. However, the relationship between plasma miR-143 or miR-145 levels and the left ventricular (LV) function in patients with heart diseases remains unclear. Blood samples were taken from the antecubital vein in patients with heart diseases (n = 52), such as coronary artery disease, old myocardial infarction, cardiomyopathy, and valvular heart disease, and controls without heart diseases (n = 22). We measured plasma miR-143 and -145 levels by quantitative RT-PCR using TaqMan MicroRNA Assays and THUNDERBIRD Probe qPCR Mix. Plasma BNP levels were also measured. Echocardiography was performed to measure the LV ejection fraction (LVEF) and LV dilation. Plasma miR-143 and miR-145 levels were significantly higher in patients with heart diseases than in controls, respectively. Plasma miR-143 and miR-145 levels were significantly higher in patients with LVEF < 50% than in those with LVEF ≧ 50%, respectively. Plasma miR-143 and miR-145 levels were inversely correlated with LVEF, respectively. Plasma miR-143 and miR-145 levels were positively correlated with LV end-systolic dimension, respectively. Plasma miR-143 and -145 levels were positively correlated with plasma BNP levels, respectively. Plasma BNP levels were inversely correlated with LVEF. Plasma miR-143 and miR-145 levels are elevated in patients with LV dysfunction and may counteract LV dysfunction.

Long-term results following off-pump coronary-artery bypass grafting in left ventricular dysfunction.

Severe left ventricular (LV) dysfunction is an independent risk factor for early and long-term mortality after coronary-artery bypass grafting (CABG). Off-pump CABG (OPCAB) significantly reduces the early incidence of major complications in high-risk patients. Moreover, bilateral internal thoracic artery (BITA) grafting after CABG is associated with improved long-term outcomes. We aimed to evaluate the impact of multivessel OPCAB with BITA grafting for complete revascularization on postoperative and long-term outcomes in patients with low LV ejection fraction (EF). We included 121 patients with EF ≤ 30.0% who underwent isolated multivessel OPCAB (average LVEF, 24.8%) between April 2007 and December 2019. Sixty-six patients received BITA grafts, while 55 had single internal thoracic artery (SITA) grafts. We conducted multivariate analyses to examine the correlation between perioperative data and late mortality rate. The early mortality rate was 1.65%. After excluding in-hospital mortality cases, we performed long-term follow-up of 119 patients. Early postoperative echocardiography showed significant LVEF improvement in 89 (75.2%) patients. However, LVEF remained ≤ 30.0% in 30 (24.8%) patients. We recorded 15 and 30 cases of cardiac death and cardiac events, respectively, during the long-term follow-up period. Postoperative LVEF ≤ 30.0% (P < 0.01) and no use of BITA grafting (P = 0.03) were significant predictors of cardiac death and events; moreover, hemodialysis was a significant predictor of all-cause mortality rather than cardiac death. Multivessel OPCAB in patients with severe LV dysfunction was associated with acceptable in-hospital mortality and early postoperative improvement in LV function. Additionally, OPCAB with BITA grafting may provide long-term benefits with respect to cardiac death and events. However, the long-term benefits were significantly limited in patients without early postoperative improvement in LV function and patients with chronic hemodialysis.Clinical registration number: 5590 (14/5/2020 Tokyo Women's Medical University).

A case of refractory disseminated subcutaneous abscess with intrahousehold transmission by a USA300-LV-like strain of PVL-positive community-acquired MRSA clone.

A 44-year-old man with hypertension and dyslipidemia presented with pain in the buttocks. The patient was diagnosed with perianal ischiorectal fossa abscesses and cellulitis. He was subsequently diagnosed with a perineal subcutaneous abscess after a week, a right lower leg impetigo after a month, right periorchitis, a scrotal abscess, and Fournier's gangrene after two months. The patient was treated with various antimicrobials and underwent incisional drainage. Methicillin-resistant Staphylococcus aureus (MRSA) was detected in all draining specimens. Her daughter and son, who lived with the patient, presented with subcutaneous abscesses caused by MRSA. Suspecting repeated infections and household infections by virulent types of MRSA, such as PVL-positive strains, we performed genetic analyses of his and his son's strains. The results showed that the genotype and toxin gene profiles [ST8/t008/SCCmec type IVc/Panton-Valentine leucocidin (PVL) (+)/arginine catabolic mobile element (ACME) (-)] of both strains matched. single nucleotide polymorphism (SNP) analysis confirmed genetic homology between the two, concluding that home transmission by the same clone had occurred. In addition, the strain in this case differed from USA300 [ST8/t008/SCCmec type IVa/PVL (+) ACME (+)], which is a PVL-positive MRSA worldwide, including Japan, and its genetic profile matches that of USA300-LV, which is detected mainly in South America. Furthermore, SNP analysis showed that this strain is similar to USA300-LV/J (derived from USA300-LV) detected on Ishigaki Island, Okinawa Prefecture, Japan. This is the first report of refractory infections and household transmission of USA300-LV/J. Therefore, it is necessary to closely monitor both the USA300 and the USA300-LV.

Echocardiographic parameters of cardiac structure and function in the diagnosis of acute myocarditis in adult patients: A systematic review and meta-analysis.

BACKGROUND: Transthoracic echocardiography (TTE) plays a key role in the initial work-up of myocarditis where the identification of pathologic structural and functional changes may assist in its diagnosis and management. The aim of this systematic review was to appraise the evidence for the utility of echocardiographic parameters of cardiac structure and function in the diagnosis of myocarditis in adult populations. METHODS: A systematic literature search of medical databases was performed using PRISMA principles to identify all relevant studies assessing TTE parameters in adult patients with myocarditis (1995-2020; English only; PROSPERO registration CRD42021243598). Data for a range of structural and functional TTE parameters were individually extracted and those with low heterogeneity were then meta-analyzed using a random-effects model for effect size, and assessed through standardized mean difference (SMD). RESULTS: Available data from six studies (with a pooled total of 269 myocarditis patients and 240 controls) revealed that myocarditis can be reliably differentiated from healthy controls using echocardiographic measures of left ventricular (LV) size and systolic function, in particular LV end-diastolic diameter, LV ejection fraction (LVEF) and LV global longitudinal strain (LV-GLS) (p ≤ .01 for all). LV-GLS demonstrated the highest overall effect size, followed by LVEF and LVEDD (SMD: |0.46-1.98|). Two studies also demonstrated that impairment in LV-GLS was associated with adverse cardiovascular outcomes in this population, irrespective of LVEF. CONCLUSIONS: LV-GLS demonstrated the greatest overall effect size and therefore ability to differentiate myocarditis populations from healthy controls. GLS was also shown to be a predictor of adverse cardiovascular outcomes, in this population. HIGHTLIGHTS: What is already known on this subject? Myocarditis is a disease process that is often a diagnosis of exclusion, as it frequently mimics other acute cardiac pathologies. Transthoracic echocardiography is traditionally the initial imaging modality used for noninvasive structural assessment in populations with myocarditis. What might this study add? This study demonstrates that left ventricular (LV) global longitudinal strain, LV ejection fraction and LV end-diastolic diameter can differentiate between myocarditis patients and healthy controls. LV-GLS demonstrated the greatest overall effect size when comparing these two populations, in comparison to the other measures. How might this impact on clinical practice? This study demonstrates that assessment of myocardial deformation indices allows for sensitive discrimination between myocarditis patients from healthy controls. Routine assessment of LV-GLS may serve as an important diagnostic tool in the acute care setting.

Simulated Effects of Acute Left Ventricular Myocardial Infarction on Mitral Regurgitation in an Ovine Model.

Ischemic mitral regurgitation (IMR) occurs from incomplete coaptation of the mitral valve (MV) after myocardial infarction (MI), typically worsened by continued remodeling of the left ventricular (LV). The importance of LV remodeling is clear as IMR is induced by the post-MI dual mechanisms of mitral annular dilation and leaflet tethering from papillary muscle (PM) distension via the MV chordae tendineae (MVCT). However, the detailed etiology of IMR remains poorly understood, in large part due to the complex interactions of the MV and the post-MI LV remodeling processes. Given the patient-specific anatomical complexities of the IMR disease processes, simulation-based approaches represent an ideal approach to improve our understanding of this deadly disease. However, development of patient-specific models of left ventricle-mitral valve (LV-MV) interactions in IMR are complicated by the substantial variability and complexity of the MR etiology itself, making it difficult to extract underlying mechanisms from clinical data alone. To address these shortcomings, we developed a detailed ovine LV-MV finite element (FE) model based on extant comprehensive ovine experimental data. First, an extant ovine LV FE model (Sci. Rep. 2021 Jun 29;11(1):13466) was extended to incorporate the MV using a high fidelity ovine in vivo derived MV leaflet geometry. As it is not currently possible to image the MVCT in vivo, a functionally equivalent MVCT network was developed to create the final LV-MV model. Interestingly, in pilot studies, the MV leaflet strains did not agree well with known in vivo MV leaflet strain fields. We then incorporated previously reported MV leaflet prestrains (J. Biomech. Eng. 2023 Nov 1;145(11):111002) in the simulations. The resulting LV-MV model produced excellent agreement with the known in vivo ovine MV leaflet strains and deformed shapes in the normal state. We then simulated the effects of regional acute infarctions of varying sizes and anatomical locations by shutting down the local myocardial contractility. The remaining healthy (noninfarcted) myocardium mechanical behaviors were maintained, but allowed to adjust their active contractile patterns to maintain the prescribed pressure-volume loop behaviors in the acute post-MI state. For all cases studied, the LV-MV simulation demonstrated excellent agreement with known LV and MV in vivo strains and MV regurgitation orifice areas. Infarct location was shown to play a critical role in resultant MV leaflet strain fields. Specifically, extensional deformations of the posterior leaflets occurred in the posterobasal and laterobasal infarcts, while compressive deformations of the anterior leaflet were observed in the anterobasal infarct. Moreover, the simulated posterobasal infarct induced the largest MV regurgitation orifice area, consistent with experimental observations. The present study is the first detailed LV-MV simulation that reveals the important role of MV leaflet prestrain and functionally equivalent MVCT for accurate predictions of LV-MV interactions. Importantly, the current study further underscored simulation-based methods in understanding MV function as an integral part of the LV.

Molecular Pathways and Animal Models of Hypoplastic Left Heart Syndrome.

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease (CHD) with underdevelopment of left-sided heart structures. While previously uniformly fatal, surgical advances now provide highly effective palliation that allows most HLHS patients to survive their critical CHD. Nevertheless, there remains high morbidity and mortality with high risk of heart failure. As hemodynamic compromise from restricted aortic blood flow has been suggested to underlie the poor LV growth, this suggests the possibility of prenatal fetal intervention to recover LV growth. As such interventions have yielded ambiguous results, the optimization of therapy will require more mechanistic insights into the developmental etiology for HLHS. Clinical studies have shown high heritability for HLHS, with an oligogenic etiology indicated in conjunction with genetic heterogeneity. This is corroborated with the recent recovery of mutant mice with HLHS. With availability-induced pluripotent stem cell (iPSC)-derived cardiomyocytes from HLHS mice and patients, new insights have emerged into the cellular and molecular etiology for the LV hypoplasia in HLHS. Cell proliferation defects were observed in conjunction with metaphase arrest and the disturbance of Hippo-YAP signaling. The left-sided restriction of the ventricular hypoplasia may result from epigenetic perturbation of pathways regulating left-right patterning. These findings suggest new avenues for fetal interventions with therapies using existing drugs that target the Hippo-YAP pathway and/or modulate epigenetic regulation.

Fluorescent α-Conotoxin [Q1G, ΔR14]LvIB Identifies the Distribution of α7 Nicotinic Acetylcholine Receptor in the Rat Brain.

α7 nicotinic acetylcholine receptors (nAChRs) are mainly distributed in the central nervous system (CNS), including the hippocampus, striatum, and cortex of the brain. The α7 nAChR has high Ca2+ permeability and can be quickly activated and desensitized, and is closely related to Alzheimer's disease (AD), epilepsy, schizophrenia, lung cancer, Parkinson's disease (PD), inflammation, and other diseases. α-conotoxins from marine cone snail venom are typically short, disulfide-rich neuropeptides targeting nAChRs and can distinguish various subtypes, providing vital pharmacological tools for the functional research of nAChRs. [Q1G, ΔR14]LvΙB is a rat α7 nAChRs selective antagonist, modified from α-conotoxin LvΙB. In this study, we utilized three types of fluorescein after N-Hydroxy succinimide (NHS) activation treatment: 6-TAMRA-SE, Cy3 NHS, and BODIPY-FL NHS, labeling the N-Terminal of [Q1G, ΔR14]LvΙB under weak alkaline conditions, obtaining three fluorescent analogs: LvIB-R, LvIB-C, and LvIB-B, respectively. The potency of [Q1G, ΔR14]LvΙB fluorescent analogs was evaluated at rat α7 nAChRs expressed in Xenopus laevis oocytes. Using a two-electrode voltage clamp (TEVC), the half-maximal inhibitory concentration (IC50) values of LvIB-R, LvIB-C, and LvIB-B were 643.3 nM, 298.0 nM, and 186.9 nM, respectively. The stability of cerebrospinal fluid analysis showed that after incubation for 12 h, the retention rates of the three fluorescent analogs were 52.2%, 22.1%, and 0%, respectively. [Q1G, ΔR14]LvΙB fluorescent analogs were applied to explore the distribution of α7 nAChRs in the hippocampus and striatum of rat brain tissue and it was found that Cy3- and BODIPY FL-labeled [Q1G, ΔR14]LvΙB exhibited better imaging characteristics than 6-TAMARA-. It was also found that α7 nAChRs are widely distributed in the cerebral cortex and cerebellar lobules. Taking into account potency, imaging, and stability, [Q1G, ΔR14]LvΙB -BODIPY FL is an ideal pharmacological tool to investigate the tissue distribution and function of α7 nAChRs. Our findings not only provide a foundation for the development of conotoxins as visual pharmacological probes, but also demonstrate the distribution of α7 nAChRs in the rat brain.

Vectorcardiography signs of a failing Fontan: Heart rate, PR interval, RtQRSvm, QRSvm and SPQRS-T angle as noninvasive markers of late Fontan complications and mortality.

BACKGROUND: Limited data exists on interpreting vectorcardiography (VCG) parameters in the Fontan population. OBJECTIVE: The purpose of this study was to demonstrate the associations between ECG/VCG parameters and Fontan failure (FF). METHODS/RESULTS: 107 patients with a Fontan operation after 1990 and without significant ventricular pacing were included. FF and Fontan survival (FS) groups were compared. The average follow-up after Fontan operation was 11.8 years ±7.1 years. 14 patients had FF (13.1%) which was defined as having protein-losing-enteropathy (1.9%), plastic bronchitis (2.8%), Fontan takedown (1.9%), heart transplant (5.6%), NYHA class III-IV (2.8%) or death (0.9%). A 12­lead ECG at last follow up or prior to FF was assessed for heart rate, PR interval, QRS duration, Qtc and left/right sided precordial measures (P-wave, QRS and T-wave vector magnitudes, spatial P-R and QRS-T angles). Transthoracic echocardiogram evaluated atrioventricular valve regurgitation and ventricular dysfunction at FF or last follow up. A cox multivariate regression analysis adjusted for LV dominance, ventricular dysfunction, HR, PR, QTc, Pvm, QRSvm, SPQRST-angle, RtPvm, RtQRSvm and RtTvm. Ventricular dysfunction, increased heart rate and prolonged PR interval were significantly associated to FF at the multivariate analysis. ROC analysis and Kaplan-meier analysis revealed an increased total mortality associated with a heart rate > 93 bpm, PR interval > 155 mv, QRSvm >1.91 mV, RtQRSvm >1.8 mV and SPQRST angle >92.3 mV with p values <0.001 to 0.018. CONCLUSION: We demonstrate the importance of ECG/VCG monitoring in the Fontan population and suggest specific indicators of late complications and mortality.

Baseline Echocardiography and Laboratory Findings in MIS-C and Associations with Clinical Illness Severity.

Children with COVID-associated multisystem inflammatory syndrome (MIS-C) may develop severe disease. We explored the association of admission echocardiographic and laboratory parameters with MIS-C disease severity. This retrospective, single center study of consecutive MIS-C patients (4/2020-12/2021) excluded those with preexisting cardiomyopathy, congenital heart disease, or prior cardiotoxic therapy. Our hypothesis was that worse admission echocardiographic and laboratory parameters were associated with more severe disease based on vasoactive medication use. Univariable and multivariable logistic regression models assessed the association between vasoactive medication use and baseline variables. Of 118 MIS-C patients, median age was 7.8 years (IQR 4.6, 11.8), 48% received vasoactive medication. Higher admission brain natriuretic peptide [OR 1.07 (95% CI 1.02,1.14), p = 0.019], C-reactive protein [OR 1.08 (1.03,1.14), p = 0.002], troponin [OR 1.05 (1.02,1.1), p = 0.015]; lower left ventricular ejection fraction [LVEF, OR 0.96 (0.92,1), p = 0.042], and worse left atrial reservoir strain [OR 0.96 (0.92,1), p = 0.04] were associated with vasoactive medication use. Only higher CRP [OR 1.07 (1.01, 1.11), p = 0.034] and lower LVEF [0.91 (0.84,0.98), p = 0.015] remained independently significant. Among those with normal admission LVEF (78%, 92/118), 43% received vasoactive medication and only higher BNP [OR 1.09 (1.02,1.19), p = 0.021 per 100 pg/mL] and higher CRP [OR 1.07 (1.02,1.14), p = 0.013] were associated with use of vasoactive medication. Nearly half of all children admitted for MIS-C subsequently received vasoactive medication, including those admitted with a normal LVEF. Similarly, admission strain parameters were not discriminatory. Laboratory markers of systemic inflammation and cardiac injury may better predict early MIS-C disease severity.