Role and Mechanism of Lamellar Derived Growth Factor /AKT Pathway in Ventricular Remodeling Induced by Pressure Overload.

This study aimed to investigate the role and underlying mechanisms of the platelet-derived growth factor (PDGF)/protein kinase B (AKT) signaling pathway in pressure overload-induced ventricular remodeling. Ventricular remodeling, a critical pathological process in heart failure, is commonly triggered by pressure overload. While PDGF is known to promote cell proliferation and growth, the AKT pathway is crucial for cell growth, survival, and metabolism. However, the specific role of the PDGF/AKT pathway in pressure overload-induced ventricular remodeling remains unclear. Thus, this study aimed to elucidate the precise mechanisms of PDGF/AKT involvement in this process using animal models and cell experiments. 45 female C57BL/6 mice were utilized, randomly divided into three groups: model group (M group, n = 15), control group (C group, n = 15), and experimental group (E group, n = 15). M group mice underwent thoracotomy without aortic constriction (AC). C group mice received phosphate-buffered saline (PBS) and dimethyl sulfoxide (DMSO) treatment following AC surgery. E group mice were treated with the PDGF receptor inhibitor AG1296 and PBS solution after AC surgery. Additionally, 293 T cells were categorized into three groups: PDGF shRNA transfected group (downregulating PDGF expression, D group), PDGF overexpression group (B group), and control group (NV group). Left ventricular end-systolic volume (LVESV) and ejection fraction (FS) of the mice were measured via echocardiography. Western blot analysis was conducted to assess the expression levels of p-AKT and t-AKT in myocardial tissues. Furthermore, myocardial cell area was measured using hematoxylin and eosin (HE) staining and image analysis software. The LVESV in the C group was significantly higher than in the M and E groups (48.32 ± 3.08 mL vs. 18.24 ± 3.19 mL and 25.44 ± 3.12 mL, P < 0.05). The FS in the C group was significantly lower compared to the M and E groups (21.18 ± 2.99% vs. 42.45 ± 3.02% and 26.89 ± 2.54%, P < 0.05). Western blot analysis revealed that p-AKT and t-AKT levels were significantly elevated in the C group and PDGF overexpression group (B group) compared to the M and PDGF shRNA groups (D group) (P < 0.05). HE staining showed a significant increase in myocardial cell cross-sectional area in the C and D groups, with the most pronounced enlargement in the D group (P < 0.05). PDGF facilitates pressure overload-induced ventricular remodeling and myocardial fibrosis. Inhibition of the PDGF/AKT signaling pathway effectively mitigates myocardial cell hypertrophy and ventricular remodeling. These findings offer novel potential targets and therapeutic strategies for the treatment of pressure overload-related heart failure.

Robustness of tricuspid regurgitation reduction at 1 year following edge-to-edge repair for primary tricuspid regurgitation.

BACKGROUND AND OBJECTIVE: Within recent years, transcatheter tricuspid edge-to-edge repair (T-TEER) has emerged as a safe and effective treatment option in patients with secondary tricuspid regurgitation (TR). However, for primary TR, data on the robustness and durability of TR reduction 1 year following T-TEER is limited. METHODS: All consecutive patients treated with T-TEER for TR at two high-volume centers between September 2018 and December 2022 were enrolled in a registry. Primary TR was defined as tricuspid valve (TV) prolapse or flail TV leaflets as assessed by pre- and peri-interventional transesophageal echocardiography (TEE). RESULTS: 201 patients were included in this analysis, of whom 27 (13.4%) were classified as primary TR and 174 (86.6%) as TR of secondary origin. All-cause mortality during 1-year follow-up was reached by 50 patients (24.9%) [primary: 7 (25.9%), secondary: 43 (24.7%)], and 151 (75.1%) completed follow-up with transthoracic echocardiography (TTE). Patients' median age was 80 (76-83) years, 112 (55.7%) were female and 181 (90.1%) reported a New-York heart association functional class (NYHA-FC) of III or IV. The remaining baseline clinical and echocardiographic parameters were comparable between the groups, but secondary TR patients had a significantly higher TRI-SCORE (5 (4-8) vs. 7 (5-14), P = 0.010). In both groups, an immediate reduction of TR-Grade post-intervention was observed. This reduction was sustained at follow-up with 80.0% of the primary TR patients classified as moderate or less and 61.8% of the secondary TR patients. This translated to a significant improvement of NHYA-FC in both groups. Kaplan-Meier analysis revealed no differences regarding rates for all-cause mortality between the groups (P < 0.99). CONCLUSION: T-TEER achieves a robust TR reduction in primary TR patients 1 year after intervention with noninferior clinical results to treatment for secondary TR with regards to mortality, re-hospitalization, and NYHA-FC.

Ambulatory blood pressure is associated with left ventricular geometry after 10 years in hypertensive patients with continuous antihypertensive treatment.

Both aging and high blood pressure (BP) are associated with a risk of left ventricular concentricity and hypertrophy. We hypothesized that optimal BP management improves left ventricular remodeling beyond aging. Among 558 hypertensive patients on continuous antihypertensive treatment and without concurrent heart disease who were referred to a cardiology clinic with echocardiography and ambulatory BP monitoring data, 142 patients' echocardiographic data was available after 10 years. Baseline BP and changes in left ventricular geometry were evaluated. Mean age at baseline was 71.0 years old. Baseline daytime BP was 129.9/72.4 ± 17.1/10.2 mmHg and nighttime BP was 122.5/67.1 ± 16.9/9.1 mmHg. After 10 years, left ventricular mass index (LVMI) and relative wall thickness (RWT) significantly decreased from 104.5 ± 26.3 to 97.9 ± 26.4 g/m2, p = 0.003 and 0.51 ± 0.09 to 0.47 ± 0.09, p < 0.001, consecutively. Among patients with hypertrophic geometry at baseline, 17.2% reverted to normal geometry at follow-up. Daytime systolic BP (136.9 ± 18.5 mmHg vs 126.2 ± 16.5 mmHg, p = 0.03), nighttime systolic BP (126.2 ± 17.7 mmHg vs 116.3 ± 16.0 mmHg, p = 0.038) and daytime pulse pressure (63.5 ± 17.3 mmHg vs 53.1 ± 14.9 mmHg, p = 0.022) at baseline were higher in patients who remained hypertrophic than those without hypertrophy at follow-up. On logistic regression analysis, daytime, nighttime systolic BP, and daytime pulse pressure were significantly related to the regression of hypertrophy adjusted for age, sex, eGFR, BMI, LVMI, and RWT at baseline. For conclusion, antihypertensive treatment for 10 years improved LV geometry despite aging. Ambulatory BP and pulse pressure at baseline predicted the change of LV geometry after 10 years.

Correlation of serum homocysteine and cystatin C levels with prognosis in heart failure with preserved ejection fraction patients.

OBJECTIVE: This study investigated the relationship of serum homocysteine (Hcy) and cystatin C (Cys C) levels with the prognosis of patients with heart failure with preserved ejection fraction (HFpEF). METHODS: A total of 178 patients with HFpEF who were admitted to our hospital between December 2019 and November 2020 were included. Patients were grouped based on their serum Hcy and Cys C levels: high Hcy level, normal Hcy level, high Cys C level, and normal Cys C level. Cardiac function, ventricular remodeling indices, and prognosis were compared among patients in these groups. Additionally, the predictive value of serum Hcy and Cys C levels for adverse cardiovascular events in HFpEF patients was analyzed. RESULTS: Patients' mean age in the high Hcy level, normal Hcy level, high Cys C level, and normal Cys C level groups was 69.21 ± 4.17,67.74 ± 4.28,69.95 ± 4.98, and 67.06 ± 4.13 years old, respectively. The high Hcy level group exhibited a lower proportion of class II cardiac function according to the New York Heart Association (NYHA) classification and a higher proportion of class IV cardiac function than the normal Hcy level group, with statistically significant differences. Similarly, the high Cys C level group had a lower proportion of class II cardiac function and a higher proportion of class IV cardiac function compared with the normal Cys C level group, with statistically significant differences. Left ventricular end-diastolic internal diameter (LVEDD), left ventricular end-systolic internal diameter (LVESD), and left ventricular mass index (LVMI) were significantly higher in both the high Hcy level and high Cys C level groups compared with the normal group, with statistically significant differences. The rates of all-cause mortality and class I endpoint events were significantly higher in the high Hcy level and high Cys C level groups than in the normal group. Multifactorial logistic regression analysis demonstrated that adverse cardiovascular events were significantly associated with cardiac function class, LVEDD, LVESD, LVMI, Hcy, and Cys C in patients with HFpEF. The area under the curve (AUC) values for Hcy and Cys C, determined using receiver operating characteristic (ROC) curve analysis, were 0.778 (optimal critical value, 25.38) and 0.681 (optimal critical value, 1.56), respectively, for predicting adverse cardiovascular events. Both Hcy and Cys C serum levels were positively correlated with LVEDD, LVESD, LVMI, and NYHA classification. CONCLUSION: Serum levels of Hcy and Cys C were closely associated with cardiac function, ventricular remodeling indices, and prognosis in patients with HFpEF. These levels may serve as valuable indices for assessing HFpEF patients' health status and prognosis, providing important insights into their potential role as biomarkers for HFpEF management and prognosis.

Ramipril After Transcatheter Aortic Valve Implantation in Patients Without Reduced Ejection Fraction: The RASTAVI Randomized Clinical Trial.

BACKGROUND: Patients with aortic stenosis may continue to have an increased risk of heart failure, arrhythmias, and death after successful transcatheter aortic valve implantation. Renin-angiotensin system inhibitors may be beneficial in this setting. We aimed to explore whether ramipril improves the outcomes of patients with aortic stenosis after transcatheter aortic valve implantation. METHODS AND RESULTS: PROBE (Prospective Randomized Open, Blinded Endpoint) was a multicenter trial comparing ramipril with standard care (control) following successful transcatheter aortic valve implantation in patients with left ventricular ejection fraction >40%. The primary end point was the composite of cardiac mortality, heart failure readmission, and stroke at 1-year follow-up. Secondary end points included left ventricular remodeling and fibrosis. A total of 186 patients with median age 83 years (range 79-86), 58.1% women, and EuroSCORE-II 3.75% (range 3.08-4.97) were randomized to receive either ramipril (n=94) or standard treatment (n=92). There were no significant baseline, procedural, or in-hospital differences. The primary end point occurred in 10.6% in the ramipril group versus 12% in the control group (P=0.776), with no differences in cardiac mortality (ramipril 1.1% versus control group 2.2%, P=0.619) but lower rate of heart failure readmissions in the ramipril group (3.2% versus 10.9%, P=0.040). Cardiac magnetic resonance analysis demonstrated better remodeling in the ramipril compared with the control group, with greater reduction in end-systolic and end-diastolic left ventricular volumes, but nonsignificant differences were found in the percentage of myocardial fibrosis. CONCLUSIONS: Ramipril administration after transcatheter aortic valve implantation in patients with preserved left ventricular function did not meet the primary end point but was associated with a reduction in heart failure re-admissions at 1-year follow-up. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT03201185.

Crotonylation of NAE1 Modulates Cardiac Hypertrophy via Gelsolin Neddylation.

BACKGROUND: Cardiac hypertrophy and its associated remodeling are among the leading causes of heart failure. Lysine crotonylation is a recently discovered posttranslational modification whose role in cardiac hypertrophy remains largely unknown. NAE1 (NEDD8 [neural precursor cell expressed developmentally downregulated protein 8]-activating enzyme E1 regulatory subunit) is mainly involved in the neddylation modification of protein targets. However, the function of crotonylated NAE1 has not been defined. This study aims to elucidate the effects and mechanisms of NAE1 crotonylation on cardiac hypertrophy. METHODS: Crotonylation levels were detected in both human and mouse subjects with cardiac hypertrophy through immunoprecipitation and Western blot assays. Tandem mass tag (TMT)-labeled quantitative lysine crotonylome analysis was performed to identify the crotonylated proteins in a mouse cardiac hypertrophic model induced by transverse aortic constriction. We generated NAE1 knock-in mice carrying a crotonylation-defective K238R (lysine to arginine mutation at site 238) mutation (NAE1 K238R) and NAE1 knock-in mice expressing a crotonylation-mimicking K238Q (lysine to glutamine mutation at site 238) mutation (NAE1 K238Q) to assess the functional role of crotonylation of NAE1 at K238 in pathological cardiac hypertrophy. Furthermore, we combined coimmunoprecipitation, mass spectrometry, and dot blot analysis that was followed by multiple molecular biological methodologies to identify the target GSN (gelsolin) and corresponding molecular events contributing to the function of NAE1 K238 (lysine residue at site 238) crotonylation. RESULTS: The crotonylation level of NAE1 was increased in mice and patients with cardiac hypertrophy. Quantitative crotonylomics analysis revealed that K238 was the main crotonylation site of NAE1. Loss of K238 crotonylation in NAE1 K238R knock-in mice attenuated cardiac hypertrophy and restored the heart function, while hypercrotonylation mimic in NAE1 K238Q knock-in mice significantly enhanced transverse aortic constriction-induced pathological hypertrophic response, leading to impaired cardiac structure and function. The recombinant adenoviral vector carrying NAE1 K238R mutant attenuated, while the K238Q mutant aggravated Ang II (angiotensin II)-induced hypertrophy. Mechanistically, we identified GSN as a direct target of NAE1. K238 crotonylation of NAE1 promoted GSN neddylation and, thus, enhanced its protein stability and expression. NAE1 crotonylation-dependent increase of GSN promoted actin-severing activity, which resulted in adverse cytoskeletal remodeling and progression of pathological hypertrophy. CONCLUSIONS: Our findings provide new insights into the previously unrecognized role of crotonylation on nonhistone proteins during cardiac hypertrophy. We found that K238 crotonylation of NAE1 plays an essential role in mediating cardiac hypertrophy through GSN neddylation, which provides potential novel therapeutic targets for pathological hypertrophy and cardiac remodeling.

Myeloid-derived suppressor cells alleviate adverse ventricular remodeling after acute myocardial infarction.

The fundamental pathophysiological mechanism in the progression of chronic heart failure following acute myocardial infarction (AMI) is ventricular remodeling, in which innate and adaptive immunity both play critical roles. Myeloid-derived suppressor cells (MDSCs) have been demonstrated to function in a range of pathological conditions, such as infections, inflammation, autoimmune diseases, and tumors. However, it is unclear how MDSCs contribute to cardiac remodeling following AMI. This study aimed to identify the function and underlying mechanism of MDSCs in controlling cardiac remodeling following AMI. Following AMI in mice, MDSCs frequencies changed dynamically, considerably increased on day 7 in blood, spleens, lymph nodes and hearts, and decreased afterwards. Consistently, mice with AMI displayed enhanced cardiac function on day 14 post-AMI, reduced infract size and higher survival rates on day 28 post-AMI following the adoptive transfer of MDSCs. Furthermore, MDSCs inhibited the inflammatory response by decreasing pro-inflammatory cytokine (TNF-α, IL-17, Cxcl-1, and Cxcl-2) expression, up-regulating anti-inflammatory cytokine (TGF-ß1, IL-10, IL-4, and IL-13) expression, reducing CD3+ T cell infiltration in the infarcted heart and enhancing M2 macrophage polarization. Mechanistically, MDSCs improved the release of anti-inflammatory factors (TGF-ß1 and IL-10) and decreased the injury of LPS-induced cardiomyocytes in vitro in a manner dependent on cell-cell contact. Importantly, blockade of IL-10 partially abolished the cardioprotective role of MDSCs. This study found that MDSCs contributed to the restoration of cardiac function and alleviation of adverse cardiac remodeling after AMI possibly by inhibiting inflammation.

Comparative Study Between the Effects of High Doses of Rosuvastatin and Atorvastatin on Ventricular Remodeling in Patients with ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Most studies reported that treating ST-Elevation Myocardial Infarction (STEMI) patients with high doses of rosuvastatin or atorvastatin could improve left ventricular remodeling and cardiac function. PURPOSE: The current study compared the impact of high doses of rosuvastatin and atorvastatin on hypertrophy, fibrosis markers, serum inflammatory markers, and left ventricular function in STEMI patients after primary percutaneous coronary intervention (PCI). METHOD: After primary PCI, eighty STEMI patients were randomized to receive either 20 mg of rosuvastatin (n = 40) or 40 mg of atorvastatin (n = 40) once daily for 3 months. Soluble Suppression of Tumorigenicity-2 (sST2), Matrix Metalloproteinase-9 (MMP9), C-Reactive Protein (CRP), lipid parameters, liver enzymes, and echocardiographic parameters were assessed for the two groups at baseline and after 3 months. RESULTS: After 3 months of treatment, a statistically significant reduction was observed in the rosuvastatin group regarding the levels of CRP (16 ± 6 vs. 20 ± 10 mg/L, P = 0.024) and MMP9 (104 ± 33 vs. 130 ± 42 ng/L, P = 0.003) compared with the atorvastatin group. The median percentage decrease in sST2 level in the rosuvastatin group was higher (6.1%) than in the atorvastatin group (2.3%) after 3 months of treatment. Also, in the rosuvastatin group, LVEF was significantly increased (48.5 ± 9 vs. 43.5 ± 11%, P = 0.029), while LVEDV and LVESV were significantly decreased compared to those of the atorvastatin group (101 [81/135] vs. 134 [100/150] ml, P = 0.041) (53 [37/75] vs. 73 [52/92] ml, P = 0.033), respectively. CONCLUSION: High-intensity rosuvastatin was superior to high-intensity atorvastatin in reducing the inflammatory response and myocardial fibrosis, thus improving ventricular remodeling and cardiac function better in STEMI patients. TRIAL REGISTRATION: This randomized controlled trial was registered on October 11, 2022, on ClinicalTrials.gov under registration number: NCT05895123 "retrospectively registered".

Load Dependency of Ventricular Pump Function: Impact on the Non-Invasive Evaluation of the Severity and the Prognostic Relevance of Myocardial Dysfunction.

Ventricular pump function, which is determined by myocyte contractility, preload and afterload, and, additionally, also significantly influenced by heart rhythm, synchrony of intraventricular contraction and ventricular interdependence, explains the difficulties in establishing the contribution of myocardial contractile dysfunction to the development and progression of heart failure. Estimating myocardial contractility is one of the most difficult challenges because the most commonly used clinical measurements of cardiac performance cannot differentiate contractility changes from alterations in ventricular loading conditions. Under both physiological and pathological conditions, there is also a permanent complex interaction between myocardial contractility, ventricular anatomy and hemodynamic loading conditions. All this explains why no single parameter can alone reveal the real picture of ventricular dysfunction. Over time there has been increasing recognition that a load-independent contractility parameter cannot truly exist, because loading itself changes the myofilament force-generating capacity. Because the use of a single parameter is inadequate, it is necessary to perform multiparametric evaluations and also apply integrative approaches using parameter combinations which include details about ventricular loading conditions. This is particularly important for evaluating the highly afterload-sensitive right ventricular function. In this regard, the existence of certain reluctance particularly to the implementation of non-invasively obtainable parameter combinations in the routine clinical praxis should be reconsidered in the future. Among the non-invasive approaches used to evaluate ventricular function in connection with its current loading conditions, assessment of the relationship between ventricular contraction (e.g., myocardial displacement or deformation) and pressure overload, or the relationship between ejection volume (or ejection velocity) and pressure overload, as well as the relationship between ventricular dilation and pressure overload, were found useful for therapeutic decision-making. In the future, it will be unavoidable to take the load dependency of ventricular function much more into consideration. A solid basis for achieving this goal will be obtainable by intensifying the clinical research necessary to provide more evidence for the practical importance of this largely unsolved problem.

Non-Invasive Imaging for Native Aortic Valve Regurgitation.

Aortic regurgitation (AR) is associated with left ventricular volume and pressure overload, resulting in eccentric left ventricular (LV) remodeling and enlargement. This condition may be well tolerated for years before the onset of myocardial dysfunction and symptoms. Echocardiography plays a crucial role in the diagnosis of AR, assessing its mechanism and severity, and detecting LV remodeling. The assessment of AR severity is challenging and frequently requires the integration of information from multiple different measurements to assess the severity. Recent data suggests that echocardiographically derived LV volumes (end-systolic volume index > 45 ml/m2), an ejection fraction threshold of <60%, and abnormal global longitudinal strain may help identify early dysfunction and may be used to improve clinical outcomes. Consequently, these parameters can identify candidates for surgery. Cardiac magnetic resonance imaging is emerging as a valuable tool for assessing severity when it remains unclear after an echocardiographic evaluation. This review emphasizes the importance of imaging, particularly echocardiography, in the evaluation of AR. It focuses on various echocardiographic parameters, including technical details, and how to integrate them for assessing the mechanism and severity of AR, as well as LV remodeling.

Relationship of Subendocardial Perfusion to Myocardial Injury, Cardiac Structure, and Clinical Outcomes Among Patients With Hypertension.

BACKGROUND: Coronary microvascular dysfunction has been implicated in the development of hypertensive heart disease and heart failure, with subendocardial ischemia identified as a driver of sustained myocardial injury and fibrosis. We aimed to evaluate the relationships of subendocardial perfusion with cardiac injury, structure, and a composite of major adverse cardiac and cerebrovascular events consisting of death, heart failure hospitalization, myocardial infarction, and stroke. METHODS: Layer-specific blood flow and myocardial flow reserve (MFR; stress/rest myocardial blood flow) were assessed by 13N-ammonia perfusion positron emission tomography in consecutive patients with hypertension without flow-limiting coronary artery disease (summed stress score <3) imaged at Brigham and Women's Hospital (Boston, MA) from 2015 to 2021. In this post hoc observational study, biomarkers, echocardiographic parameters, and longitudinal clinical outcomes were compared by tertiles of subendocardial MFR (MFRsubendo). RESULTS: Among 358 patients, the mean age was 70.6±12.0 years, and 53.4% were male. The median MFRsubendo was 2.57 (interquartile range, 2.08-3.10), and lower MFRsubendo was associated with older age, diabetes, lower renal function, greater coronary calcium burden, and higher systolic blood pressure (P<0.05 for all). In cross-sectional multivariable regression analyses, the lowest tertile of MFRsubendo was associated with myocardial injury and with greater left ventricular wall thickness and volumes compared with the highest tertile. Relative to the highest tertile, low MFRsubendo was independently associated with an increased rate of major adverse cardiac and cerebrovascular events (adjusted hazard ratio, 2.99 [95% CI, 1.39-6.44]; P=0.005) and heart failure hospitalization (adjusted hazard ratio, 2.76 [95% CI, 1.04-7.32; P=0.042) over 1.1 (interquartile range, 0.6-2.8) years median follow-up. CONCLUSIONS: Among patients with hypertension without flow-limiting coronary artery disease, impaired MFRsubendo was associated with cardiovascular risk factors, elevated cardiac biomarkers, cardiac structure, and clinical events.

Effect of astragalus injection on left ventricular remodeling in HFmrEF: a systematic review and meta-analysis.

Objectives: The aim of this meta-analysis is to evaluate the effect of astragalus injection (AI) on left ventricular remodeling (LVR) in patients with heart failure with mildly reduced ejection fraction (HFmrEF). Methods: The randomized controlled trials (RCTs) of AI in treating HFmrEF were retrieved from 8 major English and Chinese electronic databases, up until November 30, 2023. To evaluate the methodological quality of the included studies, the Cochrane bias risk tool and the Modified Jadad Scale were employed. Stata 17.0 software was utilized for statistical analysis, sensitivity analysis, and assessment of publication bias. Results: Ten RCTs with 995 patients (562 males and 433 females) were identified. Meta-analysis indicated that compared to conventional treatment (CT), AI significantly improved LVR, specifically increasing left ventricular ejection fraction (LVEF, MD = 4.56, 95% CI: 3.68-5.44, p < 0.00001), decreasing left ventricular end-diastolic volume (LVEDV, MD = -7.89, 95% CI: -11.13 to -4.64, p < 0.00001), left ventricular end-diastolic diameter (LVEDD, MD = -4.18, 95% CI: -5.79 to -2.56, p < 0.00001), left ventricular end-systolic volume (LVESV, MD = -8.11, 95% CI: -11.79 to -4.43, p < 0.00001), and left ventricular end-systolic diameter (LVESD, MD = -3.42, 95% CI: -4.90 to -1.93, p < 0.00001). AI also improved clinical efficacy (RR = 4.62, 95% CI: 3.11-6.88, p < 0.00001), reduced N-terminal pro-brain natriuretic peptide (NT-pro BNP, MD = -27.94, 95% CI: -43.3 to -12.36) level, without increasing the incidence of adverse reactions (RR = 1.60, 95% CI: 0.59-4.29, p = 0.35). Sensitivity analysis confirmed the reliability of the merged results, and Begg's and Egger's tests showed no significant publication bias. Conclusion: The systematic review and meta-analysis revealed that combining AI with CT improves LVR without increasing adverse events in HFmrEF patients. However, caution is needed in interpreting the results due to limited evidence. Future high-quality RCTs are needed to support these conclusions. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, PROSPERO [CRD42022347248].

Deficiency of the sphingosine-1-phosphate (S1P) transporter Mfsd2b protects the heart against hypertension-induced cardiac remodeling by suppressing the L-type-Ca2+ channel.

The erythrocyte S1P transporter Mfsd2b is also expressed in the heart. We hypothesized that S1P transport by Mfsd2b is involved in cardiac function. Hypertension-induced cardiac remodeling was induced by 4-weeks Angiotensin II (AngII) administration and assessed by echocardiography. Ca2+ transients and sarcomere shortening were examined in adult cardiomyocytes (ACM) from Mfsd2b+/+ and Mfsd2b-/- mice. Tension and force development were measured in skinned cardiac fibers. Myocardial gene expression was determined by real-time PCR, Protein Phosphatase 2A (PP2A) by enzymatic assay, and S1P by LC/MS, respectively. Msfd2b was expressed in the murine and human heart, and its deficiency led to higher cardiac S1P. Mfsd2b-/- mice had regular basal cardiac function but were protected against AngII-induced deterioration of left-ventricular function as evidenced by ~ 30% better stroke volume and cardiac index, and preserved ejection fraction despite similar increases in blood pressure. Mfsd2b-/- ACM exhibited attenuated Ca2+ mobilization in response to isoprenaline whereas contractility was unchanged. Mfsd2b-/- ACM showed no changes in proteins responsible for Ca2+ homeostasis, and skinned cardiac fibers exhibited reduced passive tension generation with preserved contractility. Verapamil abolished the differences in Ca2+ mobilization between Mfsd2b+/+ and Mfsd2b-/- ACM suggesting that S1P inhibits L-type-Ca2+ channels (LTCC). In agreement, intracellular S1P activated the inhibitory LTCC phosphatase PP2A in ACM and PP2A activity was increased in Mfsd2b-/- hearts. We suggest that myocardial S1P protects from hypertension-induced left-ventricular remodeling by inhibiting LTCC through PP2A activation. Pharmacologic inhibition of Mfsd2b may thus offer a novel approach to heart failure.

Fibroblast-Specific Depletion of Human Antigen R Alleviates Myocardial Fibrosis Induced by Cardiac Stress.

Cardiac fibrosis can be mitigated by limiting fibroblast-to-myofibroblast differentiation and proliferation. Human antigen R (HuR) modulates messenger RNA stability and expression of multiple genes. However, the direct role of cardiac myofibroblast HuR is unknown. Myofibroblast-specific deletion of HuR limited cardiac fibrosis and preserved cardiac functions in pressure overload injury. Knockdown of HuR in transforming growth factor-ß1-treated cardiac fibroblasts suppressed myofibroblast differentiation and proliferation. HuR deletion abrogated the expression and messenger RNA stability of cyclins D1 and A2, suggesting a potential mechanism by which HuR promotes myofibroblast proliferation. Overall, these data suggest that inhibition of HuR could be a potential therapeutic approach to limit cardiac fibrosis.

The Role of Magnetic Resonance Imaging in Risk Stratification of Patients with Acute Myocarditis.

BACKGROUND: Cardiac magnetic resonance (cMRI) is often used to diagnose acute myocarditis (AM). It is also performed after 6 months to monitor myocardial involvement. However, the clinical and predictive relevance of the 6-month cMRI is uncertain. OBJECTIVE: We used cMRI to assess the morphology and heart function of patients with AM, the correlation between left ventricular remodeling and biomarkers of heart dysfunction and myocardial fibrosis, and the involvement of myocardial fibrosis initially and 6 months after the acute episode. MATERIALS AND METHODS: We conducted a prospective study of 90 patients with the clinical suspicion of AM, where cMRI was performed within the first week after symptom onset and repeated after 6 months. RESULTS: Non-ischemic late gadolinium enhancement (LGE) was present in 88 (97.7%) patients and mainly involved the septum and inferior wall. cMRI at 6 months was associated with significantly reduced abnormalities of segmental kinetics (p < 0.001), myocardial edema (p < 0.001), presence of LGE (p < 0.05) and LGE mass (p < 0.01), native T1 mapping (p < 0.001), and presence of pericardial collection (p ≤ 0.001). At 6 months, signs of myocardial edema appeared in 34.4% of patients, and a complete cure (absence of edema and LGE) was found in 8.8% of patients. LGE disappeared in 15.2% of patients, and the mean number of myocardial segments involved decreased from 46% to 30%, remaining unchanged in 13% of patients. Patients with LGE without edema had a more severe prognostic condition than those with persistent edema. Patients with increased LGE extension on the control cMRI had a worse prognosis than those with modified or low LGE. The most significant independent predictive parameters for major cardiovascular events (MACEs) were LGE mass (adjusted OR = 1.27 [1.11-1.99], p < 0.001), myocardial edema (OR = 1.70 [1.14-209.3], p < 0.001), and prolonged native T1 (OR = 0.97 [0.88-3.06], p < 0.001). The mid-wall model of LGE and the presence of edema-free LGE were MACE-independent predictors. CONCLUSIONS: LGE, myocardial edema, and prolonged native T1 were predictors of MACEs. LGE does not necessarily mean constituted fibrosis in the presence of edema and may disappear over time. LGE without edema could represent fibrosis, whereas the persistence of edema represents active inflammation and could be associated with the residual chance of complete recovery. cMRI should be performed in all patients with AM at 6 months to evaluate progress and prognosis.

[Endothelial-mesenchymal transition, ventricular remodeling after myocardial infarction, and research progress of Chinese medicine intervention].

Ventricular remodeling after myocardial infarction(VRAMI) is a pathological phenomenon triggered by the abrupt occlusion of coronary arteries, leading to myocardial ischemia and hypoxia. This intricate process encompasses alterations in the dimensions, composition, and elasticity of the ventricular tissue and reflects pathophysiological reactions and self-repair after cardiomyocytes are damaged. The characteristic pathological manifestation of VRAMI is the presence of myocardial fibrosis(MF), wherein fibrotic cardiac tissue undergoes a loss of contractile and relaxation capacity, ultimately culminating in heart failure(HF) and significantly impacting the patient's prognosis. Endothelial-mesenchymal transition(EndMT) is a biological process in which endothelial cells, in response to diverse pathological stimuli such as ischemia and hypoxia in the embryonic development period, undergo morphological alterations and functional impairment, progressively acquiring mesenchymal cell properties and ultimately differentiating into mesenchymal cells. The ongoing advancement of the EndMT process will result in an excessive buildup of collagen, thereby inducing structural harm to the myocardium and exacerbating the processes of VRAMI and MF. Recent investigations have demonstrated the pivotal involvement of EndMT in the pathological advancement of VRAMI. Consequently, a targeted intervention aimed at effectively impeding VRAMI, safeguarding cardiac function, and potentially serving as a novel therapeutic target for the prevention and treatment of VRAMI. This article provides a comprehensive review of recent Chinese and international literature, focusing on the role and pathophysiological mechanisms of EndMT in VRAMI. Additionally, it discusses the research progress of innovative targeted interventions using both traditional Chinese and Western medicine, so as to offer new insights and a theoretical foundation for the clinical treatment of the disease.

Macrophage-mediated heart repair and remodeling: A promising therapeutic target for post-myocardial infarction heart failure.

Heart failure (HF) remains prevalent in patients who survived myocardial infarction (MI). Despite the accessibility of the primary percutaneous coronary intervention and medications that alleviate ventricular remodeling with functional improvement, there is an urgent need for clinicians and basic scientists to further reveal the mechanisms behind post-MI HF as well as investigate earlier and more efficient treatment after MI. Growing numbers of studies have highlighted the crucial role of macrophages in cardiac repair and remodeling following MI, and timely intervention targeting the immune response via macrophages may represent a promising therapeutic avenue. Recently, technology such as single-cell sequencing has provided us with an updated and in-depth understanding of the role of macrophages in MI. Meanwhile, the development of biomaterials has made it possible for macrophage-targeted therapy. Thus, an overall and thorough understanding of the role of macrophages in post-MI HF and the current development status of macrophage-based therapy will assist in the further study and development of macrophage-targeted treatment for post-infarction cardiac remodeling. This review synthesizes the spatiotemporal dynamics, function, mechanism and signaling of macrophages in the process of HF after MI, as well as discusses the emerging bio-materials and possible therapeutic agents targeting macrophages for post-MI HF.

Pro-angiogenic cytokine features of left ventricular remodeling in patients with bicuspid aortic valve.

OBJECTIVE: Bicuspid aortic valve (BAV) is prone to promote left ventricular remodeling (LVR), which is associated with adverse clinical outcomes. Although the association between angiogenic activity and LVR has been established, pro-angiogenic cytokine features and potential biomarker candidates for LVR in patients with BAV remain to be clarified. METHODS: From November 2018 to May 2019, patients with BAV diagnosed by transthoracic echocardiography at our institution were included. LVR was diagnosed on the basis of echocardiographic calculations of relative wall thickness (RWT) and left ventricular mass index (LVMI). A multiplex ELISA array was used to measure the plasma levels of 60 angiogenesis-related cytokines. RESULTS: Among 103 patients with BAV, 71 were categorized into the LVR group and 32 into the normal left ventricular (LV) geometry group. BAV patients with LVR demonstrated increased LVMI, elevated prevalence of moderate to severe aortic stenosis and aortic regurgitation, and decreased LV ejection fraction (LVEF). Plasma levels of angiopoietin-1 were elevated in BAV patients with or without LVR compared with healthy controls (P = 0.001, P < 0.001, respectively), and were negatively correlated with RWT (r = -0.222, P = 0.027). Plasma levels of angiopoietin-2 were elevated in the LVR group (P = 0.001) compared with the normal LV geometry group, and were negatively correlated with LVEF (r = -0.330, P = 0.002). CONCLUSION: Decreased angiogenesis plays a crucial role in the occurrence and progression of LVR in patients with BAV. Disturbance in the pro- and anti-angiogenesis equilibrium in BAV patients with LVR may reflect the aggravation of endothelial injury and dysfunction.