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Despite the close association between aortic stenosis (AS) and cardiac damage (CD), it is unclear if CD is limited to patients with moderate and severe AS and which factors affect its progression. Although altered valvular hemodynamic status may drive the development of CD in AS, commonly occurring comorbidities may contribute. The aim of this study was to determine the prevalence of and factors associated with CD in mild AS. This retrospective study included 9,611 patients with mild AS (peak aortic valve velocity [V max ] 2-3 m/s and description of abnormal aortic valve) from 2010 through 2021. CD was staged using the Genereux classification. All but 20% (n = 1,901; stage 0) of patients with mild AS demonstrated CD: 1,613 (17%) stage 1, 4,843 (50%) stage 2, 891 (9%) stage 3, and 363 (4%) stage 4. Patients with higher stages had more comorbidities (hypertension, heart failure, ischemic heart disease, stroke, peripheral arterial disease, chronic kidney disease, chronic pulmonary disease, and diabetes mellitus) but had valvular hemodynamic status similar to those without CD. CD stage did not worsen with higher V max range (stage >1 in 64% with V max <2.5 m/s vs 61% with V max ≥2.5 m/s) but increased with the number of comorbidities, with stage >1 occurring in 50%, 53%, 60%, 66%, 72%, and 73% in the presence of 0, 1, 2, 3, 4, and 5 or more comorbidities, respectively. CD was highly prevalent in patients with mild AS. Among patients with mild AS, there was no relationship between the degree of CD and AS severity; instead, CD was highly associated with comorbidities. [Display omitted] [ABSTRACT FROM AUTHOR]

Cyclophosphamide (CYP) is widely used to treat various types of cancer. In addition to the therapeutic properties of this drug, unfortunately, its side effects are still not fully understood. This study investigated the protective effect of curcumin (CURC) and berberine (BER) on CYP‐induced cardiac damage. Thirty‐six male rats were equally divided into the control, dimethyl sulfoxide (DMSO), CYP, CYP + CURC, CYP + BER and CYP + BER + CURC groups. Troponin‐I, Creatine kinase‐myocardial band (CK‐MB), total cholesterol, triglyceride levels in serum samples, and reactive oxygen species (ROS), poly(ADP‐ribose) polymerase‐1 (PARP‐1), and transient receptor potential melastatin 2 (TRPM2) channel levels in heart tissue were measured using an enzyme‐linked immunoassay (ELISA) kit. In addition, histopathological examination and immunohistochemical investigation of the TRPM2 channel, fibroblast specific protein‐1 (FSP1), transforming growth factor‐beta‐ 1 (TGF‐β1) and α‐smooth muscle actin (α‐SMA) expressions were determined in heart tissue. The CYP group's troponin‐I, total cholesterol, triglyceride, CK‐MB, ROS, PARP‐1 and TRPM2 channel levels were higher than in the other groups in the ELISA measurements (p < 0.05). In contrast, these parameters in the group treated with CURC and BER together with CYP were lower than in the CYP group (p < 0.05). Additionally, CUR and BER reduced CYP‐induced pathological damage, TRPM2, FSP1, TGF‐β1 and α‐SMA expressions. The data showed that CYP administration can cause cardiac damage by increasing the TRPM2 channel, TGF‐β1, FSP1 and α‐SMA expression levels. Therefore, we concluded that CURC and BER administration following CYP application may be used as therapeutic agents to prevent CYP‐induced cardiac damage. [ABSTRACT FROM AUTHOR]

Mitral annular calcification (MAC) is a progressive degenerative process associated with comorbidities and increased mortality. A staging system that considers extramitral cardiac damage in MAC may help improve patient selection for mitral valve interventions. This study sought to develop a transthoracic echocardiogram (TTE)-based cardiac staging system in patients with MAC and significant mitral valve dysfunction and assess its prognostic utility. We retrospectively evaluated all adults who underwent TTE over 1 year at Mayo Clinic with MAC and significant mitral valve dysfunction defined as mitral stenosis and/or at least moderate mitral regurgitation. Patients were categorized into 5 stages according to extramitral cardiac damage by TTE. All-cause mortality and heart failure hospitalization were assessed. For the 953 included patients, the mean age was 76.2 ± 10.7 years, and 54.0% were women. Twenty-eight (2.9%) patients were classified in stages 0 to 1, 499 (52.4%) in stage 2, 115 (12.1%) in stage 3, and 311 (32.6%) in stage 4. At the 3.8-year follow-up, mortality was significantly higher in patients in stages 2 to 4 compared to stages 0 to 1 and increased with each stage. Survival differences were maintained after adjustment for age, diabetes mellitus, and glomerular filtration rate. The rate of heart failure hospitalization was significantly higher in stages 3 and 4 compared to stages 0 to 1. Similar results were observed in subgroup analysis in patients with moderate or severe MAC, predominant mitral stenosis, or predominant mitral regurgitation. Using the proposed extramitral cardiac damage staging system in patients with MAC and significant mitral valve dysfunction, more advanced stages are associated with higher mortality. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] [ABSTRACT FROM AUTHOR]

BACKGROUND: The extent of cardiac damage and its association with clinical outcomes in patients undergoing transcatheter edge-to-edge repair (TEER) for degenerative mitral regurgitation remains unclear. This study was aimed to investigate cardiac damage in patients with degenerative mitral regurgitation treated with TEER and its association with outcomes. METHODS: We analyzed patients with degenerative mitral regurgitation treated with TEER in the Optimized Catheter Valvular Intervention-Mitral registry, which is a prospective, multicenter observational data collection in Japan. The study subjects were classified according to the extent of cardiac damage at baseline: no extravalvular cardiac damage (stage 0), mild left ventricular or left atrial damage (stage 1), moderate left ventricular or left atrial damage (stage 2), or right heart damage (stage 3). Two-year mortality after TEER was compared using Kaplan-Meier analysis. RESULTS: Out of 579 study participants, 8 (1.4%) were classified as stage 0, 76 (13.1%) as stage 1, 319 (55.1%) as stage 2, and 176 (30.4%) as stage 3. Two-year survival was 100% in stage 0, 89.5% in stage 1, 78.9% in stage 2, and 75.3% in stage 3 (P=0.013). Compared with stage 0 to 1, stage 2 (hazard ratio, 3.34 [95% CI, 1.03–10.81]; P=0.044) and stage 3 (hazard ratio, 4.51 [95% CI, 1.37–14.85]; P=0.013) were associated with increased risk of 2-year mortality after TEER. Significant reductions in heart failure rehospitalization rate and New York Heart Association functional scale were observed following TEER (both, P<0.001), irrespective of the stage of cardiac damage. CONCLUSIONS: Advanced cardiac damage is associated with an increased risk of mortality in patients undergoing TEER for degenerative mitral regurgitation. [ABSTRACT FROM AUTHOR]

Background: Prenatal alcohol exposure (PAE) has been linked to congenital heart disease and fetal alcohol syndrome. The heart primarily relies on mitochondria to generate energy, so impaired mitochondrial function due to alcohol exposure can significantly affect cardiac development and function. Our study aimed to investigate the impact of PAE on myocardial and mitochondrial functions in offspring mice. Methods: We administered 30% alcohol (3 g/kg) to pregnant C57BL/6 mice during the second trimester. We assessed cardiac function by transthoracic echocardiography, observed myocardial structure and fibrosis through staining tests and electron transmission microscopy, and detected cardiomyocyte apoptosis with dUTP nick end labeling assay and real‐time quantitative PCR. Additionally, we measured the reactive oxygen species content, ATP level, and mitochondrial DNA copy number in myocardial mitochondria. Mitochondrial damage was evaluated by assessing the level of mitochondrial membrane potential and the opening degree of mitochondrial permeability transition pores. Results: Our findings revealed that PAE caused cardiac systolic dysfunction, ventricular enlargement, thinned ventricular wall, cardiac fibrosis in the myocardium, scattered loss of cardiomyocytes, and disordered arrangement of myocardial myotomes in the offspring. Furthermore, we observed a significant increase in mitochondrial reactive oxygen species content, a decrease in mitochondrial membrane potential, ATP level, and mitochondrial DNA copy number, and sustained opening of mitochondrial permeability transition pores in the heart tissues of the offspring. Conclusions: These results indicated that PAE had adverse effects on the cardiac structure and function of the newborn mice and could trigger oxidative stress in their myocardia and contribute to mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

Single-dose del Nido solution was recently used in human donation after circulatory death (DCD) heart procurement. We compared the effect of del Nido cardioplegia on myocardial edema, inflammatory response, and injury in human DCD hearts and human donation after brain death (DBD) hearts with different warm ischemic times (WIT) and subsequent cold saline storage times (CST). A total of 24 human hearts, including 6 in the DBD group and 18 in the DCD group—were procured for the research study. The DCD group was divided into 3 subgroups based on WIT: 20, 40, and ≥60 minutes. All hearts received 1 L of del Nido cardioplegia before being placed in cold saline for 6 hours. Left ventricular biopsies were performed at 0, 2, 4, and 6 hours. Temporal changes in myocardial edema, inflammatory cytokines (TNF-α, IL-6, and IL-1β), and histopathology injury scores were compared between the DBD and DCD groups. DCD hearts showed more profound changes in myocardial edema, inflammation, and injury than DBD hearts at baseline and subsequent CST. The DCD heart with WIT of 20 and 40 minutes with CST of 4 and 2 hours, respectively, appeared to have limited myocardial edema, inflammation, and injury. DCD hearts with WIT ≥60 minutes showed severe myocardial edema, inflammation, and injury at baseline and subsequent CST. Single-dose cold del Nido cardioplegia and subsequent cold normal saline storage can preserve both DCD and DBD hearts. DCD hearts have been shown to be able to tolerate a WIT of 20 minutes and subsequent CST of 4 hours without experiencing significant myocardial edema, inflammation, and injury. [Display omitted] [ABSTRACT FROM AUTHOR]

Paraquat (PQ) an herbicide that is commonly used to remove undesirable grasses. However, PQ also causes cardiac damage through reactive oxygen species (ROS) production. Didymin (DYD) is a dietary flavone, present in citrus fruits and campanula. DYD displays multiple therapeutic activities i.e., anti-oxidant, hepatoprotective, neuroprotective and free radical salvaging. Therefore, the present study was planned to explore the ameliorative effect of DYD against PQ instigated cardiac damage. 24 rats were separated into 4 groups, control, PQ administered PQ + DYD co-administered orally and DYD only administered group. PQ intoxication significantly reduced anti-oxidants including (SOD, GST, GSH, CAT, GPx and GSR activities, while increasing malondialdehyde (MDA) and ROS levels. PQ intoxication escalated the level of cardiac injury marker i.e., creatine kinase myoglobin binding (CK-MB), troponin, creatinine phosphokinase (CPK) and lactate dehydrogenase (LDH). PQ also augmented inflammatory markers i.e., (TNF-α, IL-1β, NF-κB, IL-6 levels and COX-2 activity). Moreover, PQ intoxication escalated the apoptotic proteins levels (Bax, Caspase-3 and Caspase-9), while decreasing Bcl-2 level. PQ intoxication also prompted histomorphological anomalies in the heart of rats. Conversely, DYD therapy restored all the anomalies and structural abnormalities owing to its cardioprotective potentials.

Food-grade titanium dioxide (E171) and zinc oxide nanoparticles (ZnO NPs) are found in diverse products for human use. E171 is used as whitening agent in food and cosmetics, and ZnO NPs in food packaging. Their potential multi-organ toxicity has raised concerns on their safety. Since mitochondrial dysfunction is a key aspect of cardio-pathologies, here, we evaluate the effect of chronic exposure to E171 and ZnO NPs in rats on cardiac mitochondria. Changes in cardiac electrophysiology and body weight were measured. E171 reduced body weight more than 10% after 5 weeks. Both E171 and ZnO NPs increased systolic blood pressure (SBP) from 110–120 to 120–140 mmHg after 45 days of treatment. Both NPs altered the mitochondrial permeability transition pore (mPTP), reducing calcium requirement for permeability by 60% and 93% in E171- and ZnO NPs-exposed rats, respectively. Treatments also affected conformational state of adenine nucleotide translocase (ANT). E171 reduced the binding of EMA to Cys 159 in 30% and ZnO NPs in 57%. Mitochondrial aconitase activity was reduced by roughly 50% with both NPs, indicating oxidative stress. Transmission electron microscopy (TEM) revealed changes in mitochondrial morphology including sarcomere discontinuity, edema, and hypertrophy in rats exposed to both NPs. In conclusion, chronic oral exposure to NPs induces functional and morphological damage in cardiac mitochondria, with ZnO NPs being more toxic than E171, possibly due to their dissociation in free Zn2+ ion form. Therefore, chronic intake of these food additives could increase risk of cardiovascular disease. [ABSTRACT FROM AUTHOR]

Cardiac damage caused by radiation in the long term varies according to the radiation dose received by the heart. In this study, it was aimed to evaluate the damage caused by different radiation doses in the heart, together with hemodynamic parameters, immunhistochemistry, and histopathological analyzes for long term. The animals were divided into four groups: The rats in control group (Group 1) were not irradiated; the rats in group 2 were irradiated with 5 Gy; the rats in group 3 were irradiated with 10 Gy and the rats in group 4 were irradiated with 20 Gy. Hemodynamic parameters and indices were determined from the impedance cardiography (ICG) recording in the whole groups before they were irradiated with RT and 180 days after RT. And then, interleukin-1β, interleukin-10, TNF-α, apopthosis were determined in all groups. In addition, histological changes of heart and aorta were evaluated. Histopathologic, cytokine and hemodynamic findings supported that cardiac damage increased with increasing radiation dose. it is important in terms of being an alternative and supportive method to other methods to be able to detect heart diseases caused by RT with the ICG method. [ABSTRACT FROM AUTHOR]

Regular waterpipe smoking (Reg-WPS) is well recognized for its deleterious effect on the heart. However, there is a paucity of experimental studies on the impact of occasional waterpipe smoking (Occ-WPS), also known as nondaily smoking, versus Reg-WPS on cardiac homeostasis, and the mechanisms underlying these effects. Hence, we aimed, in the present study, to investigate the effect of Occ-WPS (30 min/day, 1 day/week) versus Reg-WPS (30 min/day, 5 days/ week) for 6 months on systolic blood pressure (SBP), cardiac injury, oxidative markers, chemokines, proinflammatory cytokines, DNA damage and mitochondrial function compared with air (control) exposed mice. Our results show that SBP was increased following exposure to either Occ-WPS or Reg-WPS compared with air-exposed mice. Moreover, we found that only Reg-WPS induced a significant elevation in the levels of troponin I, brain natriuretic peptide, lactate dehydrogenase, and creatine phosphokinase. However, the atrial natriuretic peptide (ANP) was significantly increased in both Occ-WPS and Reg-WPS groups. Compared with air-exposed mice, the levels of lipid peroxidation, reduced glutathione and monocyte chemoattractant protein-1 were only significantly augmented in the Reg-WPS. However, catalase, superoxide dismutase, and CXCL1 were significantly increased in both OccWPS and Reg-WPS. The concentrations of the adhesion molecules E-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 were solely elevated in the heart of mice exposed to Reg-WPS. Similarly, the concentrations of interleukin-1β and tumor necrosis factor α were only significantly augmented in the Reg-WPS. However, both Occ-WPS and Reg-WPS triggered significant augmentation in the levels of IL17 and DNA damage compared to the control groups. Furthermore, while Occ-WPS induced a slight but statistically insignificant elevation in the concentrations of mammalian targets of rapamycin and nuclear factor erythroid-derived 2-like 2 (Nrf2) expression, Reg-WPS exposure increased their levels substantially, in addition to p53 and mitochondrial complexes II & III, and IV activities compared with air-exposed mice. In conclusion, our findings show that while the long-term Occ-WPS exposure induced an elevation of SBP, ANP, antioxidant enzymes, IL17, CXCL1, and cardiac DNA damage, Reg-WPS exposure was consistently associated with the elevation of SBP and occurrence of cardiac damage, inflammation, oxidative stress, DNA damage and mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

Recently, a staging system using 4 grades has been proposed to quantify the extent of cardiac damage associated with aortic stenosis (AS), namely AS-related cardiac damage staging (ASCDS). ASCDS is independently associated with all-cause mortality and important clinical outcomes. To evaluate whether it might be associated with the occurrence of conduction system disorders after TAVI, a total of 119 symptomatic patients with severe AS who underwent a TAVI were categorized according to ASCDS: group 1 (13.5%): no or LV damage; group 2 (58.8%): left atrial/mitral valve damage, atrial fibrillation (AF); group 3 (27.7%): low-flow state, pulmonary vasculature/tricuspid valve/RV damage. After TAVI, 34% of patients exhibited LBBB and 10% high-degree atrioventricular block (HD-AVB). No patient in group 1 developed HD-AVB whereas new LBBB was frequent in groups 2 and 3. Twenty-one patients presented with paroxysmal AF with a higher rate for each group increment (group 1: n = 0, 0%; group 2: n = 11, 15.7%; group 3: n = 10, 30.3%) (p = 0.012). Patients in group 3 had the higher rate of permanent pacemaker implantation (PPMI) (group 1: n = 1, 6.3%; group 2: n = 7, 10%; group 3: n = 9, 27.3%) (p = 0.012). In conclusion, ASCDS might help identify patients at higher risk of conduction disorders and PPMI requirement after TAVI. [ABSTRACT FROM AUTHOR]

[Display omitted] [ABSTRACT FROM AUTHOR]

Regular waterpipe smoking (Reg-WPS) is well recognized for its deleterious effect on the heart. However, there is a paucity of experimental studies on the impact of occasional waterpipe smoking (Occ-WPS), also known as nondaily smoking, versus Reg-WPS on cardiac homeostasis, and the mechanisms underlying these effects. Hence, we aimed, in the present study, to investigate the effect of Occ-WPS (30 min/day, 1 day/week) versus Reg-WPS (30 min/day, 5 days/week) for 6 months on systolic blood pressure (SBP), cardiac injury, oxidative markers, chemokines, proinflammatory cytokines, DNA damage and mitochondrial function compared with air (control) exposed mice. Our results show that SBP was increased following exposure to either Occ-WPS or Reg-WPS compared with air-exposed mice. Moreover, we found that only Reg-WPS induced a significant elevation in the levels of troponin I, brain natriuretic peptide, lactate dehydrogenase, and creatine phosphokinase. However, the atrial natriuretic peptide (ANP) was significantly increased in both Occ-WPS and Reg-WPS groups. Compared with air-exposed mice, the levels of lipid peroxidation, reduced glutathione and monocyte chemoattractant protein-1 were only significantly augmented in the Reg-WPS. However, catalase, superoxide dismutase, and CXCL1 were significantly increased in both Occ-WPS and Reg-WPS. The concentrations of the adhesion molecules E-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 were solely elevated in the heart of mice exposed to Reg-WPS. Similarly, the concentrations of interleukin-1β and tumor necrosis factor α were only significantly augmented in the Reg-WPS. However, both Occ-WPS and Reg-WPS triggered significant augmentation in the levels of IL17 and DNA damage compared to the control groups. Furthermore, while Occ-WPS induced a slight but statistically insignificant elevation in the concentrations of mammalian targets of rapamycin and nuclear factor erythroid-derived 2-like 2 (Nrf2) expression, Reg-WPS exposure increased their levels substantially, in addition to p53 and mitochondrial complexes II & III, and IV activities compared with air-exposed mice. In conclusion, our findings show that while the long-term Occ-WPS exposure induced an elevation of SBP, ANP, antioxidant enzymes, IL17, CXCL1, and cardiac DNA damage, Reg-WPS exposure was consistently associated with the elevation of SBP and occurrence of cardiac damage, inflammation, oxidative stress, DNA damage and mitochondrial dysfunction.

Recently, a staging system using 4 grades has been proposed to quantify the extent of cardiac damage associated with aortic stenosis (AS), namely AS-related cardiac damage staging (ASCDS). ASCDS is independently associated with all-cause mortality and important clinical outcomes. To evaluate whether it might be associated with the occurrence of conduction system disorders after TAVI, a total of 119 symptomatic patients with severe AS who underwent a TAVI were categorized according to ASCDS: group 1 (13.5%): no or LV damage; group 2 (58.8%): left atrial/mitral valve damage, atrial fibrillation (AF); group 3 (27.7%): low-flow state, pulmonary vasculature/tricuspid valve/RV damage. After TAVI, 34% of patients exhibited LBBB and 10% high-degree atrioventricular block (HD-AVB). No patient in group 1 developed HD-AVB whereas new LBBB was frequent in groups 2 and 3. Twenty-one patients presented with paroxysmal AF with a higher rate for each group increment (group 1: n = 0, 0%; group 2: n = 11, 15.7%; group 3: n = 10, 30.3%) (p = 0.012). Patients in group 3 had the higher rate of permanent pacemaker implantation (PPMI) (group 1: n = 1, 6.3%; group 2: n = 7, 10%; group 3: n = 9, 27.3%) (p = 0.012). In conclusion, ASCDS might help identify patients at higher risk of conduction disorders and PPMI requirement after TAVI.

[Display omitted] [ABSTRACT FROM AUTHOR]

T-2 toxin is a highly cardiotoxic environmental contaminant. Selenium can uphold the cardiovascular system's functionality. Selenium insufficiency is common. The aim of this study was to elucidate the effects of low selenium diet alone or in combination with T-2 toxin on myocardial tissue damage. Thirty-two Sprague-Dawley rats of 3 weeks of age were randomized into control, low selenium diet, low selenium diet combined with T-2 toxin groups (at doses of 10 ng/g and 100 ng/g body weight) for 12-weeks intervention. Pathohistology and ultrastructural changes in cardiac tissue were observed. Changes in cardiac metabolites were analyzed using untargeted metabolomics. The findings demonstrated that cardiac tissue abnormalities, interstitial bleeding, inflammatory cell infiltration, and mitochondrial damage can be brought on by low selenium diet alone or in combination with the T-2 toxin. A low selenium diet alone or in combination with the T-2 toxin affected cardiac metabolic profiles and resulted in aberrant modifications in many metabolic pathways, including the metabolism of amino acids, cholesterol, and thiamine. Accordingly, low selenium diet and T-2 toxin may have a synergistic effect. Our findings provide fresh insights into the processes of cardiac injury by revealing the effects of low selenium diet and T-2 toxin on cardiac metabolism. [ABSTRACT FROM AUTHOR]

Paraquat (PQ) an herbicide that is commonly used to remove undesirable grasses. However, PQ also causes cardiac damage through reactive oxygen species (ROS) production. Didymin (DYD) is a dietary flavone, present in citrus fruits and campanula. DYD displays multiple therapeutic activities i.e., anti-oxidant, hepatoprotective, neuroprotective and free radical salvaging. Therefore, the present study was planned to explore the ameliorative effect of DYD against PQ instigated cardiac damage. 24 rats were separated into 4 groups, control, PQ administered PQ + DYD co-administered orally and DYD only administered group. PQ intoxication significantly reduced anti-oxidants including (SOD, GST, GSH, CAT, GPx and GSR activities, while increasing malondialdehyde (MDA) and ROS levels. PQ intoxication escalated the level of cardiac injury marker i.e., creatine kinase myoglobin binding (CK-MB), troponin, creatinine phosphokinase (CPK) and lactate dehydrogenase (LDH). PQ also augmented inflammatory markers i.e., (TNF-α, IL-1β, NF-κB, IL-6 levels and COX-2 activity). Moreover, PQ intoxication escalated the apoptotic proteins levels (Bax, Caspase-3 and Caspase-9), while decreasing Bcl-2 level. PQ intoxication also prompted histomorphological anomalies in the heart of rats. Conversely, DYD therapy restored all the anomalies and structural abnormalities owing to its cardioprotective potentials. [ABSTRACT FROM AUTHOR]

Backround: Complement activation may facilitate hypertension through its effects on immune responses. The anaphylatoxin C5a, a major inflammatory effector, binds to the C5a receptors 1 and 2 (C5aR1, C5aR2). We have recently shown that C5aR1-/- mice have reduced hypertensive renal injury. The role of C5aR2 in hypertension is unknown., Methods: For examination of C5aR2 expression on infiltrating and resident renal cells a tandem dye Tomato-C5aR2 knock-in reporter mouse was used. Human C5aR2 expression was analyzed in a single-cell RNAseq data set from the kidneys of hypertensive patients. Finally, we examined the effect of angiotensin II-induced hypertension in C5aR2-deficient mice., Results: Flow cytometric analysis of leukocytes isolated from kidneys of the reporter mice showed that dendritic cells are the major C5aR2-expressing population (34%) followed by monocyte/macrophages (30%) and neutrophils (14%). Using confocal microscopy C5aR2 was not detected in resident renal or cardiac cells. In the human kidney, C5aR2 was also mainly found in monocytes, macrophages, and dendritic cells with a significantly higher expression in hypertension (P < 0.05). Unilateral nephrectomy was performed followed by infusion of Ang II (0.75 ng/g/min) and a high salt diet in wildtype (n = 18) and C5aR2-deficient mice (n = 14). Blood pressure, renal injury (albuminuria, glomerular filtration rate, glomerular and tubulointerstitial injury, inflammation), and cardiac injury (cardiac fibrosis, heart weight, gene expression) did not differ between hypertensive wildtype and C5aR2-/- mice., Conclusions: In summary, C5aR2 is mainly expressed in myeloid cells in the kidney in mice and humans but its deficiency has no effect on Ang II-induced hypertensive injury., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

• Perinatal NP exposure induced myocardial mitophagy in offspring rats. • The apoptosis induced by NP in NRCMs was affected by autophagy. • 3. Myocardial mitophagy mediated by PINK1/Parkin regulated NRCMs' damage induced by NP. This study investigated whether perinatal exposure to nonylphenol (NP) induces mitochondrial autophagy (i.e., mitophagy) damage in neonatal rat cardiomyocytes (NRCMs) and whether the PINK1/Parkin signaling pathway is involved in NP-induced primary cardiomyocyte injury. In vivo : Perinatal NP exposure increased apoptosis and mitochondrial damage in NRCMs. Mitochondrial swelling and autophagosome-like structures with multiple concentric membranes were observed in the 100 mg/kg NP group, with an increase in the number of autophagosomes. Disorganized fiber arrangement and elevated serum myocardial enzyme levels were observed with increasing NP dosage. Additionally, NP exposure led to increased MDA levels and decreased SOD activity and ATP levels in myocardial tissue. The mRNA expression levels of autophagy-related genes, including Beclin-1, p62, and LC3B, as well as the expression of mitochondrial autophagy–related proteins (PINK1, p-Parkin, Parkin, Beclin-1, p62, LC3-I, LC3-II, and LC3-II/I) and apoptosis-related proteins (Bax and caspase-3), increased, whereas the expression levels of the mitochondrial membrane protein TOMM20 and the anti-apoptotic protein Bcl-2 decreased. In vitro : NP increased ROS levels, LDH release, and decreased ATP levels in NRCMs. CsA treatment significantly inhibited the expression of autophagy-related proteins (Beclin-1, LC3-II/I, and p62) and apoptosis-related proteins (caspase-3 and Bax), increased the expression levels of TOMM20 and Bcl-2 proteins, increased cellular ATP levels, and inhibited LDH release. The inhibition of the PINK1/Parkin signaling pathway suppressed the expression of mitochondrial autophagy–related proteins (PINK1, p-Parkin, Parkin, Beclin-1, LC3-II/I, and p62) and apoptosis-related proteins (caspase-3 and Bax), increased TOMM20 and Bcl-2 protein expression, increased ATP levels, and decreased LDH levels in NRCMs. This study is novel in reporting that perinatal NP exposure induced myocardial injury in male neonatal rats, thereby inducing mitophagy. The PINK1/Parkin signaling pathway was involved in this injury by regulating mitophagy. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: The extent of cardiac damage and its association with clinical outcomes in patients undergoing transcatheter edge-to-edge repair (TEER) for degenerative mitral regurgitation remains unclear. This study was aimed to investigate cardiac damage in patients with degenerative mitral regurgitation treated with TEER and its association with outcomes., Methods: We analyzed patients with degenerative mitral regurgitation treated with TEER in the Optimized Catheter Valvular Intervention-Mitral registry, which is a prospective, multicenter observational data collection in Japan. The study subjects were classified according to the extent of cardiac damage at baseline: no extravalvular cardiac damage (stage 0), mild left ventricular or left atrial damage (stage 1), moderate left ventricular or left atrial damage (stage 2), or right heart damage (stage 3). Two-year mortality after TEER was compared using Kaplan-Meier analysis., Results: Out of 579 study participants, 8 (1.4%) were classified as stage 0, 76 (13.1%) as stage 1, 319 (55.1%) as stage 2, and 176 (30.4%) as stage 3. Two-year survival was 100% in stage 0, 89.5% in stage 1, 78.9% in stage 2, and 75.3% in stage 3 ( P =0.013). Compared with stage 0 to 1, stage 2 (hazard ratio, 3.34 [95% CI, 1.03-10.81]; P =0.044) and stage 3 (hazard ratio, 4.51 [95% CI, 1.37-14.85]; P =0.013) were associated with increased risk of 2-year mortality after TEER. Significant reductions in heart failure rehospitalization rate and New York Heart Association functional scale were observed following TEER (both, P <0.001), irrespective of the stage of cardiac damage., Conclusions: Advanced cardiac damage is associated with an increased risk of mortality in patients undergoing TEER for degenerative mitral regurgitation., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: UMIN000023653., Competing Interests: Disclosures Dr Sugiura has received research grant from Edwards and honoraria for lectures from Edwards Lifesciences and Abbott Medical, outside the submitted work. Drs Kubo, Saji, Izumo, Watanabe, and Amaki are clinical proctors of transcatheter edge-to-edge repair for Abbott Medical, and have received consultant fee from Abbott Medical. Drs Asami and Kodama have received speaker fees from Abbott Medical. Drs Yamamoto and Nakajima are clinical proctors of transcatheter edge-to-edge repair for Abbott Medical and have received lecture fees from Abbott Medical. Dr Yamaguchi is clinical proctor of transcatheter edge-to-edge repair for Abbott Medical and has received a lecture fee and a scholarship donation from Abbott Medical. Dr Ohno has received consultant, advisor, and speaker fees from Abbott Medical. Drs Enta, Shirai, Mizuno, and Bota are clinical proctors of transcatheter edge-to-edge repair for Abbott Medical. Dr Nickenig has received research grants and speaker honoraria from Abbott, outside the submitted work. The other authors report no conflicts.

Background: The prognostic value of cardiac damage staging classification based on the extent of extravalvular damage has been proposed in moderate/severe aortic stenosis (AS)., Objectives: The purpose of this study was to assess the association of cardiac damage staging with mortality across the spectrum of patients with AS following aortic surgical or transcatheter aortic valve replacement (AVR)., Methods: We conducted a pooled meta-analysis of Kaplan-Meier-derived reconstructed time-to-event data from studies published through February 2023., Results: In total, 16 studies (n = 14,499) met our eligibility criteria and included 12,282 patients with symptomatic severe AS and 2,217 patients with asymptomatic severe/moderate AS. For patients with symptomatic severe AS, all-cause mortality was 24.0%, 27.7%, 38.0%, 56.3%, and 57.3% at 5 years in patients with cardiac damage stage 0, 1, 2, 3, and 4, respectively (stage 0 as reference; HR in stage 1: 1.30 [95% CI: 1.03-1.64]; P  = 0.029; stage 2: 1.74 [95% CI: 1.41-2.16]; P  < 0.001; stage 3: 2.92 [95% CI: 2.35-3.64]; P  < 0.001, and stage 4: 3.51 [95% CI: 2.79-4.41]; P  < 0.001). For patients with asymptomatic moderate/severe AS, all-cause mortality was 19.3%, 36.9%, 51.7%, and 67.8% at 8 years in patients with cardiac damage stage 0, 1, 2, and 3 to 4, respectively (HR in stage 1: 1.70 [95% CI: 1.21-2.38]; P  = 0.002; stage 2: 2.20 [95% CI: 1.60-3.02]; P  < 0.001; and stage 3 to 4: 3.90 [95% CI: 2.79-5.47]; P  < 0.001)., Conclusions: In patients undergoing AVR across the symptomatic and severity spectrum of AS, cardiac damage staging at baseline has important prognostic implications. This pooled meta-analysis in patients undergoing AVR suggests that staging of baseline cardiac damage could be considered for timing and selection of therapy in patients with moderate or severe AS to determine the need for earlier AVR or adjunctive pharmacotherapy to prevent irreversible cardiac damage and improve the long-term prognosis., Competing Interests: Mr Xander Jacquemyn was supported by the Belgian American Educational Foundation. Dr Généreux has served as a consultant for Abbott Vascular, Abiomed, BioTrace Medical, Boston Scientific, CARANX Medical, Cardiovascular System Inc (PI Eclipse Trial), Edwards Lifesciences (PI EARLY-TAVR trial, PI PROGRESS trial), GE Healthcare, iRhythm Technologies, Medtronic, Opsens, Pi-Cardia, Puzzle Medical, Saranas, Shockwave, Siemens, Soundbite Medical Inc, Teleflex, and 4C Medical (PI feasibility study); has served as an advisor for Abbott Vascular, Abiomed, BioTrace Medical, Edwards Lifesciences, and Medtronic; has received speaker fees from Abbott Vascular, Abiomed, BioTrace Medical, Edwards Lifesciences, Medtronic, and Shockwave; has served as a proctor for and received an institutional research grant from Edwards Lifesciences, and has equity in Pi-Cardia, Puzzle Medical, Saranas, and Soundbite Medical Inc. Dr Pibarot has received funding from Edwards Lifesciences, Medtronic, Pi-Cardia, and Cardiac Phoenix for echocardiography core laboratory analyses and research studies in the field of transcatheter valve therapies, for which he received no personal compensation, and has received lecture fees from Edwards Lifesciences and Medtronic. The Cardiovascular Research Foundation (Dr Cohen and Leon) receives research funding from Edwards Lifesciences (no direct compensation). Dr Clavel holds a young investigator grant from the QHLI. Dr Gillam has served as a consultant for Edwards Lifesciences; and has core lab contracts with Edwards Lifesciences and Medtronic. Dr Sultan received institutional research support from Abbott, Artivion, Boston Scientific, Edwards, Medtronic, and Terumo Aortic. Dr Cohen has received research grant support and consulting income from Edwards Lifesciences, Medtronic, Boston Scientific, and Abbott. Dr Bax: The Department of Cardiology (LUMC, The Netherlands) has received research grants from Medtronic, Biotronik, Edwards Lifesciences, and Boston Scientific and has received speaker fees from Abbott Vascular and Edwards Lifesciences. Dr Leon serves on the PARTNER Trial Executive Committee for Edwards Lifesciences (nonpaid); has received institutional research grants from and has served as a nonpaid advisor for Abbott, Boston Scientific, and Medtronic; has served as a nonpaid advisor for Sinomed; and has equity in Medinol. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: Cardiac damage has gained increasing attention as a valid prognostic marker of mortality after transcatheter aortic valve replacement (TAVR). However, studies investigating the possible association between cardiac damage and hospitalization burden in TAVR patients are lacking., Aims: This study aimed to investigate the impact of baseline cardiac damage on the hospitalization burden before, during, and after TAVR in an all-comers population., Methods: All consecutive patients who underwent TAVR between 2016 and 2020 were included. Electronic medical records of all patients were examined to validate cardiovascular (CV) and heart failure (HF) related hospitalizations from 6 months before to 1 year after TAVR. Baseline cardiac damage was defined according to the staging classification by Généreux et al. RESULTS: Among 1397 TAVR patients, 94 (6.7%) had stage 0, 368 (26.4%) stage 1, 736 (52.7%) stage 2, 115 (8.2%) stage 3, and 84 (6.0%) stage 4 cardiac damage. Patients with more advanced cardiac damage at baseline had more HF hospitalizations within 6 months before TAVR (p < 0.01) and with a longer length of stay (LoS) (p < 0.01). Regarding the index TAVR admission, there was no difference in procedure time (p = 0.26) or LoS (p = 0.18) between groups. Still, TAVR patients with more advanced baseline cardiac damage had a higher risk of CV and HF rehospitalization after TAVR (p < 0.05)., Conclusions: Baseline cardiac damage in patients undergoing TAVR has an impact on the pre- and post-procedural cardiovascular hospitalization burden. However, the cardiac damage status does not affect the TAVR procedure time or index TAVR admission length of stay., (© 2024 The Authors. Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.)

Sphingolipids exert important roles within the cardiovascular system and related diseases. Perturbed sphingolipid metabolism was previously reported in cerebral and renal tissues of spontaneously hypertensive rats (SHR). Specific defects related to the synthesis of sphingolipids and to the metabolism of Sphingosine-1-Phospahte (S1P) were exclusively identified in the stroke-prone (SHRSP) with the respect to the stroke-resistant (SHRSR) strain. In this study, we explored any existing perturbation in either protein or gene expression of enzymes involved in the sphingolipid pathways in cardiac tissue from both SHRSP and SHRSR strains, compared to the normotensive Wistar Kyoto (WKY) strain. The two hypertensive rat models showed an overall perturbation of the expression of different enzymes involved in the sphingolipid metabolism in the heart. In particular, whereas the expression of the S1P-metabolizing-enzyme, SPHK2, was significantly reduced in both SHR strains, SGPL1 protein levels were decreased only in SHRSP. The protein levels of S1P receptors 1–3 were reduced only in the cardiac tissue of SHRSP, whereas S1PR2 levels were reduced in both SHR strains. The de novo synthesis of sphingolipids was aberrant in the two hypertensive strains. A significant reduction of mRNA expression of the Sgms1 and Smpd3 enzymes, implicated in the metabolism of sphingomyelin, was found in both hypertensive strains. Interestingly, Smpd2 , devoted to sphingomyelin degradation, was reduced only in the heart of SHRSP. In conclusion, alterations in the expression of sphingolipid-metabolizing enzymes may be involved in the susceptibility to cardiac damage of hypertensive rat strains. Specific differences detected in the SHRSP, however, deserve further elucidation. • Sphingolipids may play an important role in the pathophysiology of cardiovascular system • SHRSP and SHRSR show an overall perturbation of the expression of genes and proteins involved in sphingolipid homeostasis • Some alterations in sphingolipid metabolism are strain specific [ABSTRACT FROM AUTHOR]

Moderate aortic stenosis is increasingly recognized as a disease entity with poor prognosis. Diagnosis of moderate aortic stenosis may be complemented by laboratory tests and advanced imaging techniques focused at detecting signs of cardiac damage such as increase of cardiac enzymes (N-terminal pro-B-type Natriuretic Peptide, troponin), left ventricular remodeling (hypertrophy, reduced left ventricular ejection fraction), or myocardial fibrosis. Therapy should include guideline-directed optimal medical therapy for heart failure. Patients with signs of cardiac damage may benefit from early intervention, which is the focus of several ongoing randomized controlled trials. As yet, no evidence-based therapy exists to halt the progression of aortic valve calcification., Competing Interests: Nicolas M. Van Mieghem has received grant support/research contracts from Abbott Vascular, Boston Scientific, Medtronic, Edwards Lifesciences, Daiichy Sankyo, Astra Zeneca and PulseCath BV and has received consulting/speaker fees from Abbot Vascular, Boston Scientific Corporation, Medtronic, Daiichy Sankyo, PulseCath BV, JenaValve, and Amgen. Ricardo P.J. Budde has received institutional support and speaker fees from Siemens and is member of the executive board of the European Society of Cardiovascular Radiology. Alexander Hirsch has received a research grant and consultancy fees from GE Healthcare and speaker fees from GE Healthcare and Bayer. He is also a member of the medical advisory board of Medis Medical Imaging Systems. All other authors declare to have no conflicts of interest., (© 2024 The Authors.)