American journal of physiology. Heart and circulatory physiology最新文献

{"title":"Mlc2v-Cre induces germline recombination in a sex-biased manner.","authors":"Termeh Aslani, Rimshah Abid, Reshani Jeyaratnam, Wenbin Liang, Kyoung-Han Kim","doi":"10.1152/ajpheart.00122.2025","DOIUrl":"https://doi.org/10.1152/ajpheart.00122.2025","url":null,"abstract":"<p><p>The myosin light chain-2 ventricular isoform (MLC2V), encoded by the <i>Myl2</i> gene, is a sarcomeric protein in ventricular cardiomyocytes, making Mlc2v-Cre mice (<i>Myl2</i>^{tm1(cre)Krc/AchakJ}) a valuable tool for ventricle-specific gene targeting. However, we observed unexpected recombination in nonmuscular tissues of offspring from Mlc2v-Cre breeders, suggesting off-target Cre activity and germline transmission. This study aims to quantify the prevalence and sex-dependency of off-target recombination in Mlc2v-Cre mice. To address this, Mlc2v-Cre mice were crossed with <i>Rosa26</i>^tdTomato reporter mice, and Cre-Lox recombination was visualized in the resulting embryos. Our results demonstrate that Mlc2v-Cre induces germline recombination in both male and female breeders, with a higher incidence in females, leading to the unintended generation of a whole body recombined allele, independent of <i>Cre</i> transgene, in the offspring. This was further supported by MLC2V and tdTomato expression in male and female germ cells. These findings highlight the importance of validating Cre-mediated recombination specificity to avoid confounding experiment outcomes and ensure accurate data interpretation.<b>NEW & NOTEWORTHY</b> Although the Mlc2v-Cre mouse line is widely used for ventricle-specific gene targeting in cardiac research, this study shows that both male and female Mlc2v-Cre mice can cause unexpected germline recombination, with a higher incidence in females. To avoid confounding results from whole body gene targeting, these findings underscore the need to validate off-target recombination.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":"328 6","pages":"H1168-H1175"},"PeriodicalIF":4.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sustained tenascin-C expression drives neointimal hyperplasia and promotes aortocaval fistula failure.","authors":"Luis A Gonzalez, Weichang Zhang, Hualong Bai, Ryosuke Taniguchi, Abhay B Ramachandra, Daniel G Jovin, Yuichi Ohashi, Mytien Nguyen, Carly Thaxton, Bogdan Yatsula, Roberto I Vazquez-Padron, Jay D Humphrey, Kathleen A Martin, Themis R Kyriakides, Alan Dardik","doi":"10.1152/ajpheart.00661.2024","DOIUrl":"https://doi.org/10.1152/ajpheart.00661.2024","url":null,"abstract":"<p><p>End-stage kidney disease (ESKD) impacts over 740,000 individuals in the United States, with many patients relying on arteriovenous fistulae (AVF) for hemodialysis due to superior patency and reduced infections. However, AVF patency is reduced by thrombosis and neointimal hyperplasia, yielding a 1-yr patency of only 40%-50%. We hypothesized that tenascin-C (TNC), a regulator of inflammation and immune responses after injury, also regulates venous remodeling during AVF maturation. AVF were created in wild-type (WT) and <i>Tnc</i> knockout (<i>Tnc</i>^-/-) mice, and proteomic analyses were conducted to identify protein changes between sham and AVF WT tissue. Immunofluorescence and Western blot assays compared venous tissue from WT and <i>Tnc</i>^-/- mice. In vitro studies using human umbilical vein endothelial cells and human umbilical vein smooth muscle cells examined TNC-siRNA effects on thrombomodulin (THBD) and NF-κB. Macrophages from WT and <i>Tnc</i>^-/- mice were assessed for anti-inflammatory phenotype polarization and tissue factor expression. TNC expression was spatially and temporally regulated in WT mice with AVF, and TNC colocalized with matrix remodeling but not with THBD expression; TNC expression was downregulated in patent AVF but sustained in occluded AVF, both in WT mice and human AVF specimens. <i>Tnc</i>^-/- mice had reduced AVF patency, less wall thickening, and increased thrombosis, with increased THBD expression. In vitro, TNC-siRNA increased THBD and reduced NF-κB activation. Macrophages from <i>Tnc</i>^-/- mice showed increased anti-inflammatory macrophage polarization and tissue factor expression, facilitating thrombosis. Sustained TNC expression drives neointimal hyperplasia and AVF failure by promoting a prothrombotic, inflammatory microenvironment. Targeting TNC pathways may enhance AVF patency and improve dialysis outcomes.<b>NEW & NOTEWORTHY</b> This study identifies Tenascin-C (TNC) as a key regulator of arteriovenous fistula (AVF) patency. TNC is spatially and temporally regulated, driving neointimal hyperplasia and thrombosis by promoting a prothrombotic, inflammatory microenvironment. In <i>Tnc</i>^-/- mice, reduced TNC expression increased thrombomodulin and anti-inflammatory macrophage polarization but impaired wall thickening and AVF patency. These findings link sustained TNC expression to AVF failure and suggest that targeting TNC pathways could enhance AVF outcomes in patients requiring hemodialysis.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":"328 6","pages":"H1147-H1167"},"PeriodicalIF":4.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PVAT adipocyte: energizing, modulating, and structuring vascular function during normotensive and hypertensive states.","authors":"C Javier Rendon, Stephanie W Watts, G Andres Contreras","doi":"10.1152/ajpheart.00093.2025","DOIUrl":"https://doi.org/10.1152/ajpheart.00093.2025","url":null,"abstract":"<p><p>Hypertension represents the most common form of cardiovascular disease. It is characterized by significant remodeling of the various layers of the vascular system, including the outermost layer: the perivascular adipose tissue (PVAT). Given the tissue's pivotal role in regulating blood pressure, a comprehensive understanding of the changes that occur within PVAT during the progression of hypertension is essential. This article reviews the mechanisms through which PVAT modulates blood pressure, including the secretion of bioactive soluble factors, provision of mechanical support, and adipose-specific functions such as adipogenesis, lipogenesis, lipolysis, and extracellular matrix remodeling. Additionally, this review emphasizes the influence of hypertension on each of these regulatory mechanisms, thereby providing a deeper insight into the pathophysiological interplay between hypertension and PVAT biology.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":"328 6","pages":"H1204-H1217"},"PeriodicalIF":4.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural and functional adaptations of human cardiomyocytes in metabolic disease and heart failure.","authors":"Judith Huettemeister, Markus Bögner, Dirk Eggert-Doktor, Emanuel Heil, Uwe Primessnig, Sophie C Reimers, Marzena Kirk, Girish Ramesh, Timo Zadegh Nazari-Shafti, Herko Grubitzsch, Simon Sündermann, Christoph Knosalla, Kun Zhang, Volkmar Falk, Frank R Heinzel, Felix Hohendanner","doi":"10.1152/ajpheart.00903.2024","DOIUrl":"https://doi.org/10.1152/ajpheart.00903.2024","url":null,"abstract":"<p><p>Heart failure (HF), obesity, and diabetes are associated with structural and functional changes that affect the heart at both the organ and cellular levels. Studying isolated adult single cardiomyocytes provides valuable mechanistic insights. However, isolating single cardiomyocytes from human tissue is particularly challenging. This study presents an optimized multiple-step digestion protocol to isolate viable cardiomyocytes from atrial and ventricular human tissue obtained perioperatively or through myocardial biopsies. Using this method and resource, we analyzed calcium-signaling during excitation-contraction coupling and structural features such as t-tubules and mitochondria using confocal microscopy in patients with or without HF, obesity, or diabetes. In a subset of patients undergoing open heart surgery, tissue samples and serum from the great cardiac vein were obtained either under control conditions or upon cardiac volume challenge (VC). We isolated viable cells and observed distinct structural differences between atrial and ventricular cardiomyocytes, including variations in t-tubular and cell size. In atrial cardiomyocytes, when comparing control with patients with HF, the t-tubular networks were unchanged. However, patients with obesity exhibited significantly more t-tubules associated with larger cell sizes. Furthermore, mitochondrial density appeared higher in patients with overweight and diabetes, suggesting that the metabolic status influences cardiomyocyte structure. Finally, when exposing isolated cardiomyocytes with VC serum from the respective patients, excitation-contraction coupling was markedly enhanced, indicating a distention-related alteration of the cardiac secretome with immediate effects on cardiomyocytes. In summary, an optimized protocol for isolating human cardiomyocytes confirmed structural features, identified disease-related changes, and allowed studying the dynamic impact of cardiac distention on secretome-related cardiomyocyte function.<b>NEW & NOTEWORTHY</b> This study presents a novel protocol for isolating human cardiomyocytes, uncovering atrial-ventricular structural differences, obesity-related increases in t-tubules and mitochondria, and metabolic influences on cell architecture. It highlights the dynamic effects of cardiac volume challenge on excitation-contraction coupling through secretome alterations. These advancements provide insights into how conditions like obesity and diabetes reshape cardiomyocyte structure and function, advancing our understanding of heart disease mechanisms.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":"328 6","pages":"H1193-H1203"},"PeriodicalIF":4.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143971116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"lncRNAs in vascular senescence and microvascular remodeling.","authors":"Warlley Rosa Cunha, Maria Martin de la Vega, Paula Rodrigues de Barros, Cristina Espinosa-Diez","doi":"10.1152/ajpheart.00750.2024","DOIUrl":"https://doi.org/10.1152/ajpheart.00750.2024","url":null,"abstract":"<p><p>Long noncoding RNAs (lncRNAs) have emerged as critical regulators of vascular senescence and microvascular remodeling, processes that significantly contribute to the development of age-related diseases in organs such as the kidneys, heart, and lungs. Through mechanisms like chromatin remodeling, transcriptional regulation, and posttranscriptional modifications, lncRNAs modulate gene expression, thereby influencing cellular processes such as apoptosis, inflammation, fibrosis, and angiogenesis. In chronic kidney disease, cardiovascular disease, and pulmonary disorders, lncRNAs play a central role in promoting vascular dysfunction, endothelial cell aging, and fibrosis. This review focuses on how lncRNAs contribute to endothelial dysfunction, fibrosis, and vascular aging, emphasizing their roles in disease progression within the kidneys, heart, and lungs, where lncRNA-mediated vascular changes play a significant role in disease progression. Understanding the interactions between lncRNAs, vascular senescence, and microvascular remodeling offers promising avenues for developing targeted therapeutic strategies to mitigate the impact of aging on vascular health.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":"328 6","pages":"H1238-H1252"},"PeriodicalIF":4.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The vulnerable preterm heart: tale from the two chambers.","authors":"Bradley A Ruple, Jonah M Simmons, Robert I Liem, Kanokwan Bunsawat","doi":"10.1152/ajpheart.00254.2025","DOIUrl":"10.1152/ajpheart.00254.2025","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":"328 6","pages":"H1176-H1178"},"PeriodicalIF":4.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12094171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144061945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic and vascular insulin resistance: partners in the pathogenesis of cardiovascular disease in diabetes.","authors":"William B Horton, Kaitlin M Love, Justin M Gregory, Zhenqi Liu, Eugene J Barrett","doi":"10.1152/ajpheart.00826.2024","DOIUrl":"https://doi.org/10.1152/ajpheart.00826.2024","url":null,"abstract":"<p><p>Vascular insulin resistance has emerged as a pivotal factor in the genesis of cardiovascular disease (CVD) in people with diabetes. It forms a complex pathogenic partnership with metabolic insulin resistance to significantly amplify the CVD risk of diabetes and other affected populations. Metabolic insulin resistance (characterized by quantitatively diminished insulin action on glucose metabolism in skeletal muscle, liver, and adipose tissue) is a hallmark of diabetes, obesity, and related conditions. In contrast, vascular insulin resistance is a less appreciated and not well-quantified complication of these conditions. Importantly, an impaired vascular response to insulin contributes directly to vascular dysfunction and over 40 years of research has convincingly shown that vascular and metabolic insulin resistance synergize to create an environment that predisposes individuals to CVD. In this review, we examine the multifaceted vascular actions of insulin, including its roles in regulating blood pressure, blood flow, endothelial health, and arterial stiffness. We also examine how these processes become disrupted in the setting of vascular insulin resistance, which subsequently undermines endothelial function, compromises tissue microvascular perfusion, and promotes vascular rigidity and atherosclerosis. We then highlight potential therapeutic strategies with demonstrated efficacy to improve vascular insulin sensitivity in people with diabetes and suggest that targeting disordered vascular insulin signaling holds promise not only for refining the functional understanding of vascular insulin resistance but also for developing innovative treatments with potential to reduce CVD risk and improve cardiovascular outcomes in people with diabetes.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":"328 6","pages":"H1218-H1236"},"PeriodicalIF":4.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143973234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Validation of magnetic resonance imaging-derived venous oxygen saturation and oxygen consumption measurements during exercise.","authors":"Rachel J Skow, Stephen J Foulkes, Hendrik Mugele, Dean R Perkins, Justin S Lawley, Corey R Tomczak, Michael D Nelson, Andre La Gerche, Mark J Haykowsky, Richard B Thompson","doi":"10.1152/ajpheart.00134.2025","DOIUrl":"https://doi.org/10.1152/ajpheart.00134.2025","url":null,"abstract":"<p><p>Accurate measurement of venous oxygen saturation ([Formula: see text]) is fundamental for quantifying oxygen consumption (V̇o₂) and its Fick determinants. This study evaluated the validity of a novel magnetic resonance imaging (MRI) approach using susceptometry-based oximetry (SBO) to noninvasively measure [Formula: see text] during exercise. First, [Formula: see text] was measured from an antecubital vein in 14 adults (26 ± 5 yr; 8 males) via portable blood analyzer (iSTAT) at rest and during two 5-min bouts of rhythmic handgrip exercise at 30% of maximum voluntary contraction, with temporally matched SBO measures of [Formula: see text] during an identical in-scanner exercise protocol. Separately, 21 adults (27 ± 6 yr; 8 males) completed incremental step ergometry exercise with simultaneous pulmonary V̇o₂ measurement (indirect calorimetry) and MRI-derived V̇o₂ from the Fick determinants (MRI_Fick), including inferior vena cava [Formula: see text] (SBO) and cardiac output (cardiac MRI). Agreement between methods was assessed by interclass correlation coefficients (ICCs), linear regression, and Bland-Altman plots. There was good to excellent agreement between iSTAT and SBO [Formula: see text] for arm exercise (ICC: 0.86, 95% CI: 0.71-0.93, <i>P</i> < 0.01; mean bias: +5.2%). Test-retest reliability demonstrated excellent agreement for [Formula: see text] measures between trials using iSTAT (ICC: 0.97; 95% CI: 0.93-0.96, <i>P</i> < 0.01; mean bias: -2.7%) and SBO (ICC: 0.90, 95% CI: 0.80-0.95, <i>P</i> < 0.01; mean bias: -0.3%), V̇o₂ calculated from MRI_Fick demonstrated excellent agreement with pulmonary V̇o₂ (ICC: 0.98, 95% CI: 0.97-0.99, <i>P</i> < 0.01; mean bias: +0.10 L/min). MRI-SBO-derived [Formula: see text] measurements demonstrated excellent reliability and strong agreement with both venous measures and respiratory gas analysis, validating this technique across a wide range of [Formula: see text] values during exercise.<b>NEW & NOTEWORTHY</b> Noninvasive MRI susceptometry-based [Formula: see text] measurements demonstrated excellent repeatability and validity against established direct blood sampling during localized handgrip exercise. The technique's accuracy for determining V̇o₂ during step ergometer exercise was validated through strong agreement between combined cardiac MRI and susceptometry-based Fick calculations and reference pulmonary measures, establishing this method as a reliable tool for noninvasive assessment of oxygen uptake and its Fick determinants across varying exercise intensities.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":"328 6","pages":"H1179-H1192"},"PeriodicalIF":4.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144061946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relative contribution of correcting the diet and voluntary exercise to myocardial recovery in a murine model of heart failure with preserved ejection fraction.","authors":"Emylie-Ann Labbé, Sara-Ève Thibodeau, Èlisabeth Walsh-Wilkinson, Maude Chalifour, Pierre-Olivier Sirois, Juliette Leblanc, Audrey Morin-Grandmont, Marie Arsenault, Jacques Couet","doi":"10.1152/ajpheart.00092.2025","DOIUrl":"https://doi.org/10.1152/ajpheart.00092.2025","url":null,"abstract":"<p><p>Using a two-hit murine model of heart failure with preserved ejection fraction (HFpEF), we studied cardiac reverse remodelling (RR) after stopping the causing stress (Angiotensin II (AngII) + High-fat diet (HFD); MHS) and then introducing voluntary exercise (VE) and feeding the animals with a low-fat diet. This led to extensive left ventricle (LV) RR. We then studied the relative contribution to RR of only correcting the diet or allowing VE after stopping AngII. We next evaluated myocardial recovery after an extended period (12 weeks instead of four) by exposing the animals to a second MHS. Our observations revealed a sex-specific response. Stopping AngII but continuing the HFD blocked RR in females, not males. Correcting the diet or implementing VE normalized most gene markers of LV hypertrophy or extracellular matrix remodelling, irrespective of sex. Twelve weeks of recovery was associated with normal LV morphology and function, except for several abnormal diastolic echocardiographic parameters. A second MHS after these 12 weeks led to a loss of ejection fraction in males. The response of females was like that after the first MHS, suggesting a better myocardial recovery. The MHS likely changed myocardial glucose metabolism. Pyruvate dehydrogenase (PDH) activity, which is responsible for pyruvate entry in the mitochondria, was reduced after MHS, and this was accompanied by an increase in PDH phosphorylation and pyruvate dehydrogenase kinase 4 content. RR normalized these. Our results suggest sex-specific RR after stopping the MHS and that myocardial anomalies remaining make males more sensitive to a second HFpEF-inducing stress.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CCR2⁺ MONOCYTE-DERIVED MACROPHAGES DRIVE CARDIAC HYPERTROPHY IN EARLY HFPEF.","authors":"Jana Raman, Steven John Simmonds, Ellen Caluwé, Rick van Leeuwen, Caroline Walschap, Mathias Stroobants, Ümare Cöl, Petra Vandervoort, Stephane Heymans, Elizabeth A V Jones","doi":"10.1152/ajpheart.00022.2025","DOIUrl":"https://doi.org/10.1152/ajpheart.00022.2025","url":null,"abstract":"<p><p>Heart Failure with Preserved Ejection Fraction is a chronic syndrome driven by systemic inflammation. Resident and monocyte-derived macrophages play opposing roles in several heart diseases. Though general ablation of macrophages has previously been studied in HFpEF, the individual contribution of these subsets to HFpEF development is unknown. We induced preclinical HFpEF in mice using a model consisting of high-fat diet, chronic low-dose angiotensin II administration, and salt supplemented drinking water. Our model was marked by circulating Ly6C^hi monocytosis and elevated pro-inflammatory CCR2⁺ macrophage infiltration at the expense of the cardioprotective TIMD4⁺ resident macrophage subset. Beyond an inflammatory signature typical of HFpEF, the mouse model also faithfully recreates cardiac fibrosis, hypertrophy, and functional changes in the heart as measured by echocardiography and pressure-volume loops. The experimental mice also show exercise intolerance. Using a loss-of-function genetic model, we found that CCR2 ablation prevented classical macrophage infiltration and improved the resident TIMD4⁺ macrophage representation early in HFpEF development. CCR2^-/- mice showed a higher accumulation of dysfunctional mitochondria in the heart with diffusely organized cristae without worsened mitochondrial fusion (Mitofusin2) or functioning in general (TOM20). Loss of CCR2 did prevent LV hypertrophy in our preclinical model but it did not resolve the cardiac fibrosis or diastolic dysfunction. Mitochondrial damage has been suggested to drive hypertrophy, however, we found that preventing classical macrophage recruitment increased the presence of damaged mitochondria, even though hypertrophy is resolved. In the future, our results can contribute to successful therapeutic immunomodulation to tackle HFpEF, if combined with anti-fibrotic treatment.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}