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

{"title":"Differential effects of myosin activators on myocardial contractile function in nonfailing and failing human hearts.","authors":"Joohee Choi, Patrick T Wood, Joshua B Holmes, Katherine L Dominic, Cristobal G Dos Remedios, Kenneth S Campbell, Julian E Stelzer","doi":"10.1152/ajpheart.00252.2024","DOIUrl":"10.1152/ajpheart.00252.2024","url":null,"abstract":"<p><p>The second-generation myosin activator danicamtiv (DN) has shown improved function compared with the first-generation myosin activator omecamtiv mecarbil (OM) in nonfailing myocardium by enhancing cardiac force generation but attenuating slowed relaxation. However, whether the functional improvement with DN compared with OM persists in remodeled failing myocardium remains unknown. Therefore, this study aimed to investigate the differential contractile responses to myosin activators in nonfailing and failing myocardium. Mechanical measurements were performed in detergent-skinned myocardium isolated from donor and failing human hearts. Steady-state force, stretch activation responses and loaded shortening velocity were analyzed at submaximal [Ca²⁺] in the absence or presence of 0.5 µmol/L OM or 2 µmol/L DN. The effects of DN and OM on Ca²⁺ sensitivity of force generation were determined by incubating myocardial preparations at various [Ca²⁺]. The inherent impairment in force generation and cross-bridge behavior sensitized the failing myocardium to the effects of myosin activators. Specifically, increased Ca²⁺ sensitivity of force generation, slowed rates of cross-bridge recruitment and detachment following acute stretch, slowed loaded shortening velocity, and diminished power output were more prominent following treatment with OM or DN in failing myocardium compared with donor myocardium. Although these effects were less pronounced with DN compared with OM in failing myocardium, DN impaired contractile properties in failing myocardium that were not affected in donor myocardium. Our results indicate that similar to first-generation myosin activators, the DN-induced slowing of cross-bridge kinetics may result in a prolongation of systolic ejection and delayed diastolic relaxation in the heart failure setting.<b>NEW & NOTEWORTHY</b> This is the first study to provide a detailed mechanistic comparison of omecamtiv mecarbil (OM) and danicamtiv (DN) in failing and nonfailing human myocardium. These findings have clinical implications and the potential to inform the clinical utility of myosin activators in the heart failure setting.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H161-H173"},"PeriodicalIF":4.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142493028","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":"What frozen human hearts can tell us about treating heart failure.","authors":"Rhiannon Q Crawford, Helene Tigro, Christopher Solís","doi":"10.1152/ajpheart.00758.2024","DOIUrl":"10.1152/ajpheart.00758.2024","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1-H2"},"PeriodicalIF":4.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666833","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":"Predictive value of triglyceride-glucose index for the evaluation of coronary artery disease severity and occurrence of major adverse cardiovascular events.","authors":"Orlando Siverio-Morales, Carmen Mora-Fernández, Carolina Hernández-Carballo, Ernesto Martín-Núñez, Ainhoa González-Luis, Alberto Martín-Olivera, Juan F Navarro-González, Javier Donate-Correa","doi":"10.1152/ajpheart.00684.2024","DOIUrl":"10.1152/ajpheart.00684.2024","url":null,"abstract":"<p><p>The triglyceride-glucose (TyG) index has been proposed as an independent predictor of coronary artery disease (CAD). In this retrospective study, we further examine this association and its utility as a predictor for major adverse cardiovascular events (MACE). A total of 870 patients who underwent coronary angiography between May 2008 and June 2009 were included in this retrospective study. The TyG index was calculated using the formula Ln [fasting TG (mg/dL) × FBG (mg/dL)/2]. The association of the TyG index with the presence and severity of CAD, cardiovascular risk factors, and inflammatory markers was evaluated at baseline. In the longitudinal study, the multivariate-adjusted Cox hazard model was used to investigate the associations of the TyG index with the occurrence of MACE during a 5-yr follow-up, which was defined as the endpoint. The TyG index was significantly associated with the presence and severity of CAD. Multiple linear regression analysis showed that a high TyG index, together with inflammatory markers and dyslipidemia, was independently associated with greater stenotic occlusion of coronary arteries (adjusted <i>R</i>² = 0.031, <i>P</i> < 0.001). Kaplan-Meier survival curve (free of MACE) by tertiles of the TyG index showed a higher incidence of MACE in the upper tertile (log-rank test, <i>P</i> = 0.02). Multivariate Cox analysis demonstrated that the risk of incident MACE during the follow-up was associated with higher levels of the TyG index, even after adjusting for inflammatory parameters and cardiovascular risk factors: hazard ratio = 1.54 (95% confidence interval: 1.18-2.13; <i>P</i> < 0.01). We conclude that an elevated TyG index is independently associated with a higher risk of CAD and a poor prognosis for MACE.<b>NEW & NOTEWORTHY</b> This retrospective study demonstrates significant associations between the TyG index and the occurrence and severity of CAD, as well as indicates the clinical value of the TyG index as a potential predictor for MACE.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H14-H20"},"PeriodicalIF":4.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666815","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":"Effect of insulin on indices of cerebral blood flow and cerebrovascular compliance in young adults.","authors":"Brian Shariffi, Jennifer L Harper, Neil J McMillan, Anna M Gonsalves, Braden J Bond, Aubrey M Pipkins, Leena N Shoemaker, Camila Manrique-Acevedo, Jaume Padilla, Jacqueline K Limberg","doi":"10.1152/ajpheart.00668.2024","DOIUrl":"10.1152/ajpheart.00668.2024","url":null,"abstract":"<p><p>Insulin has important vasodilatory effects in the peripheral circulation, but less is known about insulin's role in cerebrovascular control. Herein, we hypothesized both systemic (intravenous) and local (intranasal) insulin administration would increase indices of cerebral blood flow and reduce cerebrovascular compliance (Ci) in young adults. Participants were assigned to one of four separate protocols. Middle cerebral artery blood velocity (MCAv, transcranial Doppler ultrasound) and blood pressure (BP, finger photoplethysmography) were measured at baseline and at <i>1</i>) 2 min of carbon dioxide (CO₂) air breathing (high flow control), <i>2</i>) 60 min of euglycemic intravenous insulin infusion (40 mU/m² body surface area/min), <i>3</i>) 60 min following 160 IU of intranasal insulin, <i>4</i>) 60 minutes of time control. Ci was calculated (modified Windkessel model). Intravenous insulin increased serum insulin (6.0 ± 2.6 to 52.7 ± 12.7 μIU/mL, <i>P</i> < 0.001), whereas serum insulin was reduced following intranasal insulin (6.9 ± 4.5 to 4.9 ± 1.8 μIU/mL, <i>P</i> = 0.030). MCAv increased in response to CO₂ (60 ± 13 to 69 ± 11 cm/s, <i>P</i> < 0.001) but was unchanged with time control (50 ± 7 to 49 ± 8, <i>P</i> = 0.658) and both insulin conditions (intravenous: 61 ± 13 to 62 ± 17 cm/s, <i>P</i> = 0.531; intranasal: 57 ± 12 to 51 ± 15 cm/s; <i>p</i> = 0.061). In contrast, Ci remained at baseline levels over time (<i>P</i> = 0.438) and was reduced from baseline under CO₂ and both insulin conditions (CO₂, <i>P</i> < 0.001; intravenous, <i>P</i> = 0.021; intranasal, <i>P</i> = 0.001). Contrary to our hypothesis, there was no effect of systemic or local insulin administration on resting MCAv in young adults; however, both systemic and local insulin administration reduced Ci. These findings advance our understanding of the cerebrovascular response to acute insulin exposure.<b>NEW & NOTEWORTHY</b> Insulin has important vasodilatory effects in the peripheral circulation, but less is known about the role of insulin in cerebrovascular control. Contrary to our hypothesis, there was no effect of systemic (intravenous) nor local (intranasal) insulin administration on middle cerebral artery blood velocity; however, both systemic and local insulin administration reduced cerebrovascular compliance. Our findings advance our understanding of the cerebrovascular response to insulin and may have implications in the context of known metabolic disturbances.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H21-H28"},"PeriodicalIF":4.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142708955","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":"Cardiac dysfunction and altered gene expression in acid ceramidase-deficient mice.","authors":"Annie Kleynerman, Jitka Rybova, William M McKillop, Theresa A Dlugi, Mary L Faber, Maria Fuller, Caitlin C O'Meara, Jeffrey A Medin","doi":"10.1152/ajpheart.00289.2024","DOIUrl":"10.1152/ajpheart.00289.2024","url":null,"abstract":"<p><p>Farber disease (FD) is an ultrarare, autosomal-recessive, lysosomal storage disorder attributed to <i>ASAH1</i> gene mutations. FD is characterized by acid ceramidase (ACDase) deficiency and the accumulation of ceramide in various tissues. Classical FD patients typically manifest symptoms including lipogranulomatosis, respiratory complications, and neurological deficits, often leading to mortality during infancy. Cardiac abnormalities in several FD patients have been described; however, a detailed examination of cardiac pathology in FD has not been conducted. Here we report pronounced cardiac pathophysiology in a new P361R-FD mouse model of ACDase deficiency that we generated. P361R-FD mice displayed smaller hearts, altered cardiomyocyte architecture, disrupted tissue composition, and inclusion-containing macrophages. Echocardiography suggested ventricular atrophy, valve dysfunction, decreased cardiac output, and lowered stroke volumes. Troponin I was significantly elevated in P361R-FD mice. Hearts from P361R-FD mice were found to have increased ceramide, cholesterol, and other lipids. Histopathological analysis of heart tissue from neonatal P361R-FD mice revealed lysosomal disruption as early as <i>postnatal day 1</i>. Finally, we report cardiac conduction, striated muscle contraction, and sphingolipid homeostasis gene expression differences during cardiac development in P361R-FD mice. In summary, we investigated the heart in a mouse model of ACDase deficiency, demonstrating that ACDase deficiency induced lysosomal dysfunction, sphingolipid and cholesterol imbalances, tissue disruption, and significant inflammation, leading to impaired cardiac function in these animals.<b>NEW & NOTEWORTHY</b> This is the first characterization of cardiac function and histopathology in a mouse model of acid ceramidase deficiency. We report physiologic disruption suggestive of heart failure with preserved ejection fraction, progressive histopathology, and aberrant gene expression. We found significant lysosomal disruption at both neonatal and adult ages, suggesting a crucial role of acid ceramidase, and potentially ceramides, in cardiac development and function.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H141-H156"},"PeriodicalIF":4.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811696","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":"Averaged oxygen desaturation improves the prognostic value of the six-minute walk test in elderly patients with heart failure.","authors":"Isamu Sunayama, Kyung-Duk Min, Yoshiyuki Orihara, Junichi Ohno, Yuki Matsumoto, Aika Daimon, Yuko Soyama, Eri Manabe, Makiko Oboshi, Kohei Azuma, Masataka Sugahara, Akiyo Eguchi, Yoshiro Naito, Shinichiro Suna, Masanori Asakura, Masaharu Ishihara","doi":"10.1152/ajpheart.00578.2024","DOIUrl":"10.1152/ajpheart.00578.2024","url":null,"abstract":"<p><p>Heart failure (HF) is a major cause of hospitalization, and exercise capacity is a key prognostic marker. The six-minute walk test (6MWT) is widely used to assess exercise capacity, but six-minute walk distance (6MWD) varies among individuals, especially the elderly. This study aimed to assess the hypothesis that Δ[Formula: see text]-Ex, the average oxygen desaturation during the 6MWT, could enhance the prognostic value of 6MWD in elderly patients with HF for cardiovascular risk prediction. In this single-center, prospective observational study, 55 patients aged ≥65 yr with acute HF were evaluated before discharge. Patients were divided into small and large Δ[Formula: see text]-Ex groups and short and long 6MWD groups based on cutoff values of 6.7% and 220 m, respectively, obtained from the receiver operating characteristics curve analysis. Patients were followed up for 1 yr to assess major adverse cardiovascular events, including rehospitalization for heart failure or cardiovascular death. The mean Δ[Formula: see text]-Ex was 5.8 ± 4.3%, and the mean 6MWD was 237.5 ± 106.7 m. Patients with large Δ[Formula: see text]-Ex had significantly higher event rates [hazard ratio (HR) = 6.66; <i>P</i> < 0.001], whereas those with short 6MWD had HR of 2.40 (<i>P</i> = 0.03). Combining Δ[Formula: see text]-Ex with 6MWD improved predictive accuracy [area under the curve (AUC) = 0.78] compared with either marker alone (AUC = 0.72 for Δ[Formula: see text]-Ex and 0.62 for 6MWD). Importantly, patients with both large Δ[Formula: see text]-Ex and short 6MWD had the highest event rates, indicating the additive prognostic value of combining both markers. In conclusion, Δ[Formula: see text]-Ex is a complementary marker to 6MWD, improving risk stratification in elderly patients with HF.<b>NEW & NOTEWORTHY</b> This study evaluates the use of Δ[Formula: see text]-Ex, measured during the six-minute walk test (6MWT), as a complementary prognostic marker to the six-minute walk distance (6MWD) in elderly patients with heart failure. We hypothesize that combining Δ[Formula: see text]-Ex with 6MWD will improve the predictive accuracy for cardiovascular outcomes, offering a practical, noninvasive method for risk stratification and enhancing clinical decision-making for this patient population.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H3-H13"},"PeriodicalIF":4.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602848","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":"Perinatal iron deficiency alters the cardiac proteome and mitochondrial function in neonatal offspring.","authors":"Claudia D Holody, Andrew G Woodman, Chunpeng Nie, Si Ning Liu, Daniel Young, Alyssa Wiedemeyer, Rowan Carpenter, Ronan M N Noble, Daniel Graf, Antoine Dufour, Hélène Lemieux, Stephane L Bourque","doi":"10.1152/ajpheart.00412.2024","DOIUrl":"10.1152/ajpheart.00412.2024","url":null,"abstract":"<p><p>Iron deficiency (ID) is common during gestation and early infancy and can alter developmental trajectories with lasting consequences on cardiovascular health. Iron plays a critical role in systemic oxygen transport (via hemoglobin) and aerobic respiration (as a component of mitochondrial complexes). Perinatal ID has been shown to cause cardiac dysfunction in neonates, but the mechanisms underlying these changes have not been characterized. Here, we examined the effects of perinatal ID on cardiac mitochondrial function in rats in the early postnatal period. Female rats were fed an iron-restricted or iron-replete diet before and during pregnancy. Offspring hearts were collected postmortem for quantitative shotgun proteomic analysis [postnatal days (PD) 0 and 28] and mitochondrial function was assessed by high-resolution respirometry (at PD 0, 14, and 28). Markers of oxidative stress were measured by fluorescence microscopy and assessment of antioxidant gene expression profiles. Both male and female ID pups had reduced body weight and increased relative heart weights at all time points assessed, despite recovering from anemia by PD28. Proteomics analysis revealed dysregulation of mitochondrial proteins by ID, and these differences were most pronounced in males. In male hearts, ID increased mitochondrial content and decreased normalized mitochondrial respiration through the NADH-pathway, succinate-pathway, and fatty acid oxidation (FAO)-pathway. In conclusion, ID causes changes in cardiac mitochondrial function in neonates, which may reflect inadequate or maladaptive compensation during the transition from intrauterine to extrauterine life. Furthermore, the results presented herein, which were stratified by offspring sex, underscore the need for follow-up studies to directly assess differences in how male and female offspring cope with ID as a perinatal stressor.<b>NEW & NOTEWORTHY</b> Iron deficiency (ID) is the most common nutritional deficiency worldwide and is highly prevalent among pregnant women and young children. ID causes changes in mitochondrial protein expression and function in neonatal hearts, which may contribute to functional impairments. Improving cardiac energy metabolism may represent a novel approach to improve short- and long-term outcomes in infants affected by ID, but sex of the neonate may be an important determinant of treatment efficacy.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H101-H112"},"PeriodicalIF":4.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680633","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":"Impaired endothelial function contributes to cardiac dysfunction: role of mitochondrial dynamics.","authors":"Cristhian A Gutierrez-Huerta, Giovanni Quiroz-Delfi, Fathima Dhilhani Mohammed Faleel, Andreas M Beyer","doi":"10.1152/ajpheart.00531.2024","DOIUrl":"10.1152/ajpheart.00531.2024","url":null,"abstract":"<p><p>The endothelial microvasculature is essential for the regulation of vasodilation and vasoconstriction, and improved functioning of the endothelium is linked to improved outcomes for individuals with coronary artery disease (CAD). People with endothelial dysfunction exhibit a loss of nitric oxide (NO)-mediated vasodilation, achieving vasodilation instead through mitochondria-derived H₂O₂. Mitochondrial dynamics is an important autoregulatory mechanism that contributes to mitochondrial and endothelial homeostasis and plays a role in the formation of reactive oxygen species (ROS), including H₂O₂. Dysregulation of mitochondrial dynamics leads to increased ROS production, decreased ATP production, impaired metabolism, activation of pathological signal transduction, impaired calcium sensing, and inflammation. We hypothesize that dysregulation of endothelial mitochondrial dynamics plays a crucial role in the endothelial microvascular dysfunction seen in individuals with CAD. Therefore, proper regulation of endothelial mitochondrial dynamics may be a suitable treatment for individuals with endothelial microvascular dysfunction, and we furthermore postulate that improving this microvascular dysfunction will directly improve outcomes for those with CAD.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H29-H36"},"PeriodicalIF":4.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666812","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":"Subcomponent analysis of the directional sensitivity of dynamic cerebral autoregulation.","authors":"Ronney B Panerai, Aaron Davies, Abdulaziz Alshehri, Lucy C Beishon, Jatinder S Minhas","doi":"10.1152/ajpheart.00498.2024","DOIUrl":"10.1152/ajpheart.00498.2024","url":null,"abstract":"<p><p>The origin of the directional sensitivity (DS) of dynamic cerebral autoregulation (dCA) is not known. In 140 healthy participants (67 male, 27.5 ± 6.1 yr old), middle cerebral artery velocity (MCAv, transcranial Doppler), arterial blood pressure (ABP, Finometer), and end-tidal CO₂ (EtCO₂, capnography) were recorded at rest. Critical closing pressure (CrCP) and resistance-area product (RAP) were obtained for each cardiac cycle, as well as mean MCAv and ABP (MAP). The integrated positive and negative derivatives of MAP (MAP_+D and MAP_-D, respectively) were used as simultaneous inputs to an autoregressive moving average model to generate two distinct MCAv step responses. Similar models allowed the estimation of corresponding MAP-CrCP and MAP-RAP responses to step changes in MAP_+D and MAP_-D. The strength of DS (ΔDS) was expressed by the difference in mean values of the step responses for the time interval 12-18 s. ΔDS was significant for MCAv (8.5 ± 46.9% vs. 26.7 ± 42.0%, <i>P</i> < 0.001) and RAP (-93.9 ± 48.1 vs. -74.5 ± 43.0%, <i>P</i> < 0.001), respectively, for MAP_+D and MAP_-D inputs, but not for CrCP (2.2 ± 48.1% vs. 0.72 ± 42.9%, <i>P</i> = 0.76). Compared with males, female participants had higher MCAv (63.9 ± 15.6 cm/s vs. 55.4 ± 12.9 cm/s, <i>P</i> < 0.001) but lower EtCO₂ (<i>P</i> < 0.001) and RAP (<i>P</i> = 0.015). Sex did not influence ΔDS for any of the three-step responses. The presence of directional sensitivity in the RAP, but not in the CrCP transfer function, suggests that the origin could be solely myogenic, without metabolic involvement.<b>NEW & NOTEWORTHY</b> The directional sensitivity of the cerebral blood velocity response to a sudden change in mean arterial blood pressure (MAP) is mediated by the resistance-area product, without involvement from the cerebral critical closing pressure. The reduced amplitude of MAP spontaneous fluctuations at rest suggests that it is less likely that directional sensitivity has origins in the sympathetic control of cerebral blood vessels, thus generating the need to consider other alternatives.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H37-H46"},"PeriodicalIF":4.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680106","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":"K⁺ currents in ventricular cardiomyocytes of p.N98S-calmodulin mutant mice.","authors":"Shuai Guo, Andy Hudmon, Firoj K Sahoo, Madeleine R Motes, Wen-Chin Tsai, Peng-Sheng Chen, Michael Rubart","doi":"10.1152/ajpheart.00470.2024","DOIUrl":"https://doi.org/10.1152/ajpheart.00470.2024","url":null,"abstract":"<p><p>Missense mutations in calmodulin (CaM)-encoding genes are associated with life-threatening ventricular arrhythmia syndromes. Here, we investigated a role of cardiac K⁺ channel dysregulation in arrhythmogenic long QT syndrome (LQTS) using a knock-in mouse model heterozygous for a recurrent mutation (p.N98S) in the <i>Calm1</i> gene (Calm1^N98S/+). Single-cell patch-clamp technique and whole-heart optical voltage mapping were used to assess action potentials and whole-cell currents. Ventricular action potential duration (APD) at baseline was similar between genotypes. The β-adrenergic agonist isoproterenol prolonged APD in myocytes and isolated perfused hearts from Calm1^N98S/+, but not wild-type (Calm1^+/+), mice. Current density-voltage relationships for the small-conductance calcium-activated K⁺ (SK) current and the inward rectifier K⁺ current did not significantly differ between Calm1^+/+ and Calm1^N98S/+ ventricular cardiomyocytes ± isoproterenol. Peak densities of other voltage-gated K⁺ currents were significantly larger in Calm1^N98S/+ versus Calm1^+/+ cells at voltages ≥40 mV both without and with isoproterenol. Isoproterenol reduced outward K_ATP currents more in Calm1^N98S/+ versus Calm1^+/+ myocytes. Dialysis of Calm1^+/+ cardiomyocytes with exogenous wild-type or N98S-CaM protein (5 μmol/l) via the pipette respectively increased and eliminated SK currents. The specific SK channel inhibitor apamin did not significantly alter APD of Calm1^+/+ or Calm1^N98S/+ hearts ± isoproterenol. Thus, dysregulation of SK or voltage-gated K⁺ channels does not contribute to the β-adrenergic-induced LQTS of Calm1^N98S/+ mice, possibly because cardiomyocyte content of endogenous N98S-CaM and/or its affinity for CaM binding domains may be too low to modulate channel properties. The larger K_ATP current inhibition by isoproterenol may delay Calm1^N98S/+ myocyte repolarization at low intracellular [ATP].</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909021","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}