AJP Heart and Circulatory Physiology (Am J Physiol Heart Circ Physiol )

Publisher: American Physiological Society (1887- ), American Physical Society


The American Journal of Physiology: Heart and Circulatory Physiology publishes original investigations on the physiology of the heart, blood vessels, and lymphatics, including experimental and theoretical studies of cardiovascular function at all levels of organization ranging from the intact animal to the cellular, subcellular, and molecular levels. It embraces new descriptions of these functions and of their control systems, as well as their bases in biochemistry, biophysics, genetics, and cell biology. Preference is given to research that provides significant new insights into the mechanisms that determine the performance of the normal and abnormal heart and circulation.

  • Impact factor
  • 5-year impact
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  • Immediacy index
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  • Article influence
  • Website
    American Journal of Physiology - Heart and Circulatory Physiology website
  • Other titles
    American journal of physiology., Heart and circulatory physiology, Heart and circulatory physiology, AJP: Heart and circulatory physiology, AJP:heart, AJP:heart online
  • ISSN
  • OCLC
  • Material type
    Document, Periodical, Internet resource
  • Document type
    Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details

American Physical Society

  • Pre-print
    • Author cannot archive a pre-print version
  • Restrictions
    • Journal of Neurophysiology only (until February 2011)
  • Post-print
    • Author cannot archive a post-print version
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    • NIH funded authors, may archive papers in PubMed Central after 12 months
    • Wellcome Trust authors may use Paid Option to archive in PubMed Central
    • Authors are requested to notify publisher of funding source at time of submission and to modify copyright statement to indicate time of release in PubMed
    • Journal of Neurophysiology only - pre-print only before submission
    • Journal of Neurophysiology only - pre-print on preprint server or non peer reviewed websites
    • Journal of Neurophysiology only - pre-print must not be revised
    • Publisher's version/PDF cannot be used
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Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Cholesterol-rich caveolar microdomains and associated caveolins influence sarcolemmal ion channel and receptor function, and protective stress-signaling. However, the importance of membrane cholesterol content to cardiovascular function, and myocardial responses to ischemia-reperfusion (IR) and cardioprotective stimuli are unclear. We assessed effects of graded cholesterol depletion with methyl-β-cyclodextrin (MβCD), and lifelong knockout (KO) or overexpression (OE) of caveolin-3 (Cav-3), on cardiac function, IR tolerance and opioid receptor (OR) mediated protection. Langendorff-perfused hearts from young male C57Bl/6 mice were untreated or treated with 0.02-1.0 mM MβCD for 25 min to deplete membrane cholesterol and disrupt caveolae. Hearts were subjected to 25 min ischemia/45 min reperfusion, and the cardioprotective effects of morphine applied either acutely or chronically (sustained ligand-activated preconditioning - SLP) assessed. MβCD concentration-dependently reduced normoxic contractile function and post-ischemic outcomes in association with graded (10-30%) reductions in sarcolemmal cholesterol. Cardioprotection with acute morphine was abolished with ≥20 μM MβCD, whereas SLP was more robust, only inhibited with ≥200 μM MβCD. Deletion of Cav-3 also reduced (while Cav-3 OE improved) myocardial IR tolerance. Protection via SLP remained equally effective in Cav-3 KO mice, and was additive with innate protection arising with Cav-3 OE. These data reveal membrane cholesterol-dependence of normoxic myocardial and coronary function, IR tolerance and OR-mediated cardioprotection in murine hearts (all declining with cholesterol depletion). In contrast, baseline function appears insensitive to Cav-3 , while cardiac IR tolerance parallels Cav-3 expression. Novel SLP appears unique, being less sensitive to cholesterol depletion than acute OR protection and arising independently of Cav-3 expression.
    AJP Heart and Circulatory Physiology 07/2014;
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    ABSTRACT: In the present study, we aimed to understand the implication of VE-cadherin phosphorylation at site Y685 in cyclic angiogenic organs. To achieve this aim, we generated a knock-in mouse carrying a tyrosine-to-phenylalanine point mutation of VE-cadherin Y685 (VE-Y685F). Although homozygous VE-Y685F mice were viable and fertile, the nulliparous knock-in female mice exhibited enlarged uteri with edema. This phenotype was observed in 30% of females between 4 to 14 months old. Histological examination of longitudinal sections of the VE-Y685F uterus showed an extensive disorganization of myometrium and endometrium with highly edematous uterine glands, numerous areas with sparse cells and increased accumulation of collagen fibers around blood vessels, indicating a fibrotic state. Analysis of cross-section of ovaries showed the appearance of spontaneous cysts, which suggested increased vascular hyperpermeability. Electron microscopy analysis of capillaries in the ovary showed a slight but significant increase in the the gap size between two adjacent endothelial cell membranes in the junctions of VE-Y685F mice (WT: 11.5±0.3, n=78; VE-Y685F: 12.48±0.3, n=65; p =0.045), as well as collagen fiber accumulation around capillaries. Miles assay revealed that either basal or VEGF-stimulated permeability in the skin was increased in VE-Y685F mice. Since edema and fibrotic appearance have been identified as hallmarks of initial increased vascular permeability, we conclude that the site Y685 in VE-cadherin is involved in the physiological regulation of capillary permeability. Furthermore, this knock-in mouse model is of potential interest for further studies of diseases that are associated with abnormal vascular permeability.
    AJP Heart and Circulatory Physiology 05/2014;
  • AJP Heart and Circulatory Physiology 05/2014; 306(10):H1483.
  • AJP Heart and Circulatory Physiology 05/2014; 306(10):H1481-2.
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    ABSTRACT: During myocardial ischemia, upregulation of the Hedgehog (Hh) pathway promotes neovascularization and increases cardiomyocyte survival. The canonical Hh pathway activates a transcriptional program through the Gli family of transcription factors by derepression of the 7TM protein Smoothened (Smo). The mechanisms linking Smo to Gli are complex and, in some cell types, involve coupling of Smo to G inhibitory (Gi) proteins. In this study, we investigated for the first time the transcriptional response of cardiomyocytes to Sonic Hedgehog (Shh) and investigated the role of Gi protein utilization. Our results show that Sonic Hedgehog (Shh) strongly activates Gli1 expression by qPCR in a Smo-dependent manner in neonatal rat ventricular cardiomyocytes (NRVMs). Microarray analysis of gene expression changes elicited by Shh and sensitive to a Smo inhibitor identified a small subset of 38 cardiomyocyte-specific genes upregulated by Shh, including some in the protein kinase A and purinergic signaling pathways. In addition, NRVMs infected with an adenovirus encoding GiCT, a peptide that impairs receptor-Gi protein coupling, showed reduced activation of Hh targets. The in vitro data were confirmed in transgenic mice with cardiomyocyte-inducible GiCT expression. Transgenic GiCT mice showed specific reduction of Gli1 expression in the heart under basal conditions and failed to upregulate the Hh pathway upon ischemia and reperfusion injury unlike the nontransgenic littermate controls. This study characterizes for the first time the transcriptional response of cardiomyocytes to Shh and establishes a critical role for Smo coupling to Gi in Hh signaling in normal and ischemic myocardium.
    AJP Heart and Circulatory Physiology 05/2014;
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    ABSTRACT: Cardiac ischemia and angina pectoris are commonly experienced during exertion in a cold environment. In the current study we tested the hypotheses that oropharyngeal afferent blockade (i.e., local anesthesia of the upper airway with lidocaine) as well as systemic beta-adrenergic receptor blockade (i.e., intravenous propranolol) would improve the balance between myocardial oxygen supply and demand in response to the combined stimulus of cold air inhalation (-15 to -30° C) and isometric handgrip exercise (Cold + Grip). Young healthy subjects underwent Cold + Grip following lidocaine, propranolol, and control (no drug). Heart rate (HR), blood pressure, and coronary blood flow velocity (CBV, from Doppler echocardiography) were measured continuously. Rate pressure product (RPP) was calculated and changes from baseline were compared between treatments. The change in RPP at the end of Cold + Grip was not different between lidocaine (2441 ± 376) and control conditions (3159 ± 626); CBV responses were also not different between treatments. With propranolol, the HR (8 ± 1 versus 14 ± 3 bpm) and RPP responses to Cold + Grip were significantly attenuated. However, at peak exercise propranolol also resulted in a smaller ΔCBV (1.4 ± 0.8 versus 5.3 ± 1.4 cm/sec, P=0.035) such that the relationship between coronary flow and cardiac metabolism was impaired under propranolol (0.43 ± 0.37 versus 2.1 ± 0.63 au). These data suggest that cold air breathing and isometric exercise significantly influence efferent control of coronary blood flow. Additionally, beta-adrenergic vasodilation may play a significant role in coronary regulation during exercise.
    AJP Heart and Circulatory Physiology 05/2014;
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    ABSTRACT: We intended to determine if acute baroreflex activation therapy (BAT) increases venous capacitance and aortic conductance. BAT is effective in resistant hypertension but its effect on the systemic vasculature is poorly understood. Left ventricular (LV) and aortic pressures and sub-diaphragmatic aortic and caval flows (ultrasonic) were measured in 6 anesthetized dogs. Changes in abdominal blood volume (Vabdominal) were estimated as the integrated difference in abdominal aortic inflow and caval outflow. An electrode was implanted on the right carotid sinus. Data were measured during control and BAT. Next, sodium nitroprusside (SNP) was infused and BAT was subsequently added. Finally, angiotensin II (Ang II) was infused and 3 increased BAT currents were added. We found that BAT decreased mean aortic pressure (PAo) by 22.5±1.3 mmHg (P<0.001) and increased aortic conductance by 16.2±4.9% (P<0.01) and Vabdominal at a rate of 2.2±0.6 mL/kg/min (P<0.01). SNP decreased PAo by 17.4±0.7 mmHg (p < 0.001) and increased Vabdominal at a rate of 2.2±0.7 mL/kg/min (P<0.05). During the SNP infusion, BAT decreased PAo further, by 26.0±2.1 mmHg (P<0.001). Ang II increased PAo by 40.4±3.5 mmHg (p = 0.001). When an increased BAT current was added, PAo decreased to baseline (P<0.01) while aortic conductance increased from 62.3±5.2% to 80.2±3.3% (P<0.05) of control. Vabdominal increased at a rate of 1.8±0.9 mL/kg/min (P<0.01), reversing the Ang II effects. In conclusion, BAT increases arterial conductance, decreases PAo, and increases venous capacitance even in the presence of powerful vasoactive drugs. Increasing venous capacitance may be an important effect of BAT in hypertension.
    AJP Heart and Circulatory Physiology 05/2014;
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    ABSTRACT: The mechanical factors that modulate angiogenesis remain poorly understood. Previous in vitro studies of angiogenesis using microvessel fragments cultured within collagen constructs demonstrated that neovessel alignment can be induced via mechanical constraint of the boundaries (i.e., boundary conditions). The objective of this study was to investigate the role of mechanical boundary conditions in regulation of angiogenic alignment and growth in an in vitro model of angiogenesis. Angiogenic microvessels within three-dimensional constructs were subjected to different boundary conditions, producing different stress and strain fields during growth. Neovessel outgrowth and orientation were quantified from confocal image data after six days. Vascularity and branching decreased as the amount of constraint imposed on the culture increased. In long axis constrained hexahedral constructs, microvessels aligned parallel to the constrained axis. In contrast, constructs that were constrained along the short axis had random microvessel orientation. Finite element models were used to simulate the contraction of gels under the various boundary conditions and predict the local strain field experienced by microvessels. Results from the experiments and simulations demonstrated that microvessels aligned perpendicular to directions of compressive strain. Alignment was due to anisotropic deformation of the matrix from cell-generated traction forces interacting with the mechanical boundary conditions. These findings demonstrate that boundary conditions and thus the effective stiffness of the matrix regulate angiogenesis. This study offers a potential explanation for the oriented vascular beds that occur in native tissues and provide the basis for improved control of tissue vascularization in both native tissues and tissue engineered constructs.
    AJP Heart and Circulatory Physiology 05/2014;
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    ABSTRACT: Heart rate variability (HRV) is a function of cardiac autonomic tone that is widely used in both clinical and animal studies. In pre-clinical studies, HRV measures are frequently derived using the arterial pulse waveform from an implanted pressure telemetry device, termed pulse rate variability (PRV), instead of the electrocardiogram signal in accordance with the clinical guidelines. The acceptability of PRV as a surrogate for HRV in instrumented animals is unknown. Using rabbits implanted with intracardiac leads and chronically implanted pressure transducers, we investigated the correlation and agreement of time-domain, frequency-domain, and non-linear indices of HRV and PRV at baseline. We also investigated the effects of ventricular pacing and autonomic blockade on both measures. At baseline, HRV and PRV time- and frequency-domain parameters showed robust correlations and moderate to high agreement whereas non-linear parameters showed slightly weaker correlations and varied agreement. Ventricular pacing almost completely eliminated HRV, and spectral analysis of the PRV signal revealed an HRV-independent rhythm. After cardiac autonomic blockade with atropine or metoprolol, the changes in time- and non-normalized frequency-domain measures of PRV continued to show strong correlations and moderate to high agreement with corresponding changes in HRV measures. The blockade-induced changes in non-linear PRV indices correlated poorly with HRV changes and showed weak agreement. These results suggest that time- and frequency- domain measures of PRV are acceptable surrogates for HRV even in the context of changing cardiac autonomic tone, but caution should be used when non-linear measures are a primary endpoint or when HRV is very low as HRV-independent rhythms may predominate.
    AJP Heart and Circulatory Physiology 05/2014;
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    ABSTRACT: Impaired exercise capacity is common after the Fontan procedure and is attributed to cardiovascular limits. The Fontan circulation, however, is also distinctively vulnerable to unfavorable lung mechanics. This study aimed to define the prevalence and physiologic relevance of pulmonary dysfunction in patients with Fontan physiology. We analyzed Pediatric Heart Network Fontan Cross-sectional Study data to assess the prevalence and pattern of abnormal spirometry in Fontan patients (6-18yo), and investigated the relationship between low forced vital capacity (FVC) and maximum exercise variables including peak VO2 (pVO2) among those who demonstrated adequate effort (n=260). Average age, at time of exercise testing and Fontan completion respectively, was 13.2±3.0y and 3.5±2.2y. Aerobic capacity was reduced, pVO2=67.3±15.6% predicted. FVC averaged 79.0±14.8%pred, with 45.8% having FVC<lower limit of normal. Only 7.7% demonstrated obstructive spirometry. Patients with low FVC had lower pVO2 (64.4±15.9 vs. 69.7±14.9%pred, p<0.01); low FVC independently predicted lower pVO2 after adjusting for relevant covariates. Among those with pVO2<80%pred (n=204/260), 22.5% demonstrated a pulmonary mechanical contribution to exercise limitation (breathing reserve<20%). Those with both low FVC and ventilatory inefficiency (VE/VCO2>40) had markedly reduced pVO2 (61.5±15.3% vs. 72.0±14.9%pred,p<0.01) and a higher prevalence of pulmonary mechanical limit compared with patients with normal FVC and efficient ventilation (36.1% vs. 4.8%). In conclusion, abnormal FVC is common in young patients following the Fontan procedure and is independently associated with reduced exercise capacity. A large subset has pathologically low breathing reserve, consistent with pulmonary mechanical contribution to exercise limitation.
    AJP Heart and Circulatory Physiology 05/2014;
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    ABSTRACT: Background: Previous experiments in cultures of neonatal rat myocytes demonstrated that the shape of Cai(2+) transients measured using high-affinity Ca(2+)-sensitive dyes may be misrepresented. Objective: The purpose of this study was to examine the role of dye affinity in Cai(2+) measurements in intact adult cardiac tissue by comparing optical recordings obtained with high- and low-affinity dyes. Methods: Experiments were carried out in porcine LV wedge preparations stained locally by intramural injection via microcapillaries (diameter=150 µm) with a low-affinity Ca(2+)-sensitive dye Fluo-4FF or Fluo-2LA (Kd~7-10 μmol/L), high-affinity dye Rhod-2 (Kd=0.57 μmol/L), and Fluo-4 or Fluo-2MA (Kd~0.4 μmol/L); in addition, tissue was stained with Vm-sensitive dye RH-237. Optical recordings of Vm and Cai(2+) were made using optical fibers (diameter=325 µm) glued with the microcapillaries. Results: The durations of Cai(2+) transients measured at 50% level of recovery (CaD50) using high-affinity Fluo-4/Fluo-2MA dyes were up to ~81% longer than those measured with low-affinity Fluo-4FF/Fluo-2LA at long pacing cycle lengths (CL). In Fluo-4/Fluo-2MA measurements at long CLs, CaTs often (~50% of cases) exhibited slow upstroke rise and extended plateau. In Rhod-2 measurements, CaD50 was moderately longer (up to ~35%) than in Fluo-4FF recordings, but CaT shapes were similar. In all series of measurements, mean APD values were not significantly different (p>0.05). The delays between Vm and Cai(2+) upstrokes were comparable for low- and high-affinity dyes (p>0.05). Conclusions: Measurements of Cai(2+) transient in ventricular myocardium are strongly affected by the affinity of Ca(2+) dyes. The high-affinity dyes may overestimate the duration and alter the shape of Cai(2+) transients.
    AJP Heart and Circulatory Physiology 05/2014;
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    ABSTRACT: Increased intraluminal pressure can reduce endothelial function in resistance arteries; however the mechanism of this impairment is unknown. The purpose of this study was to determine the effect of local renin-angiotensin system inhibition on the pressure-induced blunting of endothelium-dependent vasodilation in human adipose arterioles. Arterioles (100-200 µm) were dissected from fresh adipose surgical specimens, cannulated onto glass micropipettes, pressurized to an intraluminal pressure of 60 mmHg, and constricted with endothelin-1. Vasodilation to acetylcholine (ACh) was assessed at 60 mmHg, and again after a 30 minute exposure to an intraluminal pressure of 150 mmHg. The vasodilator response to ACh was significantly reduced in vessels exposed to 150 mmHg. Exposing the vessels to the superoxide scavenger PEG-SOD (100 U/mL), the AT1 receptor antagonist losartan (10(-6) mol/L), or the ACE inhibitor captopril (10(-5) mol/L) prevented the pressure-induced reduction in acetylcholine-dependent vasodilation observed in untreated vessels. High intraluminal pressure had no effect on papaverine-induced vasodilation or angiotensin II sensitivity. Increased intraluminal pressure increased dihydroethidium fluorescence in cannulated vessels, which could be prevented by PEG-SOD or losartan treatment, and endothelial denudation. These data indicate that high intraluminal pressure can increase vascular superoxide and reduce NO-mediated vasodilation via activation of the vascular renin-angiotensin system. This study provides evidence that the local renin-angiotensin system in the human microvasculature may be pressure sensitive, and contribute to endothelial dysfunction after acute bouts of hypertension.
    AJP Heart and Circulatory Physiology 04/2014;
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    ABSTRACT: The mitochondrion has been implicated in the development of diabetic cardiomyopathy. Examination of cardiac mitochondria is complicated by the existence of spatially-distinct subpopulations including subsarcolemmal (SSM) and interfibrillar (IFM). Dysfunction to cardiac SSM has been reported in murine models of type 2 diabetes mellitus; however, subpopulation-based mitochondrial analyses have not been explored in type 2 diabetic human heart. The goal of this study was to determine the impact of type 2 diabetes mellitus on cardiac mitochondrial function in the human patient. Mitochondrial subpopulations from atrial appendages of non-diabetic and type 2 diabetic patients were examined. Complex I- and fatty acid-mediated mitochondrial respiration rates were decreased in diabetic SSM as compared to non-diabetic (P < 0.05 for both), with no change in IFM. Electron transport chain (ETC) complexes I and IV activities were decreased in diabetic SSM as compared to non-diabetic (P < 0.05 for both), with a concomitant decline in their levels (P < 0.05 for both). Regression analyses comparing co-morbidities determined that diabetes mellitus was the primary factor accounting for mitochondrial dysfunction. Linear spline models examining correlative risk for mitochondrial dysfunction indicated that diabetic patients display the same degree of state 3 and ETC complex I dysfunction in SSM regardless of the extent of glycated hemoglobin (HbA1c) and hyperglycemia. Overall, the results suggest that independent of other pathologies, mitochondrial dysfunction is present in cardiac SSM of type 2 diabetic patients and the degree of dysfunction is consistent regardless of the extent of elevated HbA1c or blood glucose levels.
    AJP Heart and Circulatory Physiology 04/2014;
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    ABSTRACT: The respiratory operating point (ventilatory or PaCO2 response) is determined by the intersection point between the controller and plant subsystem elements within the respiratory control system. However, to what extent changes in central blood volume (CBV) influence these two elements and corresponding implications for the respiratory operating point remains unclear. This study aimed to identify the mechanism for shifting the respiratory operating point under CBV shifts via equilibrium diagram analysis. Seventeen healthy male participants were exposed to water immersion (WI) or lower body negative pressure (LBNP) challenges to manipulate CBV and determine corresponding changes. The respiratory controller was characterized by determining the linear relationship between end-tidal PCO2 (PETCO2) and ventilation (VE) [VE = S • (PETCO2-B)], whereas the plant was determined by the hyperbolic relationship between VE and PETCO2 (PETCO2 = A / VE + C). Changes in VE at the operating point were not observed under either WI or LBNP conditions despite altered PETCO2 (P<0.01), indicating a moving respiratory operating point. An increase (WI) and decrease (LBNP) in CBV was shown to reset the controller element (PETCO2-intercept B) rightwards and leftwards respectively (P<0.05) without any change in the slope, while the plant curve remained unaltered at the operating point. Collectively, these findings indicate that modification of the controller element rather than the plant element is the major factor that contributes towards an alteration of the respiratory operating point during CBV shifts.
    AJP Heart and Circulatory Physiology 04/2014;

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