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POINT-COUNTERPOINTPoint:Counterpoint: There is/is not capillary recruitment in active skeletal muscle during exerciseMichael G. Clark, Stephen Rattigan, Eugene J. Barrett, and Michelle A. VincentMichael G. Clark, Stephen Rattigan, Eugene J. Barrett, and Michelle A. VincentPublished Online:01 Mar 2008https://doi.org/10.1152/japplphysiol.00779.2007This is the final version - click for previous versionMoreSectionsSupplemental MaterialPDF (75 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations POINT: THERE IS CAPILLARY RECRUITMENT IN ACTIVE SKELETAL MUSCLE DURING EXERCISEFocus.The key issue here is whether resting skeletal muscle is fully perfused. We will make the case that it is not, and thus there exists a reserve of unperfused capillaries (capillary reserve) that are recruited to carry flow not only by muscle contraction, but also by insulin.Our background.Our interest in this area arose from efforts to develop noninvasive methods to assess whether insulin affects muscle microvascular perfusion in vivo and whether muscle insulin resistance is at least in part due to impaired perfusion that diminishes insulin and glucose delivery. Since it is well accepted that bulk blood flow to working muscle increases, it was logical to apply our methods to compare exercise and insulin in terms of capillary recruitment.We cite findings obtained using five different approaches that each provides evidence of capillary recruitment. Three of these are entirely noninvasive, the other two involve surgical preparation that may appreciably alter “basal” perfusion.Exercise increases red blood cell occupancy of capillaries in muscle biopsies.Honig and colleagues (8) examined cryosections of denervated dog gracilis muscle and reported that at rest only one-third of the capillaries were perfused with erythrocytes. Muscle contraction (4/min) effectively doubled the number of capillaries containing red blood cells without increasing bulk flow. Near maximal recruitment occurred at frequencies ∼8 Hz and bulk flow increased dramatically. Certainly vessel tortuosity (with a single vessel crossing a section several times) could have led to underestimation and, conversely, denervation (with resultant high basal flow rates) to overestimulation of basal perfusion. Intriguingly, these observations supported those of Krogh (11) who first proposed a reserve of unperfused capillaries in muscle more than half a century earlier—a cornerstone of the work for which he was awarded the 1919 Nobel Prize.Exercise increased red blood cell movement in exposed muscle.Intravital microscopy of surgically exposed transparent muscle of anesthetized animals has provided evidence for (6, 7, 10, 12, 16, 18) and against capillary recruitment (see accompanying “counterpoint”). The study by Lindbom (12) viewed the rabbit tenuissimus muscle using intravital microscopy and noted that one-third to one-half of all capillaries were perfused based on red blood cell movement and these were homogeneously distributed. Electrical stimulation increased perfusion of muscle and not connective tissue capillaries. The distribution of flow between muscle and connective tissue was influenced by the oxygen tension of the superfusing solution. Thus, as the Po2 increased, muscle capillary flow decreased and, conversely, when the superfusate Po2 decreased, more capillaries were perfused. The dependence of capillary flow in such preparations on Po2 was noted by others earlier (13) and confirmed recently (17). These findings both support the presence of a capillary reserve and emphasize the sensitivity of exposed muscle preparation vasculature to environmental factors.Each of the above two methods are quite invasive, requiring general anesthesia, surgical exposure of the muscle, and, in some preparations, denervation. This makes it particularly difficult to obtain an estimate of true “basal” perfusion, which is required for any estimate of recruitment in response to exercise or other stimuli.An increase in metabolism of the exogenous marker substrate 1-methylxanthine (1-MX).This method was developed in our laboratory (15) and measures the metabolism of 1-MX as it traverses the muscle vascular network from artery to vein. Others have shown that xanthine oxidase, which is responsible for metabolizing 1-MX in muscle, is located predominantly in the capillary endothelium (9). The method has been validated in the pump-perfused isolated rat hindlimb, where the proportion of total flow that is nutritive can be manipulated (1). With this preparation, 1-MX metabolism is proportional to the volume of nutritive flow, is increased during muscle contraction (22) and decreased when nutritive flow was decreased pharmacologically (14). Applying this method in vivo to rats, we showed that field stimulation of muscle in vivo to simulate exercise increased the metabolism of 1-MX, reinforcing the above issues (4). From a number of studies it is clear that 1-MX metabolism, and thus capillary recruitment, is not dependent on bulk blood flow (for review, see Ref. 2 and references therein). Interestingly, we showed that physiological insulin also increased 1-MX metabolism, suggesting that insulin increased microvascular perfusion (15) and, by default, indicating that prior to insulin the muscles were not fully perfused. This method does not require muscle biopsies or surgical exposure and might therefore be expected to provide a more physiological “basal” environment against which to assess the impact of recruitment.Contrast-enhanced ultrasound (CEU) imaging of the muscle microvasculature.With this method an acoustic signal is obtained from intravenously infused microbubbles of inert gas as they track with erythrocytes through the vasculature. The microbubbles are smaller than red blood cells and do not change blood flow rheology. We adapted the method for use with skeletal muscle based on that described by Wei et al. (21), who validated the method to trace myocardial blood perfusion. The acoustic properties of microbubbles results in their bursting when impacted by a high energy ultrasound pulse and simultaneously emitting a signal. By introducing a variable time interval between pulses, a series of images is collected and the contributions of tissue density and large, rapidly filling vessels (arteries, arterioles, veins, and venules) subtracted from the integrated video intensity in a region of interest. From this, a replenishment curve is generated that describes the refilling rate and the volume of microvasculature filled by microbubbles. This method has the advantages of being entirely noninvasive, requiring no anesthesia, and it can be used in humans performing voluntary exercise (as opposed to electrical stimulation). As a result, this method is better suited than the others mentioned above for obtaining a true measure of basal microvascular perfusion and hence to assess increments above basal.Using this approach, changes in capillary blood volume in response to insulin (19, 23) and exercise (4) have been assessed in skeletal muscle of the rat hindlimb in vivo. The CEU data correlate well with findings obtained using the 1-MX method (4) and showed that capillary blood volume increases as much as 100% during physiological doses of insulin and 200% with field stimulation. In human forearm muscle we recently showed that mixed meal and light exercise (Fig. 1; Ref. 20) as well as insulin (3) each recruit muscle capillaries, and insulin's effect is absent in obese insulin-resistant subjects (3).Fig. 1.Microvascular blood volume (MBV), an index of capillary recruitment measured by contrast enhanced ultrasound at basal and at 60 min following ingestion of a mixed meal (top) and at basal and during 20-s interval between contractions during modest (bottom left, 25% maximum handgrip) and more intense (right,80% maximum handgrip) forearm exercise. Imaging of the human forearm was performed in a transaxial plane 5 cm distal to the antecubital fossa. Microbubbles were infused to steady state in the contralateral arm to where imaging was performed. The liquid meal (Boost, 480 kcal: 72 from fat, 328 from carbohydrate, 80 from protein) was consumed within 5 min. Plasma glucose and insulin rose to 6.6 ± 0.2 mM and 275 ± 30 pM, respectively, at 30 min. *P < 0.05 and #P < 0.01 compared with basal; †P < 0.05 and ‡P < 0.1 compared with 25% maximum grip; 2-tailed Student's t-test.Download figureDownload PowerPointThe final method we would mention has not been used to examine the effects of exercise. However, using implanted laser Doppler probes (a minimally invasive technique), capillary recruitment in muscle as measured by an increase in intramuscular hyperemia was found to increase in response to physiological hyperinsulinemia (5). This was paralleled in the same patients by an insulin-mediated increase in finger skin capillary recruitment using a noninvasive surface probe (5).In summary, we find overwhelming evidence for the positive point of view that there is capillary recruitment in active muscle during exercise. All of five different approaches support the notion of a capillary reserve in muscle that can be recruited not only by exercise but also insulin action.GRANTSJoint research between our two groups was supported in part by National Institute of Diabetes and Digestive and Kidney Diseases Grant 2 R01-DK-57878–06.REFERENCES1 Clark MG, Colquhoun EQ, Rattigan S, Dora KA, Eldershaw TP, Hall JL, Ye J. Vascular and endocrine control of muscle metabolism. Am J Physiol Endocrinol Metab 268: E797–E812, 1995.Link | ISI | Google Scholar2 Clark MG, Wallis MG, Barrett EJ, Vincent MA, Richards SM, Clerk LH, Rattigan S. Blood flow and muscle metabolism: a focus on insulin action. Am J Physiol Endocrinol Metab 284: E241–E258, 2003.Link | ISI | Google Scholar3 Clerk LH, Vincent MA, Jahn LA, Liu Z, Lindner JR, Barrett EJ. Obesity blunts insulin-mediated microvascular recruitment in human forearm muscle. 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Acta Physiol Scand Suppl 525: 1–40, 1983.PubMed | Google Scholar13 Prewitt RL, Johnson PC. The effect of oxygen on arteriolar red cell velocity and capillary density in the rat cremaster muscle. Microvasc Res 12: 59–70, 1976.Crossref | PubMed | ISI | Google Scholar14 Rattigan S, Appleby GJ, Miller KA, Steen JT, Dora KA, Colquhoun EQ, Clark MG. Serotonin inhibition of 1-methylxanthine metabolism parallels its vasoconstrictor activity and inhibition of oxygen uptake in perfused rat hindlimb. Acta Physiol Scand 161: 161–169, 1997.Crossref | PubMed | Google Scholar15 Rattigan S, Clark MG, Barrett EJ. Hemodynamic actions of insulin in rat skeletal muscle: evidence for capillary recruitment. Diabetes 46: 1381–1388, 1997.Crossref | PubMed | ISI | Google Scholar16 Segal SS. Microvascular recruitment in hamster striated muscle: role for conducted vasodilation. Am J Physiol Heart Circ Physiol 261: H181–H189, 1991.Link | ISI | Google Scholar17 Shibata M, Ichioka S, Ando J, Togawa T, Kamiya A. Nonlinear regulation of capillary perfusion in relation to ambient Po2 changes in skeletal muscle. Eur J Appl Physiol 94: 352–355, 2005.Crossref | PubMed | ISI | Google Scholar18 Sweeney TE, Sarelius IH. Arteriolar control of capillary cell flow in striated muscle. Circ Res 64: 112–120, 1989.Crossref | PubMed | ISI | Google Scholar19 Vincent MA, Clerk LH, Lindner JR, Klibanov AL, Clark MG, Rattigan S, Barrett EJ. Microvascular recruitment is an early insulin effect that regulates skeletal muscle glucose uptake in vivo. Diabetes 53: 1418–1423, 2004.Crossref | PubMed | ISI | Google Scholar20 Vincent MA, Clerk LH, Lindner JR, Price WJ, Jahn LA, Leong-Poi H, Barrett EJ. Mixed meal and light exercise each recruit muscle capillaries in healthy humans. Am J Physiol Endocrinol Metab 290: E1191–E1197, 2006.Link | ISI | Google Scholar21 Wei K, Jayaweera AR, Firoozan S, Linka A, Skyba DM, Kaul S. 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Diabetes 53: 447–453, 2004.Crossref | PubMed | ISI | Google ScholarSupplemental data1.HealthyRestingSpinotrapezius.mpg (4.16 MB)2.HeartFailureRestingSpinotrapezius.mpg (5.63 MB)3.HealthyRestingDiaphragm.wmv (2.74 MB) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited ByBlood volume versus deoxygenated NIRS signal: computational analysis of the effects muscle O2 delivery and blood volume on the NIRS signalsB. Koirala, A. Concas, Yi Sun, L. B. Gladden, and N. 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Ellis18 February 2020 | American Journal of Physiology-Endocrinology and Metabolism, Vol. 318, No. 3Krogh’s capillary recruitment hypothesis, 100 years on: Is the opening of previously closed capillaries necessary to ensure muscle oxygenation during exercise?Hugo Angleys and Leif Østergaard5 February 2020 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 318, No. 2Hyperinsulinemia does not cause de novo capillary recruitment in rat skeletal muscle20 October 2019 | Microcirculation, Vol. 27, No. 2Edward F. Adolph Distinguished Lecture. Contemporary model of muscle microcirculation: gateway to function and dysfunctionDavid C. Poole14 October 2019 | Journal of Applied Physiology, Vol. 127, No. 4Skeletal muscle interstitial O 2 pressures: bridging the gap between the capillary and myocyte10 October 2018 | Microcirculation, Vol. 26, No. 5Effects of exercise training on calf muscle oxygen extraction and blood flow in patients with peripheral artery diseaseWesley B. 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Heinonen, Jukka Kemppainen, Kimmo Kaskinoro, Juha E. Peltonen, Ronald Borra, Markus Lindroos, Vesa Oikonen, Pirjo Nuutila, Juhani Knuuti, Robert Boushel, and Kari K. Kalliokoski1 July 2010 | American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Vol. 299, No. 1Comparison of exogenous adenosine and voluntary exercise on human skeletal muscle perfusion and perfusion heterogeneityIlkka Heinonen, Jukka Kemppainen, Kimmo Kaskinoro, Juha E. Peltonen, Ronald Borra, Markus M. Lindroos, Vesa Oikonen, Pirjo Nuutila, Juhani Knuuti, Ylva Hellsten, Robert Boushel, and Kari K. Kalliokoski1 February 2010 | Journal of Applied Physiology, Vol. 108, No. 2Muscle Microcirculatory O2 Exchange in Health and Disease24 October 2009Interaction between hypoxia and training on NIRS signal during exercise: Contribution of a mathematical modelRespiratory Physiology & Neurobiology, Vol. 169, No. 1Muscle Microvascular Dysfunction in Central Obesity Is Related to Muscle Insulin Insensitivity but Is Not Reversed by High-Dose Statin Treatment10 February 2009 | Diabetes, Vol. 58, No. 5Invited review: activity-induced angiogenesis13 August 2008 | Pflügers Archiv - European Journal of Physiology, Vol. 457, No. 5Non-invasive evaluation of the capillary recruitment in the human muscle during exercise in hypoxiaRespiratory Physiology & Neurobiology, Vol. 165, No. 2-3Impaired microvascular perfusion: a consequence of vascular dysfunction and a potential cause of insulin resistance in muscleMichael G. Clark1 October 2008 | American Journal of Physiology-Endocrinology and Metabolism, Vol. 295, No. 4Measuring muscle blood flow: a key link between systemic and regional metabolismCurrent Opinion in Clinical Nutrition & Metabolic Care, Vol. 11, No. 5Rebuttal from Drs. Poole, Brown, Hudlicka1 March 2008 | Journal of Applied Physiology, Vol. 104, No. 3Point-Counterpoint CommentsJurgen Van Teeffelen, and Hans Vink1 March 2008 | Journal of Applied Physiology, Vol. 104, No. 3Last Word on Point:Counterpoint: There is/is not capillary recruitment in active skeletal muscle during exerciseDavid Poole, Margaret Brown, and Olga Hudlicka1 March 2008 | Journal of Applied Physiology, Vol. 104, No. 3 More from this issue > Volume 104Issue 3March 2008Pages & 2008 the American Physiological March 2008 in March 2008

POINT-COUNTERPOINTCounterpoint: There is not capillary recruitment in active skeletal muscle during exerciseDavid C. Poole, Margaret D. Brown, and Olga HudlickaDavid C. Poole, Margaret D. Brown, and Olga HudlickaPublished Online:01 Mar 2008https://doi.org/10.1152/japplphysiol.00779.2007aMoreSectionsPDF (53 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations The notion that a substantial proportion of capillaries do not contain moving red blood cells (RBCs) in muscle at rest but are “recruited,” i.e., begin flowing with RBCs during contractions, is one basis for our present understanding of blood-muscle exchange during exercise (20, 28). This concept emanates, in part, from August Krogh, who showed that many capillaries in resting muscle did not contain India ink after high pressure perfusion (19). Despite Krogh himself recognizing that India ink particles clumped together, more likely to prevent complete perfusion of the capillary bed at rest than during exercise, these experiments, and Krogh's O2 diffusion model based on them, are still cited by researchers invoking capillary recruitment (e.g., Refs. 22). Today capillary recruitment during exercise is accepted by many to explain important physiological phenomena, including: 1) greater blood-muscle delivery and extraction of O2, free fatty acids, and glucose and 2) reduced capillary-to-mitochondrial diffusion distances. It makes great sense that, if there were a reserve of capillaries at rest, during exercise when the muscle demands for O2 may increase up to 100-fold, all—or at least most—capillaries would contribute to meet that demand.Why, therefore, choose to oppose the concept of capillary recruitment during exercise? In Britain, the motto of The Royal Society is “Nullius in Verba” (Take nobody's word for it, see it for yourself). However, the majority of research papers invoking capillary recruitment have not visualized the capillary bed (e.g., Refs. 3, 7, 25). In his letter to the editor of The American Journal of Physiology, the eminent microcirculation expert, Professor Eugene Renkin (26) criticized Dr. Bentzer for entitling his paper “Capillary filtration coefficient is independent of number of perfused capillaries in skeletal muscle”(4) on the basis that “… its title is misleading. No direct measurements of [RBC-flowing] capillary number were made. …” The same criticism could be leveled at almost all papers that include the words capillary recruitment in their titles. Evidence that most capillaries already sustain flow in resting muscle would preclude the possibility that recruitment of previously nonperfused capillaries occurs to any great extent during contractions.Direct evidence for RBC flow in most capillaries in resting muscle.In resting muscle, intravital light microscopy shows that over 80% of capillaries support RBC flow, e.g., in rat spinotrapezius (14, 17, 24), diaphragm (15), and extensor digitorum longus (1), hamster cremaster and sartorius (8), cat sartorius (6), rabbit tenuissimus (30). However, animals in these experiments were anesthetized to facilitate muscle exteriorization and viewing of the capillary beds. To address this, Bailey and colleagues (2) employed minimally invasive techniques to measure blood flow (radioactive microspheres) and microvascular oxygen partial pressure in muscle in situ and neither criterion was altered by exteriorization. Moreover, the dynamic matching of increased O2 delivery and V̇o2 during contractions in situ was preserved in the exteriorized muscle. It is difficult to conceive how anesthesia might affect arteriolar smooth muscle function at rest (to produce a falsely high %RBC-perfused capillaries) and yet muscles increase their blood flow and V̇o2 at a ratio of ∼6:1 (11), which is precisely that seen in intact voluntary exercising animals and humans (23).Another valid concern about intravital microscopy is that there are non-RBC containing capillaries at rest that cannot be seen because of their translucency. However, neither observation of contracting (17) nor vasodilated (16) muscles revealed a significant number of such vessels (see also Refs. 8, 14). The technical requirements necessary to observe capillaries within living muscle restrict the procedure to a limited selection of animal muscles so that one question to ask is: How representative of other muscles in the animals' body and in humans are these? In anesthetized and conscious animals, Snyder et al. (29) used systemic indicator injections and demonstrated that essentially all capillaries in each muscle examined (vastus lateralis, diaphragm, soleus) were perfused within 3–7 s.Indirect evidence for RBC flow in most capillaries in resting human muscle.Noninvasive near-infrared spectroscopy (NIRS) measures muscle hemoglobin concentration ([Hb]). If there were significant recruitment of previously non-RBC containing capillaries during exercise, say from 20 to 90%, [Hb] would be expected to increase several-fold. However, the rest-to-exercise [Hb] increase is less than onefold (e.g., 10) and can be accounted for by increased capillary hematocrit (18). Thus, as in animal muscles, there is little room for substantial capillary recruitment in human muscle.Against the evidence for capillary recruitment during exercise.The literature that purports to demonstrate capillary recruitment deserves to be evaluated on its own merits, but the following must be considered as possible explanations for reports of many non-RBC flowing capillaries in resting muscle. 1) Capillaries are fragile structures, subject to damage by blunt trauma, surgery, and/or manipulations such as stretching (24). 2) Po2 within resting muscle is normally very low and raising this will cause arteriolar constriction and capillary flow stoppage (22). 3) Anesthetized preparations are often hypovolemic and hypotensive, which provokes reflex vasoconstriction.In addition, misinterpretation of histological techniques has supported the notion of capillary recruitment. The conclusion that a RBC in the muscle capillary cross-section indicates RBC flow, whereas its absence supports no flow is erroneous (e.g., Ref. 13). In resting animal muscle observed in vivo, RBC movement in flowing capillaries varies over time, appearing either continuous or stop-start (9). Muscle contractions result in more continuously flowing vessels with higher RBC velocities (5). Hargreaves et al. (12) used thioflavine S (a plasma marker) to show that, since all capillaries were perfused, during contractions the increase in muscle blood flow (microspheres) could be accounted for by the increased velocity rather than capillary recruitment. Reduced flow heterogeneity and hence augmented capillary hematocrit from rest to exercise decreases the length of inter-RBC plasma gaps and increases the probability that an RBC will appear in cross section.Is the concept that most capillaries support RBC flow in resting muscle mathematically possible?In a typical 70-kg human with 31.5 kg of muscle (45% body mass), resting muscle blood flow is estimated as ∼1 l/min (or 5.4 × 1012 RBCs/min; Refs. 20, 28). Accepting a mean value for capillary density and length of 300/mm2 and 1,000 μm, respectively, if 80% of the 8.9 × 109 capillaries support RBC flow at rest, as in the rat (14, 17, 24), this would be ∼12 RBCs per capillary per second—very close to the 15–20 RBCs per capillary/s actually measured in rat muscle (17). Whereas such calculations are certainly not proof that most skeletal muscle capillaries have RBC flow in humans at rest, they support that it is feasible.Why is it crucial that we question the dogma of capillary recruitment?If most capillaries support RBC flow at rest and are not recruited at exercise onset, increased substrate delivery must occur within already flowing capillaries. Accordingly, is the recruitment of more surface area along the length of already flowing capillaries, rather than de novo flow in previously stagnant capillaries, key to increased blood-myocyte exchange? Diabetes (21), heart failure (27), and chronic ischemia (5) decrease the proportion of RBC-perfused capillaries in resting muscle. If we do not recognize that most capillaries may support RBC flow at rest in healthy muscle, our ability to appreciate the mechanisms for impaired blood-muscle exchange, which may be pathognomonic to these and other diseases, is crippled.Nullius in verba! The online version of this article contains supplemental data showing intravital microscopy recordings demonstrating RBC flow in almost all capillaries in healthy resting spinotrapezius muscle (first video, Refs. 24, 27) and diaphragm (third video, Ref. 15). The second video demonstrates the effects of chronic heart failure (CHF; left coronary artery ligation, Ref. 27) on capillary perfusion in spinotrapezius muscle. Note, in the CHF condition, the presence of stopped RBCs in central capillaries and other capillaries that have intermittent RBC flow and/or very low/sporadic RBC flux. Adherence to the misconception that many capillaries do not flow in healthy resting muscle (i.e., capillary recruitment notion) would confound identification of the effects of this disease on capillary hemodynamics and therefore O2 delivery and substrate exchange. GRANTSThis work was supported, in part, by grants from National Heart, Lung, and Blood Institute, HLBI-17731 and -50306, and grants-in-aid from the American Heart Association, Heartland Affiliate.We thank Professors Timothy I. Musch and George A. Brooks for facilitating presentation of the capillary recruitment debate at the American College of Sports Medicine's Integrative Physiology of Exercise meeting in Indianapolis in September 2006.REFERENCES1 Anderson SI,Hudlicka O, Brown MD. Capillary red blood cell flow and activation of white blood cells in chronic muscle ischemia in the rat. Am J Physiol Heart Circ Physiol 272: H2757–H2764, 1997.Link | ISI | Google Scholar2 Bailey JK, Kindig CA, Behnke BJ, Musch TI, Schmid-Schoenbein GW, Poole DC. Spinotrapezius muscle microcirculatory function: effects of surgical exteriorization. Am J Physiol Heart Circ Physiol 279: H1331–H1337, 2000.Google Scholar3 Baron AD, Tarshoby M, Hook G, Lazaridis EN, Cronin J, Johnson A, Steinberg HO. 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Does capillary recruitment exist in young rabbit skeletal muscle? Int J Microcirc Clin Exp 6: 321–332, 1987.Google Scholar Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited ByBlood volume versus deoxygenated NIRS signal: computational analysis of the effects muscle O2 delivery and blood volume on the NIRS signalsB. Koirala, A. Concas, Yi Sun, L. B. Gladden, and N. Lai5 November 2021 | Journal of Applied Physiology, Vol. 131, No. 5August Krogh's theory of muscle microvascular control and oxygen delivery: a paradigm shift based on new data12 September 2020 | The Journal of Physiology, Vol. 598, No. 20Hyperinsulinemia does not cause de novo capillary recruitment in rat skeletal muscle20 October 2019 | Microcirculation, Vol. 27, No. 2Edward F. Adolph Distinguished Lecture. Contemporary model of muscle microcirculation: gateway to function and dysfunctionDavid C. Poole14 October 2019 | Journal of Applied Physiology, Vol. 127, No. 4Skeletal muscle interstitial O 2 pressures: bridging the gap between the capillary and myocyte10 October 2018 | Microcirculation, Vol. 26, No. 5CrossTalk opposing view: De novo capillary recruitment in healthy muscle is not necessary to explain physiological outcomes1 December 2014 | The Journal of Physiology, Vol. 592, No. 23Insulin-Induced Changes in Microvascular Vasomotion and Capillary Recruitment are Associated in Humans14 July 2014 | Microcirculation, Vol. 21, No. 5A paradigm shift for local blood flow regulationAleksander S. Golub, and Roland N. Pittman15 March 2014 | Journal of Applied Physiology, Vol. 116, No. 6Skeletal muscle capillary function: contemporary observations and novel hypotheses10 October 2013 | Experimental Physiology, Vol. 98, No. 12Bang-Bang Model for Regulation of Local Blood Flow9 August 2013 | Microcirculation, Vol. 20, No. 6Regulation of Cellular Gas Exchange, Oxygen Sensing, and Metabolic Control1 July 2013What is the Efficiency of ATP Signaling from Erythrocytes to Regulate Distribution of O2 Supply Within the Microvasculature?9 July 2012 | Microcirculation, Vol. 19, No. 5Oxygen Uptake Kinetics1 April 2012An integrated exercise response and muscle fatigue model for performance decrement estimates of workloads in oxygen-limiting environments19 July 2011 | European Journal of Applied Physiology, Vol. 112, No. 4V̇o2 on-kinetics in isolated canine muscle in situ during slowed convective O2 deliveryMatthew L. Goodwin, Andrés Hernández, Nicola Lai, Marco E. Cabrera†, and L. Bruce Gladden1 January 2012 | Journal of Applied Physiology, Vol. 112, No. 1A new method to study changes in microvascular blood volume in muscle and adipose tissue: real-time imaging in humans and ratKim A. Sjøberg, Stephen Rattigan, Natalie Hiscock, Erik A. Richter, and Bente Kiens1 August 2011 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 301, No. 2Dynamics of muscle microcirculatory and blood-myocyte O2 flux during contractions1 March 2011 | Acta Physiologica, Vol. 202, No. 3Hemodynamic Systems Analysis of Capillary Network Remodeling During the Progression of Type 2 Diabetes23 December 2010 | Microcirculation, Vol. 18, No. 1Krogh cylinders in retinal development, panretinal hypoperfusion and diabetic retinopathy29 November 2010 | Acta Ophthalmologica, Vol. 88, No. 8Erythrocytes: surveyors as well as purveyors of oxygen?Roland N. Pittman1 June 2010 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 298, No. 6The Role of Blood Vessels, Endothelial Cells, and Vascular Pericytes in Insulin Secretion and Peripheral Insulin ActionEndocrine Reviews, Vol. 31, No. 3Impairment of maximal aerobic power with moderate hypoxia in endurance athletes: do skeletal muscle mitochondria play a role?Elodie Ponsot*, Stéphane P. Dufour*, Stéphane Doutreleau, Evelyne Lonsdorfer-Wolf, Eliane Lampert, François Piquard, Bernard Geny, Bertrand Mettauer, Renée Ventura-Clapier, and Ruddy Richard1 March 2010 | American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Vol. 298, No. 3Interaction between hypoxia and training on NIRS signal during exercise: Contribution of a mathematical modelRespiratory Physiology & Neurobiology, Vol. 169, No. 1Vasomotion and insulin-mediated capillary recruitment - part of the explanation?14 July 2009 | The Journal of Physiology, Vol. 587, No. 14Muscle Microvascular Dysfunction in Central Obesity Is Related to Muscle Insulin Insensitivity but Is Not Reversed by High-Dose Statin Treatment10 February 2009 | Diabetes, Vol. 58, No. 5Non-invasive evaluation of the capillary recruitment in the human muscle during exercise in hypoxiaRespiratory Physiology & Neurobiology, Vol. 165, No. 2-3Impaired microvascular perfusion: a consequence of vascular dysfunction and a potential cause of insulin resistance in muscleMichael G. Clark1 October 2008 | American Journal of Physiology-Endocrinology and Metabolism, Vol. 295, No. 4Rebuttal from Drs. Clark, Rattigan, Barrett, and Vincent1 March 2008 | Journal of Applied Physiology, Vol. 104, No. 3Point-Counterpoint CommentsJurgen Van Teeffelen, and Hans Vink1 March 2008 | Journal of Applied Physiology, Vol. 104, No. 3Last Word on Point:Counterpoint: There is/is not capillary recruitment in active skeletal muscle during exerciseDavid Poole, Margaret Brown, and Olga Hudlicka1 March 2008 | Journal of Applied Physiology, Vol. 104, No. 3 More from this issue > Volume 104Issue 3March 2008Pages 891-893 Copyright & PermissionsCopyright © 2008 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.00779.2007aPubMed18326874History Published online 1 March 2008 Published in print 1 March 2008 Metrics

EditorialQuality and innovation: American Journal of Physiology-Heart and Circulatory Physiology continues the tradition into the digital ageWilliam C. Stanley, and Kara Hansell KeehanWilliam C. StanleyDivision of Cardiology, Department of Medicine, University of Maryland, and , and Kara Hansell KeehanExecutive Editor for the American Journal of Physiology-Heart and Circulatory Physiology, Baltimore, MarylandPublished Online:01 Jan 2011https://doi.org/10.1152/ajpheart.01047.2010This is the final version - click for previous versionMoreSectionsPDF (29 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations with the change in editorship of the American Journal of Physiology-Heart and Circulatory Physiology (AJP-Heart), we first wish to extend our sincere thanks to Alberto Nasjletti and his team for an outstanding job of piloting the journal for the last six years. The content quality and editorial operations of the journal remain strong, with emphasis on clear critiques, “no nonsense” editorial decisions, and rapid review time. We continue to be a premier journal for cardiovascular physiology, and our scientific impact is solid. When compared with those of other journals in the cardiovascular field, our strengths are many. AJP-Heart offers authors a straightforward manuscript format, without the text and figure limits used elsewhere in the industry, which frequently force authors to arbitrarily truncate their work to fit preconceived specifications. Articles published in AJP-Heart provide readers with a clear focus on the novelty and importance of the scientific questions addressed in the work, thereby enabling readers to easily assess the quality of the science presented. The new editorial team for AJP-Heart will not enforce an arbitrarily low acceptance rate. Manuscripts submitted to the journal will continue to be treated fairly, peer reviewed thoroughly and swiftly, and adjudicated based on the quality of science, not rejected based on perception of potential impact or short-term citation. In summary, our emphasis has been and will remain on quality, not fashion or flashiness. While this may sound rather old fashioned, AJP-Heart has become a proven leader in the field without compromising value or scientific excellence.With the explosion in technology over the last decade, the mechanics of submission, review, and publishing have become a moving target for all biomedical journals. AJP-Heart, with the tireless support of the American Physiological Society, has emerged as a leader in online manuscript review and publication. The new editorial team plans to capitalize on past successes and rocket into the Web era with a portfolio of new online features and content. Our leading new feature will be podcasts, insightful and witty discussions of “hot topic” papers published in the journal. Together with an associate editor as moderator, an author will address questions about the selected paper and the reviewer will weigh in. These provocative short podcasts will certainly provide unique insight into our featured papers. To expand the journal's online reach, the new editorial team will launch AJP-Heart into social media by using the outreach of sites such as Facebook and Twitter. Furthermore, the editors plan to subdivide the table of contents of each print and online issue, organizing our content by research topic. This will enable readers to quickly scan each issue for articles of interest and will also provide a new avenue for building online collections of articles by topic. We hope to further enhance the online journal by making our content archive more readily searchable, an asset to every reader and author. As we migrate away from print deeper into the e-publishing realm, the possibilities of sharing the vitally important content of AJP-Heart become virtually limitless.The world of cardiovascular physiology is more international than ever before, and so it is fitting that our new editorial team reflects our global outlook. One third of our new associate editors reside outside the United States (Canada, United Kingdom, Italy, The Netherlands, and Japan). As well, our editorial board now includes more members from Europe, Asia, Pacific Islands, South America, and Africa. The editorial team will continue to emphasize acquiring qualified, skilled reviewers and providing clear and concise decision letters with a specific and unified message. If a manuscript is sent back to the authors for revision, we will provide unambiguous instructions on the main issues discussed in the reviews. Equally important, the editors will communicate what is expected of authors in a successfully revised manuscript. Our end goal is to publish high-quality articles within a short peer review time frame.A high impact publication such as ours needs to increase the number of short-term citations and its citation index. We hope to accomplish this by increasing submissions of high-quality original investigations and by doubling the publication of review papers. At present the journal publishes approximately 10 to 12 review papers each year, which represent only ∼2% of the total papers published in AJP-Heart. This average is far below the range of 10 to 25% published in many journals in the field of cardiovascular research. The new editorial team aims to increase the total number of published review articles to 20–25 annually. These review articles will be relatively short and narrow in scope and will not compete with the broad comprehensive reviews published in Physiological Reviews. We are fortunate to have David A. Kass serve as our senior associate editor, whose focus will be to formulate themes and topics for reviews and to solicit papers on both emerging ideas and critical concepts in cardiovascular physiology. In addition, we will publish high-quality methodological and historical reviews unique to heart and circulatory physiology but outside the interest of other cardiovascular publications.Certainly, we can all agree that AJP-Heart is an esteemed journal with a reputation for publishing solid science. The incoming editorial team welcomes the opportunity to guide this journal into the future. We see the challenges of print publishing, and we look to the exciting channels of communication available on the Web. We are proud of our reputation for fairness and expediency, and we look to continue and improve on these efficient operations. We inherit a fine publication and strive to uphold a tradition of excellence.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the author(s).AUTHOR NOTESAddress for reprint requests and other correspondence: W. C. Stanley, Div. of Cardiology, Dept. of Medicine, Univ. of Maryland-Baltimore, 20 Penn St., HSF2, Rm. S022, Baltimore, MD 21201 (e-mail: [email protected]umaryland.edu).This article has no references to display. Download PDF Back to Top Next FiguresReferencesRelatedInformation Cited ByEndothelial Dysfunction3 August 2019 More from this issue > Volume 300Issue 1January 2011Pages H1-H1 Copyright & PermissionsCopyright © 2011 the American Physiological Societyhttps://doi.org/10.1152/ajpheart.01047.2010History Published online 1 January 2011 Published in print 1 January 2011 Metrics

Intracardiac mast cells (CMCs) have previously been shown to contribute to adverse remodeling and heart failure in animal models. As CMCs in human hearts remain unexplored, the aim of this study was to investigate the pathophysiological relevance of human CMCs through transcriptomic profiling. Biopsies were collected from the four heart chambers of heart failure patients undergoing heart transplantation surgery (n = 9), as well as from deceased organ donors without chronic heart failure (n = 5). Using flow cytometry, C-kit+CD45+ CMCs and C-kit-CD45+ hematopoietic cells were identified in all failing and nonfailing hearts and were sorted for RNA sequencing analysis. In comparison with other hematopoietic C-kit-CD45+ cells and CMCs in nonfailing hearts, CMCs in failing hearts demonstrated significant activation of pathways involved in cardiac remodeling and heart failure, including fibrosis-associated and inflammatory pathways. Our results support a role for mast cells in human heart failure and constitute the first in-depth characterization of mast cells in the nonfailing and failing human heart.NEW & NOTEWORTHY Intracardiac mast cells (CMCs) have been shown to contribute to remodeling and fibrosis in animal models. No phenotypical characterization of human CMCs has been conducted before the current transcriptomic profiling study. CMCs isolated from failing human hearts demonstrated activated pathways involved in cardiac remodeling and fibrosis, both compared with other hematopoietic cells and to CMCs in nonfailing hearts. The study suggests that CMCs may constitute a novel candidate for modulation in human heart failure.

Alzheimer disease (AD) is a growing health problem characterized by neurocognitive and cardiovascular dysfunction. Although parental obesity programs adverse cardiometabolic complications, including obesity, hypertension and cardiorenal dysfunction in their offspring, whether parental obesity worsens cardiac, metabolic, and cognitive function in lean offspring that are susceptible to AD (3xTg-AD mice) remains unclear. Male and female offspring from control diet-fed or high fat diet (HFD)-fed parents were examined at 26-28 weeks of age. Cognitive function was assessed by Morris Water Maze and New Object Recognition (NOR) tests, cardiac function by echocardiography and invasive hemodynamic measurements, and mitochondrial (MT) function by high-resolution respirometry in isolated cardiac fibers and brain cortex. AD offspring from obese parents (HFD-Offs) exhibited worse memory retention compared to AD offspring from lean parents (ND-Offs), whereas recognition memory assessed by NOR was not significantly different between groups although there was greater variability in HFD-Offs. Although systolic function by echocardiography was similar between groups, male HFD-Offs showed impaired diastolic relaxation with prolonged isovolumetric relaxation time (IVRT), while E/e' remained unchanged. Left ventricular catheterization showed reduced indices of contractility and relaxation, including maximal and minimal rates of pressure changes: dP/dtmax (8,038&#xb1;1011 vs. 18,704&#xb1;183 mmHg/sec), dP/dtmin (-7,724&#xb1;471 vs. -13,634&#xb1;1139) and prolonged Tau (4.0&#xb1;0.1 vs. 2.9&#xb1;0.1) in HFD-Offs compared to ND-Offs. Male HFD-Offs exhibited reduced MT glucose and fatty acid oxidation in heart and brain. These findings indicate that parental obesity exacerbates AD-related cognitive decline and cardiac dysfunction in a sex-specific manner, suggesting parental metabolic status as an important determinant of AD-related cardiometabolic vulnerability.

Milrinone, a phosphodiesterase III inhibitor, exerts positive inotropic and vasodilatory effects via cyclic adenosine monophosphate-mediated signaling pathways. However, its comprehensive hemodynamic impact, particularly on venous return, remains incompletely characterized. Using the generalized circulatory equilibrium framework, we investigated the cardiovascular effects of milrinone in normal and heart failure (HF) canine models. Ten beagle dogs (5 normal, 5 with acute left HF induced by left coronary microembolization) were studied under general anesthesia and open-chest conditions. Milrinone was administered intravenously at 0.5 &#xb5;g&#xb7;kg-1&#xb7;min-1. From the circulatory equilibrium framework, we derived the effective stressed blood volume (SBV) and the logarithmic slope (SL) of the left ventricular (LV) output curve, which indicates LV pumping capability. Milrinone infusion reduced SBV from 31.6&#x2009;&#xb1;&#x2009;1.3 to 26.5&#x2009;&#xb1;&#x2009;1.7 mL/kg in the normal model and from 35.7&#x2009;&#xb1;&#x2009;3.0 to 32.1&#x2009;&#xb1;&#x2009;3.6 mL/kg in the HF model, with a significant main effect of drug (P = 0.004) but no model &#xd7; drug interaction in two-way ANOVA (P = 0.531). In the normal group, SL was unchanged [61.6&#x2009;&#xb1;&#x2009;1.6 to 62.2&#x2009;&#xb1;&#x2009;3.5 mL&#xb7;min-1&#xb7;kg-1], resulting in decreases in aortic pressure (AP) and cardiac output (CO). In contrast, in the HF group, milrinone increased SL [18.3&#x2009;&#xb1;&#x2009;3.1 to 30.2&#x2009;&#xb1;&#x2009;4.3 mL&#xb7;min-1&#xb7;kg-1], with a significant model &#xd7; drug interaction (P = 0.044). As a result, AP and CO were preserved, while left atrial pressure was reduced. In conclusion, in the HF canine model, milrinone improves the circulatory equilibrium point by enhancing LV pumping function and reducing SBV.NEW & NOTEWORTHY Analysis using a generalized circulatory equilibrium framework demonstrates that milrinone reduces stressed blood volume, shifting the venous return curve downward in both normal and heart failure (HF) models. In contrast, milrinone shifts the cardiac output (CO) curve upward only in the HF model. Left atrial pressure is reduced without CO reduction in the HF model, whereas CO decreases in the normal model. These findings indicate that circulatory equilibrium responses to milrinone depend on cardiac function.

The Fontan procedure enhances systemic oxygenation and survival in patients with complex congenital heart defects not amenable to biventricular repair. Despite these improvements, individuals with Fontan circulation often develop progressive multisystem dysfunction, the biochemical underpinnings of which remain poorly understood. Oxylipins are bioactive lipid mediators implicated in cardiovascular disease and represent targetable pathways that may contribute to the pathophysiology of the Fontan state. The study aims to quantify plasma oxylipins in individuals with Fontan circulation, compared with matched controls, and assess correlations with hemodynamic function and exercise capacity. A total of 20 adult patients with Fontan circulation&#xa0;and 20 matched controls underwent assessment of body composition, frailty, cardiopulmonary exercise testing, and noninvasive hemodynamic evaluation. Absolute plasma oxylipin concentrations were measured using triple quadrupole HPLC-MS/MS. Compared with controls, Fontan participants exhibited significantly increased (34%) total plasma oxylipin concentrations, with a 42% elevation in &#x3c9;-6 fatty acid-derived oxylipins. Among these, metabolites generated via the 15-lipoxygenase (15-LOX) pathway were elevated by 52%. In addition, product-to-substrate ratios reflecting putative soluble epoxide hydrolase (sEH) activity for &#x3c9;-6 fatty acids were nearly threefold higher in the Fontan group. Several oxylipins derived from &#x3c9;-3 and &#x3c9;-6 fatty acids, including those generated by 15-LOX and sEH pathways, demonstrated significant correlations with key clinical parameters, including resting and exercise hemodynamics, ventilatory efficiency, and peak oxygen consumption (V&#x307;o2). Individuals with Fontan circulation exhibit marked alterations in circulating oxylipins, particularly those involving &#x3c9;-6 fatty acid metabolism via 15-LOX and sEH. These findings offer mechanistic insights and identify potentially modifiable targets.NEW & NOTEWORTHY Fontan patients exhibit a distinct oxylipin signature characterized by markedly elevated total and &#x3c9;-6-derived oxylipins, including increased 15-LOX activity and higher sEH product-to-substrate ratios, alongside reduced &#x3c9;-3 species such as 20-hydroxydocosahexanoic acid (20-HDoHE) and 17,18-dihydroxyeicosatetraenoic acid (DiHETE). Elevated &#x3c9;-6 oxylipins correlated with poorer exercise capacity, greater frailty, and impaired hemodynamics, whereas &#x3c9;-3 oxylipins showed the opposite trend. These findings identify oxylipin dysregulation as a central metabolic hallmark and potential therapeutic target in Fontan circulation.

Although a large percentage of pregnancy-related morbidity and mortality is the result of cardiovascular diseases, little is known about the underlying mechanisms that contribute to the development of adverse cardiac changes during pregnancy. It is clear that during pregnancy, the heart adapts to increased ventricular preload through the development of a reversible, pregnancy-induced cardiac hypertrophy. Cardiomyocyte growth must be supported by changes in the cardiac extracellular matrix (ECM), an extremely diverse and dynamic set of components, whose composition and regulation affect cardiac biomechanics. The ECM undergoes extensive remodeling during periods of cardiac stress, such as those experienced during pregnancy and the postpartum period; however, the full extent of ECM changes and their contributions to biomechanical changes and maternal heart plasticity remain vastly understudied. Recent studies suggest alterations in the expression of several fibrillar collagens, such as collagens I and III, and regulatory proteins, such as matrix metalloproteinases and tissue inhibitor of matrix metalloproteinases, occur during a healthy pregnancy. On the contrary, in the setting of pregnancy-associated cardiovascular diseases, such as preeclampsia and peripartum cardiomyopathy, adverse changes in ECM remodeling have been reported. This review aims to summarize the current state of the field highlighting changes in the cardiac ECM and its components during healthy pregnancies, how perturbations in ECM remodeling can lead to the development of pregnancy-related cardiovascular pathologies, and discuss the notable gaps in knowledge that need to be addressed if we are to fully understand ventricular remodeling in the context of pregnancy and reduce maternal cardiovascular disease burden.

Chronic heart failure constitutes a clinical syndrome characterized by substantial attenuation of repolarization reserve resulting from electrical remodeling. The small-conductance Ca2+-activated K+ channel (SK) has been reported to undergo upregulation in animal heart failure models and in human preparations, however its exact function is not fully understood. This study aims to elucidate the functional role of SK channels in end-stage human heart failure. SK-protein expression of undiseased and failed human ventricular tissue was investigated by Western-blot technique. Action potentials were measured by standard microelectrode technique from right ventricular papillary muscles of undiseased hearts and from right and left papillary muscles and from left midmyocardial tissue slices of failing hearts. Ionic currents were recorded by the whole-cell configuration of the patch-clamp technique on isolated cells obtained from left ventricles of failing hearts. Failing hearts exerted consistent action potential lengthening and lacked spike-and-dome compared to undiseased hearts. Western-blot revealed identical SK-expression between undiseased and failing hearts. 100 nM apamin, a commonly used selective SK-channel inhibitor, failed to alter action potential duration values of the failing hearts in left and right endocardial preparations and in left midmyocardium. Furthermore, no apamin sensitive current was identified in isolated cells. It was found weak coupling between SK2-channels and L-type Ca2+ channels. These results do not confirm the results of previous studies claiming an important role of SK-channels in the repolarization of human failing heart.

Diabetes is associated with an increased incidence of heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms are poorly understood. A shortage of mouse models reflecting the diverse HFpEF pathophysiology contributes to this inadequate understanding of disease mechanisms. We conducted a comprehensive analysis of a nongenetic, inducible type 2 diabetes mellitus (T2DM) mouse model about its suitability as a preclinical model of cardiometabolic, diabetes-induced HFpEF. T2DM was induced in C57Bl/6 mice by a high-fat/high-sucrose diet and a low-dose streptozotocin (DIO-STZ). Cardiac function was assessed in vivo by echocardiography and left ventricular catheterization and in vitro using the isolated perfused heart. Structural, molecular, and bioenergetic disturbances were analyzed by immunohistochemistry, RNA-seq, qPCR, Western blot, and extracellular flux analysis of myocardial tissue. Blood glucose, fatty acids, and ketone body levels were elevated, and insulin levels were reduced in DIO-STZ compared with chow. DIO-STZ mice showed an HFpEF phenotype with reduced cardiac output, end-diastolic volume, and increased filling pressure. No differences in myocardial fibrosis or in vitro stiffness were detected between DIO-STZ and chow. RNA-Seq pointed toward disturbances in lipid and ketone metabolism. Extracellular flux analysis revealed increased fatty acid oxidation capacity without differences in glucose metabolism. No general mitochondrial dysfunction was observed, but a reduced capacity for &#x3b2;-hydroxybutyrate oxidation. The diabetic DIO-STZ mouse model showed a pronounced functional HFpEF phenotype with underlying mechanisms that remarkably differ from other HFpEF models, making the DIO-STZ model a relevant extension of the range of HFpEF mouse models, especially for investigating molecular mechanisms or therapeutic interventions in diabetes-associated HFpEF.NEW & NOTEWORTHY Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome whose pathophysiological mechanisms are incompletely understood, potentially due to a lack of preclinical models reflecting the broad range of pathophysiological aspects. We describe a diabetic DIO-STZ mouse model showing a pronounced HFpEF with underlying mechanisms that remarkably differ from other HFpEF models, making this model a relevant extension of the range of HFpEF models, especially for investigating molecular mechanisms or therapeutical interventions in diabetes.

Compared with men, women with similar coronary artery calcification (CAC) scores face higher cardiovascular disease (CVD) mortality. We posited that circulatory factors, such as blood-borne extracellular vesicles (EVs) and metabolites, may be associated with the development of CAC and subsequent CVD in postmenopausal women. In addition, we hypothesized that a history of preeclampsia (PE), a sex-specific risk factor, might be a contributing factor. Clinical data were obtained from medical records for postmenopausal women (median age 60 yr) free of cardiovascular events with (n = 29) and without (n = 29) CAC. EVs per microliter plasma were quantified by digital flow cytometry, and plasma metabolites were measured using gas chromatography-mass spectrometry. CACs were measured by computer tomography and reported as the Agatston score. Patients with, versus those without, CAC demonstrated 1) less favorable cardiovascular and metabolic profiles; 2) elevation in six EV populations, including those positive for tissue factor, CD3 (T-cells), SM22&#x3b1; (smooth muscle cells), Pref-1 (adipocytes), fatty acid-binding protein 4 (adipocytes/macrophages), and p16 (senescent cells); 3) significantly higher levels of proline, allothreonine (amino acid metabolism), and ribitol (carbohydrate metabolism), and lower levels of lactic acid (carbohydrate metabolism); and 4) significantly increased risk of developing CVD and chronic kidney disease (CKD) (P < 0.05 for all). In the CAC-positive group, women with PE versus those with normotensive pregnancy histories demonstrated a four times higher risk of developing cardiovascular events or CKD later in life (P = 0.028). Selected plasma metabolites, EVs, and PE history could serve as biomarkers and potential therapeutic targets for CAC and CVD in postmenopausal women.NEW & NOTEWORTHY Circulating extracellular vesicles, proinflammatory/pro-oxidant metabolites, and history of preeclampsia may be used as biomarkers for diagnosis of early CAC in postmenopausal women.

LETTERS TO THE EDITORThe classical Guyton view that mean systemic pressure, right atrial pressure, and venous resistance govern venous return is/is not correctS. MagderS. MagderPublished Online:01 Nov 2006https://doi.org/10.1152/japplphysiol.00903.2006This is the final version - click for previous versionMoreSectionsPDF (28 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations Last Word: Point:Counterpoint author responds to “The classical Guyton view that mean systemic pressure, right atrial pressure, and venous resistance govern venous return is/is not correct. To the Editor: Mitzner (4) considers the concept so obvious that he asks why we even needed to have this debate. I agree! The key point is that the elastic properties of the system impose limits on the capacity of the system, and the heart can never surpass these.Permutt's (4) analysis is based on an elastic compartment analogous to lungs. He emphasizes the crucial but difficult to comprehend concept of the isovolumetric pressure-flow relationship in a system of elastic and collapsible tubes that can create flow limitation. Personally, I never understood cardiovascular physiology until I was presented with this comparison to respiratory physiology and I recommend readers who are unfamiliar with it to consult J. F. Green's monograph (2) and the paper by Permutt and Caldini (3).Green (2) suggests the analogy of a toilet instead of a bathtub. Besides being less aesthetically pleasing, it misses the key point of isovolumetric conditions. Perhaps further consideration of the bathtub model may help emphasize the importance of the isovolume condition of the elastic region. When the tub is filled to the top, increasing the force or flow from the tap does not affect flow from the drain because the inflow cannot raise the height of the water in the tub.Baker and Rothe (4) raise the issues of multiple bathtubs or varying positions of the MSFP and the localization of venous resistance. Whereas these comments are valid, a close approximation can be made by a lumped parameter model that deals with the weighted effects of the different compliant regions and what Mitzner (4) appropriately calls the “effective equivalent resistance.” The formal mathematical analysis for these was presented by Permutt and Caldini (3). The “fussy” concept of MSFP is essential for understanding the limits of the system. This debate is about steady-state conditions, although the concepts still apply in dynamic situations. Consider, for example, the model of Burkoff and Tyberg (1).Wang's (4) comments refer to pulsatile flow. Clearly the heart is the source of these pulsations, but this must not be confused with the total flow through the system. Humans have normal cardiac outputs without pulsatile flow on a daily basis in the cardiac surgery suite. However, the importance of the volume of the circuit is also very obvious in these patients when flow limitation occurs; pump flow then can only be increased by adding volume and thus increasing the elastic recoil pressure.REFERENCES1 Burkhoff D and Tyberg JV. Why does pulmonary venous pressure rise after onset of left ventricular dysfunction: a theoretical analysis. Am J Physiol Heart Circ Physiol 265: H1819–H1828, 1993.Link | ISI | Google Scholar2 Green JF. Fundamental Cardiovascular and Pulmonary Physiology (2nd ed.). Philadelphia, PA: Lea Febiger, 1987.Google Scholar3 Permutt S and Caldini P. Regulation of cardiac output by the circuit: venous return. In: Cardiovascular System Dynamics, edited by Boan J, Noordergraaf A, and Raines J. Cambridge, MA: MIT Press, 1978, p. 465–479.Google Scholar4 Pinsky MR, Permutt S, Lin Wang YY, Wang WK, Baker RD, Rothe C, and Mitzner W. Comments on Point:Counterpoint: The classical Guyton view that mean systemic pressure, right atrial pressure, and venous resistance govern venous return is/is not correct. J Appl Physiol. In press.Google Scholar Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited ByVenous return and mean systemic filling pressure: physiology and clinical applications24 May 2022 | Critical Care, Vol. 26, No. 1Function of arteries and veins in conditions of simulated cardiac arrest7 March 2021 | BioImpacts, Vol. 11, No. 2Regulation of Cardiac Output28 November 2019Venous return and the physical connection between distribution of segmental pressures and volumesGeorge L. Brengelmann23 October 2019 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 317, No. 5Right atrial pressure and venous return during cardiopulmonary bypassPer W. Moller, Bernhard Winkler, Samuel Hurni, Paul Philipp Heinisch, Andreas Bloch, Soren Sondergaard, Stephan M. Jakob, Jukka Takala, and David Berger11 August 2017 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 313, No. 2Reply to “Letter to the editor: Why persist in the fallacy that mean systemic pressure drives venous return?”David Berger, Per W. Moller, and Jukka Takala1 November 2016 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 311, No. 5Effect of PEEP, blood volume, and inspiratory hold maneuvers on venous returnDavid Berger, Per W. Moller, Alberto Weber, Andreas Bloch, Stefan Bloechlinger, Matthias Haenggi, Soren Sondergaard, Stephan M. Jakob, Sheldon Magder, and Jukka Takala7 September 2016 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 311, No. 3Is the heart a pressure or flow generator? Possible implications and suggestions for cardiovascular pedagogyBranko Furst and Anthony M. O'Leary11 April 2016 | Advances in Physiology Education, Vol. 40, No. 2The Heart: Pressure-Propulsion Pump or Organ of Impedance?Journal of Cardiothoracic and Vascular Anesthesia, Vol. 29, No. 6Physiopathologie du retour veineux systémique au cours de l’insuffisance circulatoire aiguë7 March 2014 | Réanimation, Vol. 23, No. 2Regulation of Cardiac Output8 July 2013Further ReadingCardiopulmonary interactions and volume status assessment30 August 2012 | Journal of Clinical Monitoring and Computing, Vol. 26, No. 5Understanding Guyton's venous return curvesDaniel A. Beard, and Eric O. Feigl1 September 2011 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 301, No. 3The Physiologic Implications of Isolated Alpha1 Adrenergic StimulationAnesthesia & Analgesia, Vol. 113, No. 2Phenylephrine and Tangible BiasAnesthesia & Analgesia, Vol. 113, No. 2Measurement of Stroke Volume and Cardiac Output Using Echocardiography and Doppler22 December 2010A further analysis of why pulmonary venous pressure rises after the onset of LV dysfunctionS. Magder, S. Veerassamy, and J. H. T. Bates1 January 2009 | Journal of Applied Physiology, Vol. 106, No. 1Pression veineuse centraleHaemodynamic responses to exercise, ATP infusion and thigh compression in humans: insight into the role of muscle mechanisms on cardiovascular function1 May 2008 | The Journal of Physiology, Vol. 586, No. 9 More from this issue > Volume 101Issue 5November 2006Pages 1533-1533 Copyright & PermissionsCopyright © 2006 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.00903.2006PubMed16931558History Published online 1 November 2006 Published in print 1 November 2006 Metrics

Total carotid pulse wave velocity (T-PWV), a measure of arterial stiffness, is caused by structural (S) remodeling and elevated blood pressure exerting a pressure-load on the arterial wall. Isoprostanes are oxidative stress biomarkers that have been associated with arterial stiffness. We sought to investigate the cross-sectional and longitudinal associations of urinary 8-isoprostane (iPF2&#x3b1;-III) and its metabolite (iPF2&#x3b1;-III-M), measured at a single timepoint at baseline, with carotid T-PWV, S-PWV, and load-dependent (LD)-PWV in a subset (n = 744) of participants enrolled in the Multi-Ethnic Study of Atherosclerosis. We hypothesized that higher iPF2&#x3b1;-III and iPF2&#x3b1;-III-M concentrations would be associated with higher T-PWV, S-PWV, and LD-PWV. These relationships were evaluated using multivariable linear regression models adjusted for potential confounders in the entire analytical sample and in analyses stratified by hypertension medication class and race/ethnicity. In cross-sectional analyses of the entire analytic sample, there were no associations of acute iPF2&#x3b1;-III or iPF2&#x3b1;-III-M with carotid T-PWV, S-PWV, or LD-PWV after adjusting for risk factors. In adults taking angiotensin-II acting antihypertensive medications, higher iPF2&#x3b1;-III was associated with higher S-PWV, whereas higher iPF2&#x3b1;-III-M was associated with higher T-PWV and S-PWV. In the entire analytic sample, baseline isoprostanes were not associated with carotid PWV measured nearly a decade later. However, in analyses stratified by race/ethnicity, higher baseline iPF2&#x3b1;-III was associated with higher S-PWV nearly a decade later among self-identified White participants. These results suggest that single-timepoint measures of urinary 8-isoprostane are not a robust biomarker of arterial stiffness but may be associated with structural remodeling in select populations.NEW & NOTEWORTHY We examined cross-sectional and longitudinal associations of urinary isoprostanes with carotid T-PWV, and its associated mechanisms (S-PWV and LD-PWV), in a multiethnic cohort of adults. Higher isoprostanes were cross-sectionally associated with carotid artery stiffness driven by structural remodeling in adults who self-reported taking angiotensin-II acting medications or self-identified as White. No associations were observed with isoprostanes and carotid stiffness a decade later in the entire analytic sample. Oxidative stress may augment the risk of structural remodeling in select populations.

Aortic stenosis (AS) induces complex alterations in ascending aortic flow, including increased turbulent kinetic energy (TKE), altered velocity profiles, and changes in flow organization, which can be quantified using four-dimensional (4D) flow cardiovascular magnetic resonance (CMR). The physiological relevance of these flow-derived parameters with respect to left ventricular (LV) adaptation remains incompletely understood. We investigated the associations between 4D flow CMR-derived hemodynamic metrics and established markers of LV decompensation and remodeling in patients with AS. Fifty-nine patients with AS (70&#x2009;&#xb1;&#x2009;14 yr) underwent 4D flow CMR using a Bayesian multipoint phase-contrast sequence with k-t PCA acceleration and three velocity-encoding steps in each direction. Quantified parameters included peak TKE, stroke volume-normalized systolic TKE (normalized TKEsys), peak velocity, jet angle, relative flow displacement, and mean helicity. Associations with NT-proBNP and indexed LV mass were analyzed. Peak TKE, normalized TKEsys, and peak systolic velocity were significantly associated with both indexed LV mass and NT-proBNP, whereas mean helicity was associated with indexed LV mass only. In contrast, jet angle and flow displacement showed no relationship with either marker of LV decompensation and remodeling. During long-term follow-up, no 4D flow CMR parameter was associated with adverse clinical events, likely due to timely valve replacement in most patients. In conclusion, these findings indicate that flow energetics-particularly TKE and peak systolic velocity-most closely capture the hemodynamic burden imposed on the LV supporting their physiological relevance in AS. Isolated descriptors of flow geometry, in contrast, have not shown to reflect maladaptive LV remodeling.NEW & NOTEWORTHY This study used advanced four-dimensional (4D) flow cardiovascular magnetic resonance (CMR) to investigate alterations in aortic flow of patients with aortic stenosis and its relation to left ventricular remodeling and decompensation. It shows that turbulent kinetic energy, which is a measure of irreversible energy loss downstream of a stenotic valve, and peak flow velocity are the characteristics, which best capture the hemodynamic burden imposed on the left ventricle (LV). In contrast, geometric flow descriptors such as jet angle and flow displacement lacked physiological relevance.

Blood pressure regulation involves bidirectional brain-heart interactions mediated by both neurochemical signals and mechanosensitive pathways that include recently identified piezo receptors. We review current findings on the dynamic interplay between neural activity and blood pressure, highlighting insights from neuroimaging, systemic electrophysiology, and cellular biology. At a systemic level, blood pressure dynamics is regulated by coordinated oscillatory patterns across brain, cardiac, and respiratory signaling that couple with autonomic outflow and vascular pulsatility. Central autonomic networks, sympathetic-parasympathetic activity, and beat-to-beat blood pressure variability are mainly involved in such bidirectional interactions. At the cellular level, astrocytes, pericytes, endothelial cells, and cardiac and neural glia integrate mechanical pressure signals with metabolic and synaptic activity, forming distributed mechanosensory networks within the neurovascular unit and the cardiac autonomic nervous system. We show that optimal perfusion depends on arterial pressure remaining above a critical threshold to maintain vascular patency, with autoregulatory, metabolic, neurogenic, and glia-mediated mechanisms buffering systemic pressure fluctuations. When perfusion falls, astrocyte- and pericyte-dependent baroreflex mechanisms increase sympathetic drive, whereas pressure surges and altered arterial compliance promote vasoconstriction through coordinated neurovascular and central-autonomic responses. Pathological changes in arterial compliance and pulsatility, including loss of Windkessel function and nonphysiological flow states, distort neural pressure sensing and contribute to cardiovascular, cerebrovascular, and cognitive dysfunction and altered emotional processing. Invasive and noninvasive neuromodulation strategies may offer therapeutic potential by restoring physiological mechanosensory and autonomic control. These insights highlight the importance of mapping systemic central-autonomic networks and cell-specific neuromechanotransduction in health and in neurological, cardiovascular, and psychiatric disorders (1).

Pressure-volume (PV) loop analysis remains the gold standard for assessing the intrinsic global diastolic properties of the left ventricle (LV). Traditional fitting techniques rely on local, phase-constrained fittings and are limited due to their sensitivity to noise, landmark selection, violation of assumptions, and nonconvergence. We aimed to develop and validate DIA-, a physics-informed neural network (PINN) framework capable of calculating intrinsic diastolic properties of the LV from measured instantaneous PV data, combining mechanistic interpretability with machine learning flexibility. Instantaneous LV diastolic pressure was modeled as the sum of 1) time-dependent relaxation-related pressure and 2) volume-dependent recoil and stiffness-related pressures. DIA-PINN was trained using time, LV pressure, and LV volume as inputs, enforcing data fidelity, model consistency, and physiological plausibility within the loss function. Performance was evaluated in 4,000 Monte Carlo simulations of LV PV-loops, and in clinical data from 59 patients who underwent catheterization (39 with heart failure and normal ejection fraction and 20 controls). DIA-PINN-derived indices were compared with those obtained from a previously validated global optimization method (GOM). On the simulation data, DIA-PINN accurately recovered all constitutive indices (intraclass correlation coefficients near unity) and improved GOM performance. On the clinical data, diastolic indices derived using DIA-PINN strongly correlated with GOM estimates (R > 0.90, P < 0.001) but were insensitive to initialization. DIA-PINN performed best under vena cava occlusion, as varying preload improved parameter identifiability. When applied to instantaneous pressure-volume data, a generalizable PINN framework, DIA-PINN, provides an improved method for assessing global intrinsic diastolic properties of cardiac chambers.NEW & NOTEWORTHY Our work introduces DIA-PINN, a physics-informed neural network framework to process instantaneous ventricular pressure-volume data, solving a mechanistic model of diastole with machine learning techniques. Compared with current conventional or optimization-based approaches, the PINN provides the most reliable estimates of diastolic stiffness, relaxation, and elastic recoil, insensitive to initialization. By embedding physiological constraints into network training, this approach achieves robust, interpretable, and clinically applicable quantification of gold-standard metrics of intrinsic global diastolic chamber properties.

Heart failure (HF) affects over 60 million people worldwide, with increasing prevalence as HF with preserved ejection fraction (HFpEF) among adults. Although metabolic remodeling and mitochondrial dysfunction are central features of HFpEF, the direct mechanistic link between altered cardiac metabolism and mitochondrial impairment remains elusive. Here, we investigated how cardiac metabolic remodeling drives mitochondrial impairment, leading to diastolic dysfunction in HFpEF, independent of extracardiac metabolic syndrome. Infusion of angiotensin II (1.5 &#x3bc;g/g/day) and phenylephrine (50 &#x3bc;g/g/day) in 8- to 10-wk-old male and female mice reproduced hallmark HFpEF features, including preserved EF, elevated E/E' ratio, reduced physical endurance, and impaired lung function. Cardiac mitochondria showed markedly reduced respiration, diminished complex II abundance, and impaired mitochondrial supercomplexes, accompanied by an &#x223c;20% reduction in mitochondrial calcium retention capacity and increased susceptibility to opening of the mitochondrial permeability transition pore (mPTP). Metabolomic analysis suggests a shift in mitochondrial metabolism from fatty acid (FA) to the utilization of alternative glucose substrates, characterized by reduced mitochondrial FA trafficking despite increased FA translocase. Dicarbonyl and glycative stress were substantially elevated, with mitochondrial protein glycation increased by sevenfold. Mass spectrometry identified 18 mitochondrial proteins present in a significantly glycated form, with potential implications for impairing metabolic flexibility, reducing electron transport efficiency, and promoting susceptibility to mPTP opening. Our findings demonstrate that metabolic remodeling contributes to dicarbonyl and glycative stress, which in turn compromises the integrity of mitochondrial electron transport complexes, respiratory function, and calcium retention capacity in the HFpEF heart, highlighting mitochondrial dicarbonyl detoxification and antiglycation strategies as promising therapeutic avenues.NEW & NOTEWORTHY Recent studies increasingly highlight profound metabolic remodeling within the HFpEF heart; however, it remains unclear if this is an intrinsic or systemic phenomenon. In the present study, we identify dicarbonyl and glycative stress as key drivers of mitochondrial dysfunction in an ANGII/PE mouse model with HFpEF phenotype independent of systemic metabolic disease. These findings reveal a previously unrecognized metabolic-mitochondrial axis and suggest dicarbonyl detoxification and mitochondrial antiglycation as potential therapeutic targets.

Vascular ageing has garnered increasing attention due to the global rise in ageing populations. Despite this, no comprehensive bibliometric analysis on vascular ageing has been conducted to date. This study aims to fill that gap by analyzing the landscape of vascular ageing research through a bibliometric approach. We retrieved 1,160 articles published between 1900 and 2023 from the Web of Science Core Collection. Using VOSviewer and CiteSpace, we examined publication trends, journal impact, author contributions, citation analysis, and key research themes. The United States emerged as the leading contributor in publications and international collaborations. The U.S. Department of Veterans Affairs was the most prolific institution. American Journal of Physiology - Heart and Circulatory Physiology accounted for 3.28% of the publications, while Circulation Research had the highest impact factor. The top three authors by publication volume were Seals DR, Donato AJ, and Ungvari Z. The most cited paper, published in The Lancet in 2002, underscored the significant impact of vascular ageing research. Current research keywords include "ageing," "hypertension," "oxidative stress," "arterial stiffness," "atherosclerosis," and "inflammation." This study delivers a thorough bibliometric analysis of vascular ageing, yielding insights that contribute to scientific progress. It not only helps researchers identify current hotspots within the field but also uncovers promising directions for future investigation. Furthermore, subsequent research can build upon these findings to explore underlying mechanisms, validate emerging trends through experimental approaches, and translate bibliometric insights into clinical applications aimed at age-related vascular dysfunction. This article offers a comprehensive overview of vascular ageing research. We hope these findings will foster novel insights into the mechanisms and therapeutic strategies for vascular ageing.

"Athlete's heart" is well-documented in males, but female-specific data remain limited despite increasing participation in women's sport. This systematic review examined studies investigating exercise-induced cardiac adaptation, auditing female athlete representation and methodological quality using a standardized framework. A total of 767 articles met inclusion, comprising 94,744 participants. Male-only cohorts made up 54% of studies (n = 416), whereas female-only studies represented just 5% (n = 38). Only 7% (n = 56) of studies included a male-female subanalysis, whereas 3% of studies (n = 21) used direct sex-comparative design. Notably, 6% of studies (n = 44) did not report participant sex at all. Females accounted for less than one quarter of the total sample (24%, n = 23,061 participants). Football (soccer) was the most represented sport overall (n = 13,582 participants) and in male-only studies (n = 5,242 participants). Basketball was the most common in female-only studies (n = 314 participants). Ethnicity was reported in 17% of studies (n = 127; 43,683 participants), with 80% of participants identified as White and 16% as African/Afro-Caribbean. Para-athletes comprised 0.4% of the total cohort. Echocardiography was the predominant imaging modality (88%), with 97% of studies reporting left ventricular parameters. Only 10 studies (3% of those including females) provided sufficient information to classify menstrual status, and none met best-practice recommendations. These findings highlight the need to prioritize diverse female athlete cohorts, including para-athletes, broader ethnic representation, and wider range of sport domains, to enable accurate clinical interpretation and equitable cardiovascular assessment in women.