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Introduction Methods Results Conclusion Ultrasonography as a guide for intravenous (IV) fluid therapy is increasingly accepted within the spheres of acute care. Initial investigations and protocols often focused on measures of arterial flow as an objective approach for personalising organ ‘perfusion.’ More recently, and with literature associating excessive IV fluid with adverse outcomes, venous ultrasound as a measure of organ ‘congestion’ is taking hold. Yet, arterial (i.e., ‘perfusion’) and venous (i.e., ‘congestion’) Doppler ultrasound measures are often performed separately and can be time‐consuming, especially for novices.We report a case, wherein venous and arterial Doppler were simultaneously measured using a wireless, wearable ultrasound as a means to optimise flow without congestion.Before IV volume expansion, the patient had Doppler measures consistent with low central venous pressure (CVP) and stroke volume (SV). Following IV volume expansion, venous Doppler remained the same; however, carotid corrected flow time (ccFT) increased significantly.A framework for venous‐arterial Doppler enhanced resuscitation (VADER) can be used to guide IV volume in patients at risk for venous congestion. [ABSTRACT FROM AUTHOR]

Durable mechanical circulatory support in the form of left ventricular (LV) assist device (LVAD) therapy is increasingly considered in the context of the recovery of native cardiac function. Progressive improvement in LV function may facilitate LVAD explantation and a resultant reduction in device-related risk. However, ascertaining LV recovery remains a challenge. In this study, we investigated the use of trans-aortic valvular flow rate and trans-LVAD flow rate to assess native LV systolic function using a well-established lumped parameter model of the mechanically assisted LV with pre-existing systolic dysfunction. Trans-aortic valvular ejection fraction (TAVEF) was specifically found to characterize the preload-independent contractility of the LV. It demonstrated excellent sensitivity to simulated pharmacodynamic stress tests and volume infusion tests. TAVEF may prove to be useful in the ascertainment of LV recovery in LVAD-supported LVs with pre-existing LV systolic dysfunction. [ABSTRACT FROM AUTHOR]

Cardiac excitation-contraction (E-C) coupling is influenced by (at least) three dynamic systems that couple and feedback to one another (see Abstract Figure). Here we review the mechanical effects on cardiomyocytes that include mechano-electro-transduction (commonly referred to as mechano-electric coupling, MEC) and mechano-chemo-transduction (MCT) mechanisms at cell and molecular levels which couple to Ca2+ -electro and E-C coupling reviewed elsewhere. These feedback loops from muscle contraction and mechano-transduction to the Ca2+ homeodynamics and to the electrical excitation are essential for understanding the E-C coupling dynamic system and arrhythmogenesis in mechanically loaded hearts. This white paper comprises two parts, each reflecting key aspects from the 2018 UC Davis symposium: MEC (how mechanical load influences electrical dynamics) and MCT (how mechanical load alters cell signalling and Ca2+ dynamics). Of course, such separation is artificial since Ca2+ dynamics profoundly affect ion channels and electrogenic transporters and vice versa. In time, these dynamic systems and their interactions must become fully integrated, and that should be a goal for a comprehensive understanding of how mechanical load influences cell signalling, Ca2+ homeodynamics and electrical dynamics. In this white paper we emphasize current understanding, consensus, controversies and the pressing issues for future investigations. Space constraints make it impossible to cover all relevant articles in the field, so we will focus on the topics discussed at the symposium.

Throughout its lifetime the heart is buffeted continuously by dynamic mechanical forces resulting from contraction of the heart muscle itself and fluctuations in haemodynamic load and pressure. These forces are in flux on a beat-by-beat basis, resulting from changes in posture, physical activity or emotional state, and over longer timescales due to altered physiology (e.g. pregnancy) or as a consequence of ageing or disease (e.g. hypertension). It has been known for over a century of the heart's ability to sense differences in haemodynamic load and adjust contractile force accordingly (Frank, Z. biology, 1895, 32, 370-447; Anrep, J. Physiol., 1912, 45 (5), 307-317; Patterson and Starling, J. Physiol., 1914, 48 (5), 357-79; Starling, The law of the heart (Linacre Lecture, given at Cambridge, 1915), 1918). These adaptive behaviours are important for cardiovascular homeostasis, but the mechanism(s) underpinning them are incompletely understood. Here we present evidence that the mechanically-activated ion channel, Piezo, is an important component of the Drosophila heart's ability to adapt to mechanical force. We find Piezo is a sarcoplasmic reticulum (SR)-resident channel and is part of a mechanism that regulates Ca2+ handling in cardiomyocytes in response to mechanical stress. Our data support a simple model in which Drosophila Piezo transduces mechanical force such as stretch into a Ca2+ signal, originating from the SR, that modulates cardiomyocyte contraction. We show that Piezo mutant hearts fail to buffer mechanical stress, have altered Ca2+ handling, become prone to arrhythmias and undergo pathological remodelling. [ABSTRACT FROM AUTHOR]

Haemorrhagic and severe hypovolaemic shock can be rapidly fatal unless identified and resuscitated quickly. Monitoring of haemodynamic and cellular end points is crucial in guiding treatment and improving outcomes. This article therefore focuses on the pathophysiology of hypovolaemic shock, volume resuscitation, haemostasis and approaches to management. Fluid resuscitation saves lives but debate remains regarding the ideal fluid type and strategy to use. Blood transfusion is also a critical therapy in the shocked, bleeding patient – strategies vary depending on the clinical situation. Coagulopathy can accompany haemorrhage, particularly in trauma, and administration of coagulation products should be guided by testing. The aim is to stabilize the patient until definitive control of haemorrhage can be achieved by intervention. [ABSTRACT FROM AUTHOR]

Throughout its lifetime the heart is buffeted continuously by dynamic mechanical forces resulting from contraction of the heart muscle itself and fluctuations in haemodynamic load and pressure. These forces are in flux on a beat-by-beat basis, resulting from changes in posture, physical activity or emotional state, and over longer timescales due to altered physiology (e.g. pregnancy) or as a consequence of ageing or disease (e.g. hypertension). It has been known for over a century of the heart’s ability to sense differences in haemodynamic load and adjust contractile force accordingly (Frank, Z. biology, 1895, 32, 370–447; Anrep, J. Physiol., 1912, 45 (5), 307–317; Patterson and Starling, J. Physiol., 1914, 48 (5), 357–79; Starling, The law of the heart (Linacre Lecture, given at Cambridge, 1915), 1918). These adaptive behaviours are important for cardiovascular homeostasis, but the mechanism(s) underpinning them are incompletely understood. Here we present evidence that the mechanically-activated ion channel, Piezo, is an important component of the Drosophila heart’s ability to adapt to mechanical force. We find Piezo is a sarcoplasmic reticulum (SR)-resident channel and is part of a mechanism that regulates Ca2+ handling in cardiomyocytes in response to mechanical stress. Our data support a simple model in which Drosophila Piezo transduces mechanical force such as stretch into a Ca2+ signal, originating from the SR, that modulates cardiomyocyte contraction. We show that Piezo mutant hearts fail to buffer mechanical stress, have altered Ca2+ handling, become prone to arrhythmias and undergo pathological remodelling.

Background: The change in the corrected flow time of the common carotid artery (ccFTΔ) has been used as a surrogate of changing stroke volume (SVΔ) in the critically-ill. Thus, this relatively easy-to-obtain Doppler measure may help clinicians better define the intended effect of intravenous fluids. Yet the temporal evolution of SVΔ and ccFTΔ has not been reported in volunteers undergoing a passive leg raise (PLR). Methods: We recruited clinically-euvolemic, non-fasted, adult, volunteers in a local physiology lab to perform 2 PLR maneuvers, each separated by a 5 minute ‘wash-out’. During each PLR, SV was measured by a non-invasive pulse contour analysis device. SV was temporally-synchronized with a wireless, wearable Doppler ultrasound worn over the common carotid artery that continuously measured ccFT. Results: 36 PLR maneuvers were obtained across 19 ambulatory volunteers. 8856 carotid Doppler cardiac cycles were analyzed. The ccFT increased nearly ubiquitously during the PLR and within 40–60 seconds of PLR onset; the rise in SV from the pulse contour device was more gradual. SVΔ by +5% and +10% were both detected by a +7% ccFTΔ with sensitivities, specificities and areas under the receiver operator curve of 59%, 95% and 0.77 (p < 0.001) and 66%, 76% and 0.73 (p < 0.001), respectively. Conclusions: The ccFTΔ during the PLR in ambulatory volunteers was rapid and sustained. Within the limits of precision for detecting a clinically-significant rise in SV by a non-invasive pulse contour analysis device, simultaneously-acquired ccFT from a wireless, wearable ultrasound system was accurate at detecting ‘preload responsiveness’.

Most patients who develop heart failure are unable to elevate their cardiac output on demand due to impaired contractility and/or reduced ventricular filling. Despite decades of research, few effective therapies for heart failure have been developed. In part, this may reflect the difficulty of predicting how perturbations to molecular-level mechanisms that are induced by drugs will scale up to modulate system-level properties such as blood pressure. Computer modeling might help with this process and thereby accelerate the development of better therapies for heart failure. This manuscript presents a new multiscale model that uses a single contractile element to drive an idealized ventricle that pumps blood around a closed circulation. The contractile element was formed by linking an existing model of dynamically coupled myofilaments with a well-established model of myocyte electrophysiology. The resulting framework spans from molecular-level events (including opening of ion channels and transitions between different myosin states) to properties such as ejection fraction that can be measured in patients. Initial calculations showed that the model reproduces many aspects of normal cardiovascular physiology including, for example, pressure-volume loops. Subsequent sensitivity tests then quantified how each model parameter influenced a range of system level properties. The first key finding was that the End Systolic Pressure Volume Relationship, a classic index of cardiac contractility, was ∼50% more sensitive to parameter changes than any other system-level property. The second important result was that parameters that primarily affect ventricular filling, such as passive stiffness and Ca2+ reuptake via sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), also have a major impact on systolic properties including stroke work, myosin ATPase, and maximum ventricular pressure. These results reinforce the impact of diastolic function on ventricular performance and identify the End Systolic Pressure Volume Relationship as a particularly sensitive system-level property that can be targeted using multiple therapeutic strategies.

Most patients who develop heart failure are unable to elevate their cardiac output on demand due to impaired contractility and/or reduced ventricular filling. Despite decades of research, few effective therapies for heart failure have been developed. In part, this may reflect the difficulty of predicting how perturbations to molecular-level mechanisms that are induced by drugs will scale up to modulate system-level properties such as blood pressure. Computer modeling might help with this process and thereby accelerate the development of better therapies for heart failure. This manuscript presents a new multiscale model that uses a single contractile element to drive an idealized ventricle that pumps blood around a closed circulation. The contractile element was formed by linking an existing model of dynamically coupled myofilaments with a well-established model of myocyte electrophysiology. The resulting framework spans from molecular-level events (including opening of ion channels and transitions between different myosin states) to properties such as ejection fraction that can be measured in patients. Initial calculations showed that the model reproduces many aspects of normal cardiovascular physiology including, for example, pressure-volume loops. Subsequent sensitivity tests then quantified how each model parameter influenced a range of system level properties. The first key finding was that the End Systolic Pressure Volume Relationship, a classic index of cardiac contractility, was ∼50% more sensitive to parameter changes than any other system-level property. The second important result was that parameters that primarily affect ventricular filling, such as passive stiffness and Ca2+ reuptake via sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), also have a major impact on systolic properties including stroke work, myosin ATPase, and maximum ventricular pressure. These results reinforce the impact of diastolic function on ventricular performance and identify the End Systolic Pressure Volume Relationship as a particularly sensitive system-level property that can be targeted using multiple therapeutic strategies. [ABSTRACT FROM AUTHOR]

Haemorrhagic and severe hypovolaemic shock can be rapidly fatal unless identified and resuscitated quickly. Monitoring of haemodynamic and cellular end points is crucial in guiding treatment and improving outcomes. This article therefore focuses on the pathophysiology of hypovolaemic shock, volume resuscitation, haemostasis and approaches to management. Fluid resuscitation saves lives but considerable debate remains regarding the ideal fluid type and strategy to use. Blood transfusion is also a critical therapy in the shocked, bleeding patient with a lower threshold for transfusion being appropriate in the elderly patient with less physiological reserve. Reversal of anticoagulant medications and the administration of coagulation products should support both fluid and red cell therapy to counteract the multifactorial coagulopathy that can accompany severe trauma, haemorrhage and shock. The aim is to stabilize the patient such that any interventional strategies (both percutaneous and surgical) can be considered for uncontrolled bleeding. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether percentage changes in pulse wave transit time (PWTT%Δ) induced by mini‐fluid challenges predict fluid responsiveness in mechanically ventilated anesthetized dogs. Design: Prospective experimental trial. Setting: University teaching hospital. Animals: Twelve Harrier hounds. Intervention: Each dog was anesthetized with propofol and isoflurane after premedication with acepromazine, mechanically ventilated, and had a fluid challenge. This was repeated 4 weeks later. The fluid challenge, 10 mL/kg of colloid administration over 13 minutes, consisted of 3 intermittent mini‐fluid challenges (1 mL/kg of each over a minute) with a minute interval, and the remaining colloid administration (7 mL/kg) over 7 minutes. Measurements and Main Results: Percentage change in velocity time integral of pulmonary arterial flow by echocardiography was calculated as an indication of change in stroke volume. Fluid responsiveness was defined as percentage change in velocity time integral ≥ 15% after 10 mL/kg colloid. Dogs responded on 14 fluid challenges and did not on 10. After 1, 2, 3, and 10 mL/kg of fluid challenge, PWTT%Δ1, 2, 3, 10 were measured. Receiver operator characteristic (ROC) curves were generated and areas under ROC curve were calculated for PWTT%Δ1, 2, 3. A gray zone approach was used to identify the clinically inconclusive range. The area under the ROC curve for PWTT%Δ3 was 0.91 (P = 0.001). Cutoff value for PWTT%Δ3 was −2.5% (sensitivity: 86%, specificity: 90%). The gray zone for PWTT%Δ3 was identified as between −2.9% to −1.9% for which fluid responsiveness could not be predicted reliably in 6 out of 24 fluid challenges. Conclusions: In mechanically ventilated anesthetized dogs given a mini‐fluid challenge of 3 mL/kg of colloid, PWTT%Δ could predict fluid responsiveness although the gray zone should be considered. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To evaluate whether pulse pressure variation (PPV) and pleth variability index (PVI) are more accurate than central venous pressure (CVP) for predicting fluid responsiveness in mechanically ventilated isoflurane‐anesthetized dogs after premedication with acepromazine. Design: Prospective experimental trial. Setting: University teaching hospital. Animals: Twelve Harrier hound dogs. Interventions: Each dog was anesthetized and had a fluid challenge performed. This was repeated 4 weeks later for a total of 24 fluid challenges. After premedication with intramuscular acepromazine, anesthesia was induced with propofol and maintained with isoflurane. The dogs were mechanically ventilated with constant settings. The fluid challenge consisted of 10 mL/kg of 6% hydroxyethyl starch intravenously over 13 minutes. Measurements and Main Results: Before and after the fluid challenge, PPV, PVI, CVP, and other hemodynamics were recorded. Change in velocity time integral of pulmonary arterial blood flow by echocardiography was calculated as an indication of change in stroke volume. A fluid responder was defined as an increase in velocity time integral ≥ 15%. Receiver operator characteristic (ROC) curves were used to determine cutoff values. Areas under ROC curve were calculated and compared. Dogs responded on 14 fluid challenges and did not on 10. Cutoff values for PPV and PVI were 11% (sensitivity 79%; specificity 80%) and 9.3% (sensitivity 86%; specificity 70%), respectively. The areas under the ROC curve of PPV [0.85, 95% confidence interval (CI): 0.70–1.00, P = 0.038] and PVI (0.84, 95% CI: 0.68–1.00, P = 0.043) were significantly higher than CVP (0.56, 95% CI: 0.32–0.81). Conclusions: PPV and PVI predicted fluid responsiveness more accurately than CVP and may be useful to guide fluid administration in mechanically ventilated isoflurane‐anesthetized dogs after premedication with acepromazine. [ABSTRACT FROM AUTHOR]

The mechanical events of the cardiac cycle provide the circulation with normal cardiac output and blood pressure. This requires an appropriate venous return, regulation of outflow resistance, a normal myocardial contractile state and heart rate control, together with an adequate supply of oxygenated blood via the coronary circulation. Other neural influences contribute to cardiac regulation, including natriuretic peptides and the renin–angiotensin system. The atria and ventricles are richly supplied with adrenergic nerves that may augment cardiac function, particularly with increased cardiac output during exercise. Inhibitory vagal fibres are largely confined to the sinus and atrioventricular nodes. Exercise causes increased sympathetic outflow, with a decrease in peripheral vascular resistance and increased cardiac output, heart rate, systolic blood pressure and venous return. Regular rhythmic exercise has a training effect, which enhances cardiac performance. This is important for the maintenance of many aspects of cardiovascular health. [ABSTRACT FROM AUTHOR]

The Frank-Starling Law dictates that the heart is able to match ejection to the dynamic changes occurring during cardiac filling, hence efficiently regulating isovolumetric contraction and shortening. In the last four decades, efforts have been made to identify a common fundamental basis for the Frank-Starling heart that can explain the direct relationship between muscle lengthening and its increased sensitization to Ca. The term 'myofilament length-dependent activation' describes the length-dependent properties of the myofilaments, but what is(are) the underlying molecular mechanism(s) is a matter of ongoing debate. Length-dependent activation increases formation of thick-filament strongly-bound cross-bridges on actin and imposes structural-mechanical alterations on the thin-filament with greater than normal bound Ca. Stretch-induced effects, rather than changes in filament spacing, appear to be primarily involved in the regulation of length-dependent activation. Here, evidence is provided to support the notion that stretch-mediated effects induced by titin govern alterations of thick-filament force-producing cross-bridges and thin-filament Ca-cooperative responses. [ABSTRACT FROM AUTHOR]

Background: The change in the corrected flow time of the common carotid artery (ccFTΔ) has been used as a surrogate of changing stroke volume (SVΔ) in the critically-ill. Thus, this relatively easy-to-obtain Doppler measure may help clinicians better define the intended effect of intravenous fluids. Yet the temporal evolution of SVΔ and ccFTΔ has not been reported in volunteers undergoing a passive leg raise (PLR)., Methods: We recruited clinically-euvolemic, non-fasted, adult, volunteers in a local physiology lab to perform 2 PLR maneuvers, each separated by a 5 minute 'wash-out'. During each PLR, SV was measured by a non-invasive pulse contour analysis device. SV was temporally-synchronized with a wireless, wearable Doppler ultrasound worn over the common carotid artery that continuously measured ccFT., Results: 36 PLR maneuvers were obtained across 19 ambulatory volunteers. 8856 carotid Doppler cardiac cycles were analyzed. The ccFT increased nearly ubiquitously during the PLR and within 40-60 seconds of PLR onset; the rise in SV from the pulse contour device was more gradual. SVΔ by +5% and +10% were both detected by a +7% ccFTΔ with sensitivities, specificities and areas under the receiver operator curve of 59%, 95% and 0.77 ( p < 0.001) and 66%, 76% and 0.73 ( p < 0.001), respectively., Conclusions: The ccFTΔ during the PLR in ambulatory volunteers was rapid and sustained. Within the limits of precision for detecting a clinically-significant rise in SV by a non-invasive pulse contour analysis device, simultaneously-acquired ccFT from a wireless, wearable ultrasound system was accurate at detecting 'preload responsiveness'., Competing Interests: JESK, CH, ME, AME, JKE work for Flosonics Medical, the start-up building the wearable Doppler ultrasound., (© 2023 The Author(s). Published by IMR Press.)

Haemorrhagic and severe hypovolaemic shock can be rapidly fatal unless identified and resuscitated quickly. Monitoring of haemodynamic and cellular end points is crucial in guiding treatment and improving outcomes. This review therefore focuses on the pathophysiology of hypovolaemic shock, volume resuscitation, haemostasis and approaches to management. Fluid resuscitation saves lives but considerable debate remains regarding the ideal fluid type and strategy to use. Blood transfusion is also a critical therapy in the shocked, bleeding patient with a lower threshold for transfusion being appropriate in the elderly patient with less physiological reserve. Reversal of anticoagulant medications and the administration of coagulation products should support both fluid and red cell therapy to counteract the multifactorial coagulopathy that can accompany severe trauma, haemorrhage and shock. The aim is to stabilize the patient such that any interventional strategies (both percutaneous and surgical) can be considered for uncontrolled bleeding. [ABSTRACT FROM AUTHOR]

More than a century of research on the Frank-Starling Law has significantly advanced our knowledge about the working heart. The Frank-Starling Law mandates that the heart is able to match cardiac ejection to the dynamic changes occurring in ventricular filling and thereby regulates ventricular contraction and ejection. Significant efforts have been attempted to identify a common fundamental basis for the Frank-Starling heart and, although a unifying idea has still to come forth, there is mounting evidence of a direct relationship between length changes in individual constituents (cardiomyocytes) and their sensitivity to Ca ions. As the Frank-Starling Law is a vital event for the healthy heart, it is of utmost importance to understand its mechanical basis in order to optimize and organize therapeutic strategies to rescue the failing human heart. The present review is a historic perspective on cardiac muscle function. We 'revive' a century of scientific research on the heart's fundamental protein constituents (contractile proteins), to their assemblies in the muscle (the sarcomeres), culminating in a thorough overview of the several synergistically events that compose the Frank-Starling mechanism. It is the authors' personal beliefs that much can be gained by understanding the Frank-Starling relationship at the cellular and whole organ level, so that we can finally, in this century, tackle the pathophysiologic mechanisms underlying heart failure. [ABSTRACT FROM AUTHOR]

The mechanical events of the cardiac cycle provide the circulation with normal cardiac output and blood pressure. This requires an appropriate venous return, regulation of outflow resistance, a normal myocardial contractile state and heart rate control, together with an adequate supply of oxygenated blood via the coronary circulation. Other neural influences contribute to cardiac regulation, including natriuretic peptides and the renin–angiotensin system. The atria and ventricles are richly supplied with adrenergic nerves that may augment cardiac function, particularly with increased cardiac output during exercise. Inhibitory vagal fibres are largely confined to the sinus and atrioventricular nodes. Exercise causes increased sympathetic outflow, with a decrease in peripheral vascular resistance, and increased cardiac output, heart rate, systolic blood pressure and venous return. Regular rhythmic exercise has a training effect, which enhances cardiac performance. This is important for the maintenance of many aspects of cardiovascular health. [ABSTRACT FROM AUTHOR]

Objectives To evaluate the effects of dexmedetomidine (DEX) on changes in pulse pressure variation (PPV) induced by hemorrhage followed by volume replacement (VR) during isoflurane (ISO) anesthesia. Design Prospective, randomized, crossover study. Setting Research laboratory at a veterinary teaching hospital. Animals Eight adult dogs. Interventions Anesthesia was maintained with 1.3 times the minimum alveolar concentration (MAC) of ISO alone or ISO with DEX (ISO-DEX, 1.6 μg/kg [bolus], followed by 2 μg/kg/h). Atropine was administered 30 minutes prior to hemorrhage in the ISO-DEX treatment. Ventilation was controlled (tidal volume of 12 mL/kg, positive end-expiratory pressure of 7 cm H2O, respiratory rate of 16-20/min) under neuromuscular blockade. After recording baseline data, progressive withdrawal of 10%, 20%, and 30% of blood volume (HV10, HV20, and HV30, respectively [measurements during hemorrhage, indicating x% of blood volume removed]) was followed by VR with autologous blood. Measurements and Main Results In 4 of 8 ISO dogs, hemorrhage decreased mean arterial pressure (MAP) < 60 mm Hg. Based on mean arterial pressure after hemorrhage, dogs were assigned to hypotensive (HG) and normotensive (NG) groups post hoc. During ISO, stroke index and cardiac index decreased with hemorrhage ( P < 0.05), while VR normalized or increased these variables. The PPV (%, mean [range]) was increased by hemorrhage from 7 (5-9) to 20 (12-27) and 27 (17-40) at HV20 and HV30, respectively, only in ISO dogs in the HG; PPV returned to baseline after VR. Dexmedetomidine caused increases in systemic vascular resistance (in dogs in HG and NG), and prevented the increase in PPV with hemorrhage. Conclusions During ISO anesthesia, PPV increases in individuals prone to developing hypotension from hypovolemia. Because DEX prevents the increase in PPV associated with hypovolemia, PPV should not be used to guide VR in dogs that have been given DEX. [ABSTRACT FROM AUTHOR]

Abstract: Haemorrhagic and severe hypovolaemic shock can be rapidly fatal unless identified and resuscitated quickly. Monitoring of haemodynamic and cellular end points is crucial in guiding treatment and improving outcomes. This review therefore focuses on the pathophysiology of hypovolaemic shock, volume resuscitation, haemostasis and approaches to management. Fluid resuscitation saves lives but considerable debate remains regarding the ideal fluid type and strategy to use. Blood transfusion is also a critical therapy in the shocked, bleeding patient with a lower threshold for transfusion being appropriate in the elderly patient with less physiological reserve. Reversal of anticoagulant medications and the administration of coagulation products should support both fluid and red cell therapy to counteract the multi-factorial coagulopathy that can accompany severe trauma, haemorrhage and shock. The aim is to stabilize the patient such that any interventional strategies (both percutaneous and surgical) can be considered for uncontrolled bleeding. [Copyright &y& Elsevier]

Throughout its lifetime the heart is buffeted continuously by dynamic mechanical forces resulting from contraction of the heart muscle itself and fluctuations in haemodynamic load and pressure. These forces are in flux on a beat-by-beat basis, resulting from changes in posture, physical activity or emotional state, and over longer timescales due to altered physiology (e.g. pregnancy) or as a consequence of ageing or disease (e.g. hypertension). It has been known for over a century of the heart's ability to sense differences in haemodynamic load and adjust contractile force accordingly (Frank, Z. biology, 1895, 32, 370-447; Anrep, J. Physiol., 1912, 45 (5), 307-317; Patterson and Starling, J. Physiol., 1914, 48 (5), 357-79; Starling, The law of the heart (Linacre Lecture, given at Cambridge, 1915), 1918). These adaptive behaviours are important for cardiovascular homeostasis, but the mechanism(s) underpinning them are incompletely understood. Here we present evidence that the mechanically-activated ion channel, Piezo, is an important component of the Drosophila heart's ability to adapt to mechanical force. We find Piezo is a sarcoplasmic reticulum (SR)-resident channel and is part of a mechanism that regulates Ca 2+ handling in cardiomyocytes in response to mechanical stress. Our data support a simple model in which Drosophila Piezo transduces mechanical force such as stretch into a Ca 2+ signal, originating from the SR, that modulates cardiomyocyte contraction. We show that Piezo mutant hearts fail to buffer mechanical stress, have altered Ca 2+ handling, become prone to arrhythmias and undergo pathological remodelling., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zechini, Camilleri-Brennan, Walsh, Beaven, Moran, Hartley, Diaz and Denholm.)

Abstract: The mechanical events of the cardiac cycle provide the circulation with normal cardiac output and blood pressure. This requires an appropriate venous return, regulation of outflow resistance, a normal myocardial contractile state, and heart rate control, together with an adequate supply of oxygenated blood via the coronary circulation. Other neural influences contribute to cardiac regulation, including natriuretic peptides, and the renin–angiotensin system. The atria and ventricles are richly supplied with adrenergic nerves that may augment cardiac function, particularly with increased cardiac output during exercise. Inhibitory vagal fibres are largely confined to the sinus and atrioventricular nodes. Exercise causes increased sympathetic outflow, with a decrease in peripheral vascular resistance, and increased cardiac output, heart rate, systolic blood pressure and venous return. Regular rhythmic exercise has a training effect, which enhances cardiac performance. This is important for the maintenance of many aspects of cardiovascular health. [Copyright &y& Elsevier]

Hanft LM, McDonald KS. Sarcomere length dependence of power output is increased after PKA treatment in rat cardiac myocytes. Am J Physiol Heart Circ Physiol 296: H1524-H1531, 2q09. First published February 27, 2009; doi: 10.11 52/ajpheart.00864.2008. The Frank-Starling relationship of the heart yields increased stroke volume with greater end-diastolic volume, and this relationship is steeper after β-adrenergic stimulation. The underlying basis for the Frank-Starling mechanism involves length-dependent changes in both Ca[sup2+] sensitivity of myofibrillar force and power output. In this study, we tested the hypothesis that PKA-induced phosphorylation of myofibrillar proteins would increase the length dependence of myofibrillar power output, which would provide a myofibrillar basis to, in part, explain the steeper Frank-Starling relations after β-adrenenic stimulation. For these experiments, adult rat left ventricles were mechanically disrupted, permeabilized cardiac myocyte preparatkrns were attached between a force transducer and position motor, and the length dependence of loaded shortening and power output were measured before and after treatment with PKA. PKA increased the phosphorylation of myosin binding protein C and cardiac troponin I, as assessed by autoradiography. In terms of myocyte mechanics, PKA decreased the Ca[sup2+] sensitivity of force and increased loaded shortening and power output at all relative loads when the myocyte preparations were at long sarcomere length (-2.30 μm). PKA had less of an effect on loaded shortening and power output at short sarcomere length (-2.0 μm). These changes resulted in a greater length dependence of myocyte power output after PKA treatment; peak normalized power output increased -20% with length before PKA and -40% after PKA. These results suggest that PKA-induced phosphorylation of myofibrillar proteins explains, in part, the steeper ventricular function curves (i.e., Frank-Starling relationship) after β-adrenergic stimulation of the left ventricle. [ABSTRACT FROM AUTHOR]

The present study examined the contribution of myofilament contractile proteins to regional function in guinea pig myocardium. We investigated the effect of stretch on myofilament contractile proteins, Ca2+ sensitivity, and cross-bridge cycling kinetics ( K tr) of force in single skinned cardiomyocytes isolated from the sub-endocardial (ENDO) or sub-epicardial (EPI) layer. As observed in other species, ENDO cells were stiffer, and Ca2+ sensitivity of force at long sarcomere length was higher compared with EPI cells. Maximal K tr was unchanged by stretch, but was higher in EPI cells possibly due to a higher α-MHC content. Submaximal Ca2+-activated K tr increased only in ENDO cells with stretch. Stretch of skinned ENDO muscle strips induced increased phosphorylation in both myosin-binding protein C and myosin light chain 2. We concluded that transmural MHC isoform expression and differential regulatory protein phosphorylation by stretch contributes to regional differences in stretch modulation of activation in guinea pig left ventricle. [ABSTRACT FROM AUTHOR]

Abstract: Myocardial contractile reserve is significantly attenuated in patients with advanced heart failure. The aim of this study was to identify mechanisms of impaired contractile reserve in a large animal model that closely mimics human myocardial failure. Progressive right ventricular hypertrophy and failure were induced by banding the pulmonary artery in kittens. Isometric contractile force was measured in right ventricular trabeculae (n =115) from age-matched Control and Banded feline hearts. Rapid cooling contractures (RCC) were used to determine sarcoplasmic reticulum (SR) Ca2+ load while assessing the ability of changes in rate, adrenergic stimulation and bath Ca2+ to augment contractility. The positive force–frequency relationship and robust pre- and post-receptor adrenergic responses observed in Control trabeculae were closely paralleled by increases in RCC amplitude and the RCC2/RCC1 ratio. Conversely, the severely blunted force–frequency and adrenergic responses in Banded trabeculae were paralleled by an unchanged RCC amplitude and RCC2/RCC1 ratio. Likewise, supraphysiologic levels of bath Ca2+ were associated with severely reduced contractility and RCC amplitude in Banded trabeculae compared to Controls. There were no differences in myofilament Ca2+ sensitivity or length-dependent increases in contractility between Control and Banded trabeculae. There was a significant decrease in SR Ca2+-ATPase pump abundance and phosphorylation of phospholamban and ryanodine receptor in Banded trabeculae compared with Controls. A reduced ability to increase SR Ca2+ load is the primary mechanism of reduced contractile reserve in failing feline myocardium. The similarity of impaired contractile reserve phenomenology in this feline model and transplanted hearts suggests mechanistic relevance to human myocardial failure. [Copyright &y& Elsevier]

Chronic (8 weeks) coronary artery ligation caused marked left-ventricular dysfunction (LVD) in rabbits. The positive inotropic effect observed in vivo with intraventricular injection of saline in sham-operated (control) animals was reversed in rabbits with LVD. In vitro, a step increase in filling pressure from 10 to 15 cmH2O caused an immediate increase, followed by a slow increase, in left-ventricular peak systolic pressure (LVPmax) and cardiac output (CO) over 5–7 min in sham-operated hearts. No significant slow positive inotropic effect was observed in hearts with LVD in response to a standard increase in filling pressure. Progressive increases in filling pressure increased (LVPmax) and CO to a maximum value at 20 cmH2O in control hearts. In the LVD group, progressive increases in filling pressure caused a negative inotropic response and reduced CO. Hearts from the LVD group were significantly dilated compared with control hearts but no significant changes in myocardial compliance were observed in beating or quiescent hearts. These studies reveal an impaired inotropic response to increased ventricular filling in LVD rabbit hearts; this defect included the depression of the slow inotropic response to an increased end-diastolic volume. These changes appear not to be accompanied by altered passive mechanical properties. [ABSTRACT FROM AUTHOR]

In six patients with normal left ventricles and seven post-myocardial infarction patients cardiodynamic changes during tilt and acute nitrate medication were investigated. The conductance catheter was used for on-line registration of left ventricular volumes and a microtip manometer for high-fidelity pressure recordings. We analysed left ventricular end-diastolic volume index (EDVI) ejection fraction (EF), cardiac index (CI), heart rate (HR), end-systolic pressure (ESP and end-diastolic pressure (EDP) in the supine position and 30 s after passive upright tilt. Supine and standing measurements were performed without medication and 2 min after acute nitrate medication (0·8 mg sublingual nitroglycerin).After unloading by upright tilt there was a similar reduction of average EDVI in the control group (−18 ±7 ml.m2) and in the post-infarction group (−21 ±18 mint2). The effect of nitroglycerin on EDVI (−12 ±4 mlm2 control, −7 ±6 ml.m2 post-infarction) was less than the effect of upright tilt. EF in the control group improved by + 8 ±5% (in absolute values) during passive tilt; the combined effect of tilt and nitrate was + 12 ±6% EF (p < 0·05). In the post-infarction group EF did not change significantly during tilt and/or nitrate therapy. In the patients with normal regional ventricular function, CI during tilt was maintained at a constant level. In the post-infarction group the reduction in CI was not significantAlthough the reduction in EDVI was similar in the control and infarction groups, the infarction group did not respond to the cardiodynamic change by increasing EF. The haemodynamic changes during unloading by tilt and acute nitrate medication underline that, when the contractile reserve is reduced, the Frank-Starling mechanism plays an important role in the control of pump function. [ABSTRACT FROM PUBLISHER]

There is evidence that sarcomere length is maximal and changes little during chronic cardiac enlargement, and that the failing heart does not operate on a true descending limb of the Frank-Starling curve. However, increases of ventricular end-diastolic volume over time clearly are important at the geometrical level in maintaining stroke volume.When the preload reserve is fully utilized, afterload mismatch can exist in the steady state to produce operation of the heart on an apparent descending limb of cardiac function, and further afterload mismatch can be produced by pressure loading under these conditions. The treatment of acute experimental heart failure with a mixed vasodilator (nitroprusside) can lead to an increased cardiac output by afterload reduction only when the venous return curve does not shift downward; thus, the threefold larger shift of central blood volume to the periphery in heart failure (compared to normal) counter balances the venodilator action of nitroprusside.Whether or not the inotropic ceiling of failing myocardium can be reached by positive inotropic agents is unclear, but major hemodynamic benefits in heart failure with many potent inotropic drugs are associated with the direct vasodilating properties of these agents.Thus, there appears to be little role for the Frank-Starling mechanism at the sarcomere level, whereas afterload mismatch and its correction are of major importance provided the venous return can be increased. A degree of inotropic reserve also is available, even in the severely failing myocardium, but more research is needed on the potential costs and benefits of marked sustained inotropic stimulation. [ABSTRACT FROM PUBLISHER]

The Frank-Starling-mechanism (FSM) was analyzed in isolated intact and skinned human left ventricular myocardium obtained from 11 heart transplantations (normal donor hearts (NDH), n=8; dilated cardiomyopathy (DCM), n=11). The new technique to utilize muscle strips from normal donor hearts which were actually implanted is described in detail. I) In electrically stimulated left ventricular trabeculae (37°C, oxygenated Krebs-Henseleit solution, supramaximal, electrical stimulation, frequency 1 Hz) force development was analyzed as a function of muscle length (NDH=8; DCM=11). II) In an additional series left ventricular myocardium was demembranized (“skinned”) by Triton-X-100. At different sarcomere lengths and calcium concentrations corresponding to pCa values of 4.3, 5.5, and 8.0 force development was measured (DCM=11; NDH=9). I) Developed force increased up to an optimum as a function of muscle length in intact NDH- and DCM-myocardium. However, the relative increment of developed force after any length step was smaller in DCM than in NDH. Near “Lmax” (muscle length associated with maximum developed force) passive resting tension was considerably elevated in DCM, indicating significantly incresed diastolic stiffness II) In skinned left ventricular DCM- and NDH-myocardium developed force depended on sarcomere length with an optimum near 2.2 μm. However, a reduction of activator calcium concentration from pCa 4.3 to pCa 5.5 produces a smaller percent decline in force at short sarcomere lengths in DCM than it does in NDH. the present study shows that except for diastolic stiffness and a smaller relative force increment after any, length step in DCM the Frank Starling mechanism is still present in isolated human left ventricular DCM-as in NDH-myocardium. The current study does not allow to decide whether in skinned myocardium the smaller percent decline in force after reduction of activator calcium concentrations in DCM is caused by an increased calcium sensitivity at short sarcomere lengths or decreased sensitivity at long sarcomere lengths. [ABSTRACT FROM AUTHOR]

During acute altitude exposure tachycardia increases cardiac output (Q) thus preserving systemic O2 delivery. Within days of acclimatization, however, Q normalizes following an unexplained reduction in stroke volume (SV). To investigate whether the altitude-mediated reduction in plasma volume (PV) and hence central blood volume (CBV) is the underlying mechanism we increased/decreased CBV by means of passive whole body head-down (HDT) and head-up (HUT) tilting in seven lowlanders at sea level (SL) and after 25/26 days of residence at 3454 m. Prior to the experiment on day 26, PV was normalized by infusions of a PV expander. Cardiovascular responses to whole body tilting were monitored by pulse contour analysis. After 25/26 days at 3454 m PV and blood volume decreased by 9 ± 4% and 6 ± 2%, respectively (P < 0.001 for both). SV was reduced compared to SL for each HUT angle (P < 0.0005). However, the expected increase in SV from HUT to HDT persisted and ended in the same plateau as at SL, albeit this was shifted 18 ± 20° toward HDT (P = 0.019). PV expansion restored SV to SL during HUT and to an ∼8% higher level during HDT (P = 0.003). The parallel increase in SV from HUT to HDT at altitude and SL to a similar plateau demonstrates an unchanged dependence of SV on CBV, indicating that the reduced SV during HUT was related to an attenuated CBV for a given tilt angle. Restoration of SV by PV expansion rules out a significant contribution of other mechanisms, supporting that resting SV at altitude becomes reduced due to a hypovolemia.