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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]

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.)