MMP-8 causes leftward shift in end-diastolic pressure-volume relationship and may explain the development of diastolic dysfunction in septic cardiomyopathy.

Septic cardiomyopathy (SCM) with diastolic dysfunction carries a poor prognosis, and the mechanisms underlying the development of diastolic dysfunction remain unclear. Matrix metalloproteinase-8 (MMP-8) is released from neutrophils and degrades collagen I. MMP-8 levels correlate with SCM severity. We scrutinized, for the first time, the direct impact of MMP-8 on cardiac systolic and diastolic functions. Isolated rat hearts were perfused with Krebs-Henseleit solution in a Langendorff setup with computer-controlled filling pressures of both ventricles in an isovolumetric regime. The end-diastolic pressure (EDP) varied periodically between 3 and 20 mmHg. After baseline recordings, MMP-8 (100 µg/mL) was added to the perfusion. Short-axis views of both ventricles were continuously acquired by echocardiography. MMP-8 perfusion resulted in a progressive decline in peak systolic pressures (Psys) in both ventricles, but without significant changes in their end-systolic pressure-area relationships (ESPARs). Counterintuitively, conspicuous leftward shifts of the end-diastolic pressure-area relationships (EDPARs) were observed in both ventricles. The left ventricle (LV) end-diastolic area (EDA) decreased by 32.8 ± 5.7% (P = 0.008) at an EDP of 10.5 ± 0.4 mmHg, when LV Psys dropped by 20%. The decline of Psys was primarily due to the decrease in EDA, and restoring the baseline EDA by increasing EDP recovered 81.33 ± 5.87% of the pressure drop. Collagen I generates tensile (eccentric) stress, and its degradation by MMP-8 causes end-diastolic pressure-volume relationship (EDPVR) leftward shift, resulting in diastolic and systolic dysfunctions. The diastolic dysfunction explains the clinically observed fluid unresponsiveness, whereas the decrease in end-diastolic volume (EDV) diminishes the systolic functions. MMP-8 can explain the development of SCM with diastolic dysfunction.NEW & NOTEWORTHY MMP-8, released from activated neutrophils and macrophages, is markedly elevated in sepsis, correlating with sepsis severity and mortality. MMP-8 targets collagen I of the cardiac ECM and induces diastolic dysfunction with fluid unresponsiveness, associated with decreased EDV, reduced sarcomere length, and diminished systolic function. Unlike other MMPs that predominantly cleave collagen-III and contribute to cardiac dilatation, thereby increasing sarcomere length, MMP-8 leads to a leftward shift in the EDPVR, resulting in diastolic and systolic dysfunctions.

Novel Peripheral Perfusion Dynamics Indices for Detecting and Grading Arterial Stenosis.

PURPOSE: Peripheral artery disease causes severe morbidity, especially in diabetics and the elderly. There is a need for accurate noninvasive detection of peripheral arterial stenosis. The study has tested the hypothesis that arterial stenosis and the associated adaptation of the downstream circulation yield characteristic changes in the leg perfusion dynamics that enable early diagnosis, utilizing impedance plethysmography. METHODS: The arterial perfusion dynamic was derived from impedance plethysmography (IPG). Two degrees of arterial stenosis were emulated by inflating a blood-pressure cuff around the thigh to 45 and 90 mmHg, in healthy volunteers (n = 30). IPG signals were acquired continuously throughout the experiment. Ankle and brachial blood pressures were measured at the beginning of each experiment and at the end of each emulated stenosis phase. RESULTS: Thigh compressions did not affect the pulse-transit time, but prolonged the time to the peak perfusion wave. Segmentation of the perfusion upstroke into two phases, at the time point of maximum acceleration (MAT), revealed that arterial compression prolonged only the initial slow phase duration (SPd). The MAT and SPd were proportional to the emulated stenosis severity and detected the arterial stenosis with high sensitivity (> 93%) and specificity (100%). The SPd increased from 46.4 ± 21.2 ms at baseline to 75.4 ± 38.5 ms and 145 ± 39 ms under 45 mmHg and 90 mmHg compressions (p < 0.001), without affecting the pulse-transit time. CONCLUSIONS: The novel method and indices can identify and grade the emulated arterial stenosis with high accuracy and may assist in differentiating between focal arterial stenosis and widespread arterial hardening.

SleepPPG-Net: A Deep Learning Algorithm for Robust Sleep Staging From Continuous Photoplethysmography.

Sleep staging is an essential component in the diagnosis of sleep disorders and management of sleep health. Sleep is traditionally measured in a clinical setting and requires a labor-intensive labeling process. We hypothesize that it is possible to perform automated robust 4-class sleep staging using the raw photoplethysmography (PPG) time series and modern advances in deep learning (DL). We used two publicly available sleep databases that included raw PPG recordings, totalling 2,374 patients and 23,055 hours of continuous data. We developed SleepPPG-Net, a DL model for 4-class sleep staging from the raw PPG time series. SleepPPG-Net was trained end-to-end and consists of a residual convolutional network for automatic feature extraction and a temporal convolutional network to capture long-range contextual information. We benchmarked the performance of SleepPPG-Net against models based on the best-reported state-of-the-art (SOTA) algorithms. When benchmarked on a held-out test set, SleepPPG-Net obtained a median Cohen's Kappa ( κ) score of 0.75 against 0.69 for the best SOTA approach. SleepPPG-Net showed good generalization performance to an external database, obtaining a κ score of 0.74 after transfer learning. Overall, SleepPPG-Net provides new SOTA performance. In addition, performance is high enough to open the path to the development of wearables that meet the requirements for usage in clinical applications such as the diagnosis and monitoring of obstructive sleep apnea.

The cross-bridge dynamics is determined by two length-independent kinetics: Implications on muscle economy and Frank-Starling Law.

The cellular mechanisms underlying the Frank-Starling Law of the heart and the skeletal muscle force-length relationship are not clear. This study tested the effects of sarcomere length (SL) on the average force per cross-bridge and on the rate of cross-bridge cycling in intact rat cardiac trabeculae (n=9). SL was measured by laser diffraction and controlled with a fast servomotor to produce varying initial SLs. Tetanic contractions were induced by addition of cyclopiazonic acid, to maintain a constant activation. Stress decline and redevelopment in response to identical ramp shortenings, starting at various initial SLs, was analyzed. Both stress decline and redevelopment responses revealed two distinct kinetics: a fast and a slower phase. The duration of the rapid phases (4.2 ± 0.1 msec) was SL-independent. The second slower phase depicted a linear dependence of the rate of stress change on the instantaneous stress level. Identical slopes (70.5 ± 1.6 [1/s], p=0.33) were obtained during ramp shortening at all initial SLs, indicating that the force per cross-bridge and cross-bridge cycling kinetics are length-independent. A decrease in the slope at longer SLs was obtained during stress redevelopment, due to internal shortening. The first phase is attributed to rapid changes in the average force per cross-bridge. The second phase is ascribed to both cross-bridge cycling between its strong and weak conformations and to changes in the number of strong cross-bridges. Cross-bridge cycling kinetics and muscle economy are length-independent and the Frank-Starling Law cannot be attributed to changes in the force per cross-bridge or in the single cross-bridge cycling rates.

Real-time detection, classification, and quantification of apneic episodes using miniature surface motion sensors in rats.

BACKGROUND: Real-time detection and classification of apneic episodes remain significant challenges. This study explores the applicability of a novel method of monitoring the respiratory effort and dynamics for rapid detection and classification of apneic episodes. METHODS: Obstructive apnea (OA) and hypopnea/central apnea (CA) were induced in nine tracheostomized rats, by short-lived airway obstruction and administration of succinylcholine, respectively. Esophageal pressure (EP), EtCO2, arterial O2 saturation (SpO2), heart rate, and blood pressure were monitored. Respiratory dynamics were monitored utilizing three miniature motion sensors placed on the chest and epigastrium. Three indices were derived from these sensors: amplitude of the tidal chest wall displacement (TDi), breath time length (BTL), that included inspiration and rapid expiration phases, and amplitude time integral (ATI), the integral of breath amplitude over time. RESULTS: OA induced a progressive 6.42 ± 3.48-fold increase in EP from baseline, which paralleled a 3.04 ± 1.19-fold increase in TDi (P < 0.0012), a 1.39 ± 0.22-fold increase in BTL (P < 0.0002), and a 3.32 ± 1.40-fold rise in the ATI (P < 0.024). During central hypopneic/apneic episodes, each sensor revealed a gradual decrease in TDi, which culminated in absence of breathing attempts. CONCLUSION: Noninvasive monitoring of chest wall dynamics enables detection and classification of central and obstructive apneic episodes, which tightly correlates with the EP.

Zn/Ga-DFO iron-chelating complex attenuates the inflammatory process in a mouse model of asthma.

BACKGROUND: Redox-active iron, a catalyst in the production of hydroxyl radicals via the Fenton reaction, is one of the key participants in ROS-induced tissue injury and general inflammation. According to our recent findings, an excess of tissue iron is involved in several airway-related pathologies such as nasal polyposis and asthma. OBJECTIVE: To examine the anti-inflammatory properties of a newly developed specific iron-chelating complex, Zn/Ga-DFO, in a mouse model of asthma. MATERIALS AND METHODS: Asthma was induced in BALBc mice by ovalbumin, using aluminum hydroxide as an adjuvant. Mice were divided into four groups: (i) control, (ii) asthmatic and sham-treated, (iii) asthmatic treated with Zn/Ga-DFO [intra-peritoneally (i/p) and intra-nasally (i/n)], and (iv) asthmatic treated with Zn/Ga-DFO, i/n only. Lung histology and cytology were examined. Biochemical analysis of pulmonary levels of ferritin and iron-saturated ferritin was conducted. RESULTS: The amount of neutrophils and eosinophils in bronchoalveolar lavage fluid, goblet cell hyperplasia, mucus secretion, and peri-bronchial edema, showed markedly better values in both asthmatic-treated groups compared to the asthmatic non-treated group. The non-treated asthmatic group showed elevated ferritin levels, while in the two treated groups it returned to baseline levels. Interestingly, i/n-treatment demonstrated a more profound effect alone than in a combination with i/p injections. CONCLUSION: In this mouse model of allergic asthma, Zn/Ga-DFO attenuated allergic airway inflammation. The beneficial effects of treatment were in accord with iron overload abatement in asthmatic lungs by Zn/Ga-DFO. The findings in both cellular and tissue levels supported the existence of a significant anti-inflammatory effect of Zn/Ga-DFO.

Highly sensitive monitoring of chest wall dynamics and acoustics provides diverse valuable information for evaluating ventilation and diagnosing pneumothorax.

Current practice of monitoring lung ventilation in neonatal intensive care units, utilizing endotracheal tube pressure and flow, end-tidal CO2, arterial O2 saturation from pulse oximetry, and hemodynamic indexes, fails to account for asymmetric pathologies and to allow for early detection of deteriorating ventilation. This study investigated the utility of bilateral measurements of chest wall dynamics and sounds, in providing early detection of changes in the mechanics and distribution of lung ventilation. Nine healthy New Zealand rabbits were ventilated at a constant pressure, while miniature accelerometers were attached to each side of the chest. Slowly progressing pneumothorax was induced by injecting 1 ml/min air into the pleural space on either side of the chest. The end of the experiment (tPTX) was defined when arterial O2 saturation from pulse oximetry dropped <90% or when vigorous spontaneous breathing began, since it represents the time of clinical detection using common methods. Consistent and significant changes were observed in 15 of the chest dynamics parameters. The most meaningful temporal changes were noted for features extracted from subsonic dynamics (<10 Hz), e.g., tidal amplitude, energy, and autoregressive poles. Features from the high-frequency band (10-200 Hz), e.g., energy and entropy, exhibited smaller but significant changes. At 70% tPTX, identification of asymmetric ventilation was attained for all animals. Side identification of the pneumothorax was achieved at 50% tPTX, within a 95% confidence interval. Diagnosis was, on average, 34.1 ± 18.8 min before tPTX. In conclusion, bilateral monitoring of the chest dynamics and acoustics provide novel information that is sensitive to asymmetric changes in ventilation, enabling early detection and localization of pneumothorax.

Troponin elevation in severe sepsis and septic shock: the role of left ventricular diastolic dysfunction and right ventricular dilatation*.

OBJECTIVE: Serum troponin concentrations predict mortality in almost every clinical setting they have been examined, including sepsis. However, the causes for troponin elevations in sepsis are poorly understood. We hypothesized that detailed investigation of myocardial dysfunction by echocardiography can provide insight into the possible causes of troponin elevation and its association with mortality in sepsis. DESIGN: Prospective, analytic cohort study. SETTING: Tertiary academic institute. PATIENTS: A cohort of ICU patients with severe sepsis or septic shock. INTERVENTIONS: Advanced echocardiography using global strain, strain-rate imaging and 3D left and right ventricular volume analyses in addition to the standard echocardiography, and concomitant high-sensitivity troponin-T measurement in patients with severe sepsis or septic shock. MEASUREMENTS AND MAIN RESULTS: Two hundred twenty-five echocardiograms and concomitant high-sensitivity troponin-T measurements were performed in a cohort of 106 patients within the first days of severe sepsis or septic shock (2.1 ± 1.4 measurements/patient). Combining echocardiographic and clinical variables, left ventricular diastolic dysfunction defined as increased mitral E-to-strain-rate e'-wave ratio, right ventricular dilatation (increased right ventricular end-systolic volume index), high Acute Physiology and Chronic Health Evaluation-II score, and low glomerular filtration rate best correlated with elevated log-transformed concomitant high-sensitivity troponin-T concentrations (mixed linear model: t = 3.8, 3.3, 2.8, and -2.1 and p = 0.001, 0.0002, 0.006, and 0.007, respectively). Left ventricular systolic dysfunction determined by reduced strain-rate s'-wave or low ejection fraction did not significantly correlate with log(concomitant high-sensitivity troponin-T). Forty-one patients (39%) died in-hospital. Right ventricular end-systolic volume index and left ventricular strain-rate e'-wave predicted in-hospital mortality, independent of Acute Physiology and Chronic Health Evaluation-II score (logistic regression: Wald = 8.4, 6.6, and 9.8 and p = 0.004, 0.010, and 0.001, respectively). Concomitant high-sensitivity troponin-T predicted mortality in univariate analysis (Wald = 8.4; p = 0.004), but not when combined with right ventricular end-systolic volume index and strain-rate e'-wave in the multivariate analysis (Wald = 2.3, 4.6, and 6.2 and p = 0.13, 0.032, and 0.012, respectively). CONCLUSIONS: Left ventricular diastolic dysfunction and right ventricular dilatation are the echocardiographic variables correlating best with concomitant high-sensitivity troponin-T concentrations. Left ventricular diastolic and right ventricular systolic dysfunction seem to explain the association of troponin with mortality in severe sepsis and septic shock.

Transient decrease in PaCO(2) and asymmetric chest wall dynamics in early progressing pneumothorax.

PURPOSE: Diagnosis of pneumothorax (PTX) in newborn infants has been reported as late. To explore diagnostic indices for early detection of progressing PTX, and offer explanations for delayed diagnoses. METHODS: Progressing PTX was created in rabbits (2.3 ± 0.5 kg, n = 7) by injecting 1 ml/min of air into the pleural space. Hemodynamic parameters, tidal volume, EtCO(2), SpO(2), blood gas analyses and chest wall tidal displacements (TDi) on both sides of the chest were recorded. RESULTS: (Mean ± SD): A decrease in SpO(2) below 90 % was detected only after 46.6 ± 11.3 min in six experiments. In contrary to the expected gradual increase of CO(2), there was a prolonged transient decrease of 14.2 ± 4.5 % in EtCO(2) (p < 0.01), and a similar decrease in PaCO(2) (p < 0.025). EtCO(2) returned back to baseline only after 55.2 ± 24.7 min, and continued to rise thereafter. The decrease in CO(2) was a mirror image of the 14.6 ± 5.3 % increase in tidal volume. The analysis of endotracheal flow and pressure dynamics revealed a paradoxical transient increase in the apparent compliance. Significant decrease in mean arterial blood pressure was observed after 46.2 ± 40.1 min. TDi provided the most sensitive and earliest sign of PTX, decreasing on the PTX side after 16.1 ± 7.2 min. The TDi progressively decreased faster and lower on the PTX side, thus enabling detection of asymmetric ventilation. CONCLUSIONS: The counterintuitive transient prolonged decrease in CO(2) without changes in SpO(2) may explain the delay in diagnosis of PTX encountered in the clinical environment. An earlier indication of asymmetrically decreased ventilation on the affected side was achieved by monitoring the TDi.

Early detection of deteriorating ventilation by monitoring bilateral chest wall dynamics in the rabbit.

PURPOSE: Mechanical complications during assisted ventilation can evolve due to worsening lung disease or problems in airway management. These complications affect lung compliance or airway resistance, which in turn affect the chest wall dynamics. The objective of this study was to explore the utility of continuous monitoring of the symmetry and dynamics of chest wall motion in the early detection of complications during mechanical ventilation. METHODS: The local tidal displacement (TDi) values of each side of the chest and epigastrium were measured by three miniature motion sensors in 18 rabbits. The TDi responses to changes in peak inspiratory pressure (n = 7), induction of one-lung intubation (n = 7), and slowly progressing pneumothorax (PTX) (n = 6) were monitored in parallel with conventional respiratory (SpO(2), EtCO(2), pressure and flow) and hemodynamic (HR and BP) indices. PTX was induced by injecting air into the pleural space at a rate of 1 mL/min. RESULTS: A strong correlation (R(2) = 0.99) with a slope close to unity (0.94) was observed between percent change in tidal volume and in TDi. One-lung ventilation was identified by conspicuous asymmetry development between left and right TDis. These indices provided significantly early detection of uneven ventilation during slowly developing PTX (within 12.9 ± 6.6 min of onset, p = 0.02) almost 1 h before the SpO(2) dropped (77.3 ± 27.4 min, p = 0.02). Decreases in TDi of the affected side paralleled the progression of PTX. CONCLUSIONS: Monitoring the local TDi is a sensitive method for detecting changes in tidal volume and enables early detection of developing asymmetric ventilation.

Improved vascular organization enhances functional integration of engineered skeletal muscle grafts.

Severe traumatic events such as burns, and cancer therapy, often involve a significant loss of tissue, requiring surgical reconstruction by means of autologous muscle flaps. The scant availability of quality vascularized flaps and donor site morbidity often limit their use. Engineered vascularized grafts provide an alternative for this need. This work describes a first-time analysis, of the degree of in vitro vascularization and tissue organization, required to enhance the pace and efficacy of vascularized muscle graft integration in vivo. While one-day in vitro was sufficient for graft integration, a three-week culturing period, yielding semiorganized vessel structures and muscle fibers, significantly improved grafting efficacy. Implanted vessel networks were gradually replaced by host vessels, coupled with enhanced perfusion and capillary density. Upregulation of key graft angiogenic factors suggest its active role in promoting the angiogenic response. Transition from satellite cells to mature fibers was indicated by increased gene expression, increased capillary to fiber ratio, and similar morphology to normal muscle. We suggest a "relay" approach in which extended in vitro incubation, enabling the formation of a more structured vascular bed, allows for graft-host angiogenic collaboration that promotes anastomosis and vascular integration. The enhanced angiogenic response supports enhanced muscle regeneration, maturation, and integration.

Adaptive control of cardiac contraction to changes in loading: from theory of sarcomere dynamics to whole-heart function.

The heart accommodates to rapid changes in demands. This review elucidates the adaptive control of cardiac function by loading conditions, and integrates the sarcomeric control of contraction (SCC) with isolated trabeculae and in vivo whole-heart studies. The SCC includes two feedback mechanisms: (1) cooperativity that regulates cross-bridge (XB) recruitment and the force-length relationship, and (2) mechanical feedback, whereby the filament-sliding velocity determines the XB-weakening rate and the force-velocity relationship. An isolated rat trabeculae study tested the suggested mechanisms during sarcomeric lengthening. The observations indicate that lengthening decreases the XB-weakening rate in a velocity-dependent manner, congruent with the suggested hypothesis and in contrast to alternative theories. A whole-heart level study in sheep reveals the existence of a preload-independent linear relationship between the external work (EW) and pressure-time integral during transient vena cava occlusions, for any given afterload, and not just at isovolumic contractions. The slope of this relationship decreases as the afterload increases. These findings highlight the mechanisms underlying the pressure (Frank's phenomenon) and EW (Starling's phenomenon) generation and the roles that the preload and afterload play. The theoretical, isolated fibers and whole-heart studies provide complementary information that strengthens our understanding of cardiac function from the top-down and bottom-up.

A new method for continuous monitoring of chest wall movement to characterize hypoxemic episodes during HFOV.

INTRODUCTION: Monitoring ventilated infants is difficult during high-frequency oscillatory ventilation (HFOV). This study tested the possible causes of hypoxemic episodes using a new method for monitoring chest wall movement during HFOV in newborn infants. METHODS: Three miniature motion sensors were attached to both sides of the chest and to the epigastrium to measure the local tidal displacement (TDi) at each site. A >20% change in TDi was defined as deviation from baseline. RESULTS: Eight premature infants (postmenstrual age 30.6 ± 2.6 weeks) were monitored during 10 sessions (32.6 h) that included 21 hypoxemic events. Three types of such events were recognized: decrease in TDi that preceded hypoxemia (n = 11), simultaneous decrease in TDi and SpO2 (n = 6), and decrease in SpO(2) without changes in TDi (n = 4). In the first group, decreases in TDi were detected 22.4 ± 18.7 min before hypoxemia, and were due to airway obstruction by secretions or decline in lung compliance. The second group resulted from apnea or severe abdominal contractions. In the third group, hypoxia appeared following a decrease in FiO2. CONCLUSIONS: Monitoring TDi may enable early recognition of deteriorating ventilation during HFOV that eventually leads to hypoxemia. In about half of cases, hypoxemia is not due to slowly deteriorating ventilation.

Stretch increases the force by decreasing cross-bridge weakening rate in the rat cardiac trabeculae.

Stretch increases the force and decreases energy consumption in skeletal muscles. Cardiac muscle response to stretch has been scarcely investigated, and the underlying mechanisms remain elusive. We hypothesized that stretch increases the force by modulating the cross-bridge (XB) cycling rate. Trabeculae (n=10) were isolated from rat right ventricles. Sarcomere length was measured by laser diffraction and controlled by a fast servomotor. The number of strong XBs was assessed by measuring the dynamic stiffness. Ramp stretches at different velocities (V(SL) ≤ 2.17 µm/s) and onset times were imposed on sarcomeric isometric contractions. Stretches yielded identical increase in the stress and stiffness, implying that stretch increases force by increasing the number of XBs. A unique linear relationship was observed between the instantaneous normalized stress and stiffness for all the stretch velocities (1.01 ± 0.15, R(2)=0.98 ± 0.04), suggesting that the force per XB is constant for all stretch velocities. The increase in the stress during stretch normalized by the instantaneous isometric stress was denoted as the normalized stress enhancement (σ(E)). The normalized stiffness enhancement (K(E)) was defined accordingly. The rates of σ(E) and K(E) development depended linearly on the stretch velocity (7.06 ± 1.03 and 6.57 ± 1.17 µm(-1), respectively). Moreover, it was independent of the stretch onset time, indicating that it is not dominated by XB recruitment processes, since the number of available XBs and XB recruitment vary with time during the twitch. These observations strongly suggest that stretch decreases the rate of strong XB turnover to the weak conformation in a velocity-dependent manner.

Theory of cardiac sarcomere contraction and the adaptive control of cardiac function to changes in demands.

This chapter explores the adaptive control of cardiac function by the loading conditions and relates the observed phenomena to our theory of the sarcomeric control of contraction. Our theory includes two feedback mechanisms: cooperativity-regulated cross-bridge recruitment and energy consumption, and mechanical feedback that determines the interplay between the external work and the force-time integral. The latter also suggests that cardiac efficiency is load independent. This paper explores the regulation of cardiac function by loading conditions, and the role of afterload in adult sheep in situ (n=8). Different afterloads were imposed by partial aortic occlusions. Transient inferior vena cava occlusions (IVCOs) were pre-formed at each steady afterload. A novel, highly linear relationship was found between the external work and pressure-time integral during each transient IVCO at constant afterload. Of interest, the slope of this relationship was afterload-dependent also during fast transient changes in the afterload. These observations are congruent with the suggested adaptive sarcomeric control of contraction, and may provide a powerful tool for quantifying cardiac function.

The external work-pressure time integral relationships and the afterload dependence of Frank-Starling mechanism.

The mechanisms underlying the Frank-Starling Law of the heart are elusive and the prevalent notion suggests that it is afterload independent. However, isolated fiber studies reveal that the afterload determines cardiac function through cross-bridge dependent mechanisms. The study explores the roles of the afterload, in situ. The LV was exposed by left-thoracotomy in adult sheep (72.6+/-8.2 kg, n=8). Pressure transducers were inserted into the LV and aorta, a flowmeter was placed around the aortic root, and the LV volume was assessed by sonocrystals. Occluders around the aorta and the inferior vena cava enabled control of the afterload and preload. Different afterloads were imposed by partial aortic occlusions. Transient inferior vena cava occlusions (IVCOs) were preformed whenever the afterload was steady. A highly linear relationship was found between the external work (EW) and pressure time integral (PTI) (R(2)=0.98+/-0.01) during each transient IVCO (n=48). The slope of the EW-PTI relationship (WPTiR) was preload independent since, for any given afterload, the EW and PTI lay on a straight line. Interestingly, the slope of the WPTiR was afterload dependant: The slope was 33.3+/-4.1 mJ/mmHg.s at baselines and decreased by 1.0+/-0.50 mJ/mmHg.s with every 1 mmHg.min/L increase in the peripheral resistance. A unique WPTiR was obtained during both the occlusion and release phases of each IVCO, while two distinct EW-preload or PTI-preload relationships were observed. The novel WPTiR ties the Frank (pressure development) and Starling (EW production) phenomena together. The dependence of the WPTiR on the afterload highlights the adaptive control of the Frank-Starling mechanisms to changes in the afterload.

The role of Ca2+ in coupling cardiac metabolism with regulation of contraction: in silico modeling.

The heart adapts the rate of mitochondrial ATP production to energy demand without noticeable changes in the concentration of ATP, ADP and Pi, even for large transitions between different workloads. We suggest that the changes in demand modulate the cytosolic Ca2+ concentration that changes mitochondrial Ca2+ to regulate ATP production. Thus, the rate of ATP production by the mitochondria is coupled to the rate of ATP consumption by the sarcomere cross-bridges (XBs). An integrated model was developed to couple cardiac metabolism and mitochondrial ATP production with the regulation of Ca2+ transient and ATP consumption by the sarcomere. The model includes two interrelated systems that run simultaneously utilizing two different integration steps: (1) The faster system describes the control of excitation contraction coupling with fast cytosolic Ca2+ transients, twitch mechanical contractions, and associated fluctuations in the mitochondrial Ca2+. (2) A slower system simulates the metabolic system, which consists of three different compartments: blood, cytosol, and mitochondria. The basic elements of the model are dynamic mass balances in the different compartments. Cytosolic Ca2+ handling is determined by four organelles: sarcolemmal Ca2+ influx and efflux; sarcoplasmic reticulum (SR) Ca2+ release and sequestration (SR); binding and dissociation from sarcomeric regulatory troponin complexes; and mitochondrial Ca2+ flows. Mitochondrial Ca2+ flows are determined by the Ca2+ uniporter and the mitochondrial Na+Ca2+ exchanger. The cytosolic Ca2+ determines the rate of ATP consumption by the sarcomere. Ca2+ binding to troponin regulates the rate of XBs recruitment and force development. The mitochondrial Ca2+ concentration determines the pyruvate dehydrogenase activity and the rate of ATP production by the F(1)-F(0) ATPase. The workload modulates the cytosolic Ca2+ concentration through feedback loops. The preload and afterload affect the number of strong XBs. The number of strong XBs determines the affinity of troponin for Ca2+, which alters the cytosolic Ca2+ transient. Model simulations quantify the role of Ca2+ in simultaneously controlling the power of contraction and the rate of ATP production. It explains the established empirical observation that significant changes in the metabolic fluxes can occur without significant changes in the key nucleotide (ATP and ADP) concentrations. Quantitative investigations of the mechanisms underlying the cardiac control of biochemical to mechanical energy conversion may lead to novel therapeutic modalities for the ischemic and failing myocardium.