Evaluation of cardiovascular risks of spaceflight does not support the NASA bioastronautics critical path roadmap.

INTRODUCTION: Occurrence of serious cardiac dysrhythmias and diminished cardiac and vascular function are the primary cardiovascular risks of spaceflight identified in the 2005 NASA Bioastronautics Critical Path Roadmap. METHODS: A review of the literature was conducted on experimental results and observational data obtained from spaceflight and relevant ground simulation studies that addressed occurrence of cardiac dysrhythmias, cardiac contractile and vascular function, manifestation of asymptomatic cardiovascular disease, orthostatic intolerance, and response to exercise stress. RESULTS: Based on data from astronauts who have flown in space, there is no compelling experimental evidence to support significant occurrence of cardiac dysrhythmias, manifestation of asymptomatic cardiovascular disease, or reduction in myocardial contractile function. Although there are post-spaceflight data that demonstrate lower peripheral resistance in astronauts who become presyncopal compared with non-presyncopal astronauts, it is not clear that these differences are the result of decreased vascular function. However, the evidence of postflight orthostatic intolerance and reduced exercise capacity is well substantiated by both spaceflight and ground experiments. Although attenuation of baroreflex function(s) may contribute to postflight orthostatic instability, a primary mechanism of orthostatic intolerance and reduced exercise capacity is reduced end-diastolic and stroke volume associated with lower blood volumes and consequent cardiac remodeling. CONCLUSION: Data from the literature on the current population of astronauts support the notion that the primary cardiovascular risks of spaceflight are compromised hemodynamic responses to central hypovolemia resulting in reduced orthostatic tolerance and exercise capacity rather than occurrence of cardiac dysrhythmias, reduced cardiac contractile and vascular function, or manifestation of asymptomatic cardiovascular disease. These observations warrant a critical review and revision of the 2005 Bioastronautics Critical Path Roadmap.

The lung in space.

The lung is exquisitely sensitive to gravity, which induces gradients in ventilation, blood flow, and gas exchange. Studies of lungs in microgravity provide a means of elucidating the effects of gravity. They suggest a mechanism by which gravity serves to match ventilation to perfusion, making for a more efficient lung than anticipated. Despite predictions, lungs do not become edematous, and there is no disruption to, gas exchange in microgravity. Sleep disturbances in microgravity are not a result of respiratory-related events; obstructive sleep apnea is caused principally by the gravitational effects on the upper airways. In microgravity, lungs may be at greater risk to the effects of inhaled aerosols.

Simulated microgravity induces microvolt T wave alternans.

BACKGROUND: There are numerous anecdotal reports of ventricular arrhythmias during spaceflight; however, it is not known whether spaceflight or microgravity systematically increases the risk of cardiac dysrhythmias. Microvolt T wave alternans (MTWA) testing compares favorably with other noninvasive risk stratifiers and invasive electrophysiological testing in patients as a predictor of sudden cardiac death, ventricular tachycardia, and ventricular fibrillation. We hypothesized that simulated microgravity leads to an increase in MTWA. METHODS: Twenty-four healthy male subjects underwent 9 to 16 days of head-down tilt bed rest (HDTB). MTWA was measured before and after the bed rest period during bicycle exercise stress. For the purposes of this study, we defined MTWA outcome to be positive if sustained MTWA was present with an onset heart rate

Consequences of cardiovascular adaptation to spaceflight: implications for the use of pharmacological countermeasures.

There is little evidence obtained from space flight to support the notion that occurrence of cardiac dysrhythmias, impaired cardiac and vascular function, and manifestation of asymptomatic cardiovascular disease represent serious risks during space flight. Therefore, the development of orthostatic hypotension and instability immediately after return from spaceflight probably reflect the most significant operational risks associated with the cardiovascular system of astronauts. Significant reductions in stroke volume and lower reserve for increasing peripheral vascular resistance contribute to ineffective maintenance of systemic arterial blood pressure during standing after spaceflight despite compensatory elevations in heart rate. The primary mechanism underlying reduced stroke volume appears to be a reduction in preload associated with less circulating blood volume while inadequate peripheral vasoconstriction may be caused partly by hyporeactivity of receptors that control arterial smooth muscle function. A focus for development of future countermeasures for hemodynamic responses to central hypovolemia includes the potential application of pharmacological agents that specifically target and restore blood volume (e.g., fludrocortisone, electrolyte-containing beverages) and reserve for vasoconstriction (e.g., midodrine, vasopressin). Based on systematic evaluations, acute physical exercise designed to elicit maximal effort or inspiratory resistance have shown promise as successful countermeasures that provide protection against development of orthostatic hypotension and intolerance without potential risks and side effects associated with specific pharmacological interventions.

The negative regulation of red cell mass by neocytolysis: physiologic and pathophysiologic manifestations.

We have uncovered a physiologic process which negatively regulates the red cell mass by selectively hemolyzing young circulating red blood cells. This allows fine control of the number of circulating red blood cells under steady-state conditions and relatively rapid adaptation to new environments. Neocytolysis is initiated by a fall in erythropoietin levels, so this hormone remains the major regulator of red cell mass both with anemia and with red cell excess. Physiologic situations in which there is increased neocytolysis include the emergence of newborns from the hypoxic uterine environment and the descent of polycythemic high-altitude dwellers to sea level. The process first became apparent while investigating the mechanism of the anemia that invariably occurs after spaceflight. Astronauts experience acute central plethora on entering microgravity resulting in erythropoietin suppression and neocytolysis, but the reduced blood volume and red cell mass become suddenly maladaptive on re-entry to earth's gravity. The pathologic erythropoietin deficiency of renal disease precipitates neocytolysis, which explains the prolongation of red cell survival consistently resulting from erythropoietin therapy and points to optimally efficient erythropoietin dosing schedules. Implications should extend to a number of other physiologic and pathologic situations including polycythemias, hemolytic anemias, 'blood-doping' by elite athletes, and oxygen therapy. It is likely that erythropoietin influences endothelial cells which in turn signal reticuloendothelial phagocytes to destroy or permit the survival of young red cells marked by surface molecules. Ongoing studies to identify the molecular targets and cytokine intermediaries should facilitate detection, dissection and eventual therapeutic manipulation of the process.

Hindlimb unloading and female gender attenuate baroreflex-mediated sympathoexcitation.

Exposure to a period of microgravity or bed rest produces several physiological adaptations. These changes, which include an increased incidence of orthostatic intolerance, have an impact when people return to a 1G environment or resume an upright posture. Compared with males, females appear more susceptible to orthostatic intolerance after exposure to real or simulated microgravity. Decreased arterial baroreflex compensation may contribute to orthostatic intolerance. We hypothesized that female rats would exhibit a greater reduction in arterial baroreflex function after hindlimb unloading (HU) compared with male rats. Mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were recorded in conscious animals after 13-15 days of HU. Baseline HR was elevated in female rats, and HU increased HR in both genders. Consistent with previous results in males, baroreflex-mediated activation of RSNA was blunted by HU in both genders. Maximum RSNA in response to decreases in MAP was reduced by HU (male control 513 +/- 42%, n = 11; male HU 346 +/- 38%, n = 13; female control 359 +/- 44%, n = 10; female HU 260 +/- 43%, n = 10). Maximum baroreflex increase in RSNA was lower in females compared with males in both control and HU rats. Both female gender and HU attenuated baroreflex-mediated increases in sympathetic activity. The combined effects of HU and gender resulted in reduced baroreflex sympathetic reserve in females compared with males and could contribute to the greater incidence of orthostatic intolerance in females after exposure to spaceflight or bed rest.

Cardiac health for astronauts: current selection standards and their limitations.

INTRODUCTION: The screening tests for coronary artery disease (CAD) for applicants and the active astronaut corps are similar to those performed in the 1960s. Due to the limited treatment and return capabilities of most space vehicles, an in-flight cardiac event would result in mission failure. Improved CAD screening of astronauts is, therefore, paramount to long-duration mission success. METHODS: Literature review was performed to compare active and retired astronaut populations to other asymptomatic low-risk cohorts. All populations were examined to determine the incidence and prevalence of CAD. Framingham risk scores were calculated in NASA's active and retired astronaut corps and compared with age- and gender-matched controls. RESULTS: The current standards used for astronaut selection have been successful in creating a cohort that has less risk than their age- and gender-matched counterparts from the general population. However, the existing astronaut cardiovascular screening and selection tests do not adequately rule out CAD for long-duration missions, and, therefore, a "significant" risk of cardiac event remains, especially as we look toward Exploration Class missions. CONCLUSIONS: The current astronaut selection and retention standards may not adequately prevent cardiac events from occurring with the longer duration flights. Future research should be directed toward increasing the primary and secondary prevention of CAD in the astronaut cohort. In the meantime, the space program should evaluate the use of more aggressive terrestrial screening tools. It is important not to remove all older, experienced pilots from spaceflight crews unless overt or predictable pathology has been clearly identified.

Regulation of capillary hydraulic conductivity in response to an acute change in shear.

The effects of mechanical perturbations (shear stress, pressure) on microvascular permeability primarily have been examined in micropipette-cannulated vessels or in endothelial monolayers in vitro. The objective of this study is to determine whether acute changes in blood flow shear stress might influence measurements of hydraulic conductivity (L(p)) in autoperfused microvessels in vivo. Rat mesenteric microvessels were observed via intravital microscopy. Occlusion of a third-order arteriole with a micropipette was used to divert and increase flow through a nonoccluded capillary or fourth-order arteriolar branch. Transvascular fluid filtration rate in the branching vessel was measured with a Landis technique. Flow (shear)-induced increases in L(p) disappeared within 20-30 s of the removal of the shear and could be eliminated with nitric oxide synthase inhibition. The shear-induced increase in L(p) was greater in capillaries compared with terminal arterioles. An acute change in shear may regulate L(p) by a nitric oxide-dependent mechanism that displays heterogeneity within a microvascular network.

Airway closure in microgravity.

Recent single breath washout (SBW) studies in microgravity and on the ground have suggested an important effect of airway closure on gas mixing in the human lung, reflected particularly in the phase III slope of vital capacity SBW and bolus tests. In order to explore this effect, we designed a SBW in which subjects inspired 2-l from residual volume (RV) starting with a 150 ml bolus of He and SF6. In an attempt to vary the pattern of airways closure configuration before the test, the experiments were conducted in 1G and in microgravity during parabolic flight allowing the pre-test expiration to RV to be either in microgravity or at 1.8 G, with the actual test gas inhalation performed entirely in microgravity. Contrary to our expectations, the measured phase III slope and phase IV height and volume obtained from seven subjects in microgravity were essentially identical irrespective of the gravity level during the pre-test expiration to RV. The results suggest that airway closure configuration at RV before the test inspiration has no apparent impact on phases III and IV generation.

Effects of the JNK inhibitor anthra[1,9-cd]pyrazol-6(2H)-one (SP-600125) on soluble guanylyl cyclase alpha1 gene regulation and cGMP synthesis.

The decreased expression of the nitric oxide (NO) receptor, soluble guanylyl cyclase (sGC), occurs in response to multiple stimuli in vivo and in cell culture and correlates with various disease states such as hypertension, inflammation, and neurodegenerative disorders. The ability to understand and modulate sGC expression and cGMP levels in any of these conditions could be a valuable therapeutic tool. We demonstrate herein that the c-Jun NH2-terminal kinase JNK II inhibitor anthra[1,9-cd]pyrazol-6(2H)-one (SP-600125) completely blocked the decreased expression of sGCalpha1-subunit mRNA by nerve growth factor (NGF) in PC12 cells. Inhibitors of the ERK and p38 MAPK pathways, PD-98059 and SB-203580, had no effect. SP-600125 also inhibited the NGF-mediated decrease in the expression of sGCalpha1 protein as well as sGC activity in PC12 cells. Other experiments revealed that decreased sGCalpha1 mRNA expression through a cAMP-mediated pathway, using forskolin, was not blocked by SP-600125. We also demonstrate that TNF-alpha/IL-1beta stimulation of rat fetal lung (RFL-6) fibroblast cells resulted in sGCalpha1 mRNA inhibition, which was blocked by SP-600125. Expression of a constitutively active JNKK2-JNK1 fusion protein in RFL-6 cells caused endogenous sGCalpha1 mRNA levels to decrease, while a constitutively active ERK2 protein had no effect. Collectively, these data demonstrate that SP-600125 may influence the intracellular levels of the sGCalpha1-subunit in certain cell types and may implicate a role for c-Jun kinase in the regulation of sGCalpha1 expression.

Aerosols in the study of convective acinar mixing.

Convective mixing (CM) refers to the different transport mechanisms except Brownian diffusion that irreversibly transfer inspired air into resident air and can be studied using aerosol bolus inhalations. This paper provides a review of the present understanding of how each of these mechanisms contributes to CM. Original data of the combined effect of stretch and fold and gravitational sedimentation on CM are also presented. Boli of 0.5 microm-diameter particles were inhaled at penetration volumes (V(p)) of 300 and 1200 ml in eight subjects. Inspiration was followed by a 10-s breath hold, during which small flow reversals (FR) were imposed, and expiration. There was no physiologically significant dependence in dispersion and deposition with increasing FR. The results were qualitatively similar to those obtained in a previous study in microgravity in which it was speculated that the phenomenon of stretch and fold occurred during the first breathing cycle without the need of any subsequent FR.

Automated mitral annular tracking: a novel method for evaluating mitral annular motion using two-dimensional echocardiography.

We developed an automated mitral annular tracking method based on a digital processing of high frame rate cineloop images of 2-dimensional echocardiography. In this study, its feasibility and accuracy was validated in 11 healthy volunteers and 16 patients with left ventricular (LV) dysfunction. The mitral annular excursion measured by automated mitral annular tracking agreed well with that measured by 3-dimensional echocardiography and correlated with LV ejection fraction. The longitudinal mitral annular excursion was reduced whereas the radial one was preserved for patients with LV dysfunction compared with control subjects. The novel automated mitral annular tracking method is clinically feasible and has potential capability to quantify the comprehensive mitral annular motion for evaluating LV function in a clinical setting.

Mechanism of spaceflight-induced changes in left ventricular mass.

Decrements in left ventricular (LV) mass observed after microgravity exposure have been previously postulated to be a central component of spaceflight-induced cardiovascular deconditioning. In this study, echocardiographic measurements of LV mass in astronauts demonstrated a comparative 9.1% reduction in postflight LV mass that returned to preflight values by the third day of recovery. A ground-based study in normal subjects determined that these pre- to postflight LV mass changes could be reproduced by simple dehydration. Reductions in LV mass observed immediately after spaceflight may be secondary to simple physiologic fluid exchanges.

Dynamic autoregulation of cutaneous circulation: differential control in glabrous versus nonglabrous skin.

The purpose of this project was to test the hypothesis that, independent of neural control, glabrous and nonglabrous cutaneous vasculature is capable of autoregulating blood flow. In 10 subjects, spectral and transfer function analyses of arterial pressure and skin blood flow (laser-Doppler flowmetry) from glabrous (palm) and nonglabrous (forearm) regions were performed under three conditions: baseline, ganglionic blockade via intravenous trimethaphan administration, and trimethaphan plus oscillatory lower body negative pressure (LBNP; -5 to -10 mmHg) from 0.05 to 0.07 Hz. Oscillatory LBNP was applied to regenerate mean arterial pressure variability that was abolished by ganglionic blockade. Ganglionic blockade was verified by an absence of a heart rate response to a Valsalva maneuver. Spectral power and transfer function gain between blood pressure and skin blood flow were calculated in this oscillatory frequency range (0.05-0.07 Hz). Within this frequency range, ganglionic blockade significantly decreased spectral power of blood flow in both the forearm and palm, whereas regeneration of arterial blood pressure oscillations significantly increased spectral power of forearm blood flow but not palm blood flow. During oscillatory LBNP, transfer function gain between blood pressure and skin blood flow was significantly elevated at the forearm (0.28 +/- 0.03 to 0.53 +/- 0.02 flux units/mmHg; P < 0.05) but was reduced at the palm (4.7 +/- 0.5 to 1.2 +/- 0.1 flux units/mmHg; P < 0.05). These data show that independent of neural control of blood flow, glabrous skin has the ability to buffer blood pressure oscillations and demonstrates a degree of dynamic autoregulation. Conversely, these data suggest that nonglabrous skin has diminished dynamic autoregulatory capabilities.

Intracranial pressure dynamics assessed by noninvasive ultrasound during 30 days of bed rest.

INTRODUCTION: Intracranial pressure (ICP) may be an important contributor to symptoms of space adaptation syndrome during the initial days of microgravity exposure. The temporary nature of these symptoms suggests that some physiologic adaptation or compensation occurs. Fluid shifts similar to those in microgravity can be simulated on Earth using head-down tilt (HDT) bed rest. This study was performed to calibrate a new noninvasive ICP instrument and to investigate ICP adaptation during 30 d of HDT bed rest. METHODS: A noninvasive ultrasound technique that measures small skull expansions with fluctuations in ICP was used to measure cranial oscillations before and near the end of 30-d HDT bed rest in eight healthy, male volunteers. Pulse phase-locked loop (PPLL) output voltage and arterial BP were continuously monitored and correlated. RESULTS: The amplitude of intracranial distance pulsation decreased during 30-d bed rest. Prior to bed rest, the PPLL amplitude was 25 +/- 9 mV and this amplitude was reduced by 60% to 9 +/- 4 mV (a value consistent with that of upright posture) at the end of HDT bed rest (p = 0.01). DISCUSSION: PPLL measurements of skull pulsations are acutely posture dependent, being significantly higher in supine and HDT as compared with upright posture. A cephalad fluid shift is probably the responsible mechanism. Our results indicate that there are adaptations to intracranial pooling of blood and tissue fluid during bed rest that reduce skull pulsation amplitudes to values similar to those obtained in normal upright posture. Detailed studies of the time course of cranial vessel and bone adaptations may provide insights into the potential adaptative mechanisms.

Cerebral hypoperfusion precedes nausea during centrifugation.

INTRODUCTION: Nausea and motion sickness are important operational concerns for aviators and astronauts. Understanding the underlying mechanisms associated with motion sickness may lead to new treatments. The goal of this work was to determine if changes in cerebral blood flow precede the development of nausea in subjects susceptible to motion sickness. METHODS: Cerebral flow velocity in the middle cerebral artery (transcranial Doppler), BP, and end-tidal CO2 were measured while subjects were rotated on a centrifuge (250 degrees x s(-1)). Following 5 min of rotation, subjects were translated 51.5 cm off-center, creating a +1 Gx centripetal acceleration in the nasal-occipital plane. RESULTS: There were 10 subjects who completed the protocol without symptoms while 5 developed nausea (4 while off-center and 1 while rotating on-center). Prior to nausea, subjects had significant increases in BP (+13 +/- 3 mmHg, p < 0.05) and cerebrovascular resistance (+46 +/- 17%, p < 0.05) and decreases in cerebral flow velocity both in the second (-13 +/- 4%) and last minute (-22 +/- 5%) before symptoms (p < 0.05). In comparison, subjects resistant to motion sickness demonstrated no change in BP or cerebrovascular resistance in the last minute of off-center rotation and only a 7 +/- 2% decrease in cerebral flow velocity. All subjects had significant hypocapnia (-3.8 +/- 0.4 mmHg, p < 0.05); however, this hypocapnia could not fully explain the cerebral hypoperfusion associated with the development of nausea. CONCLUSIONS: These data indicate that reductions in cerebral blood flow precede the development of nausea. Further work is necessary to determine what role cerebral hypoperfusion plays in motion sickness and whether cerebral hypoperfusion can be used to predict the development of nausea in susceptible individuals.

Simulated microgravity produces attenuated baroreflex-mediated pressor, chronotropic, and inotropic responses in mice.

Whether myocardial contractile impairment contributes to orthostatic intolerance (OI) is controversial. Accordingly, we used transient bilateral carotid occlusion (TBCO) to compare the in vivo pressor, chronotropic, and inotropic responses (parts 1 and 2) to open-loop selective carotid baroreceptor unloading in anesthetized mice. In part 3, in vitro myocyte responses to isoproterenol in mice exposed to hindlimb unweighting (HLU) for approximately 2 wk were determined. Heart rate (HR) and mean arterial pressure (MAP) responses to TBCO were measured. In control mice, TBCO increased HR (15 +/- 2 beats/min, P < 0.05) and MAP (17 +/- 2 mmHg, P < 0.05). These responses were markedly potentiated in denervated control (DC) mice, in which the aortic depressor nerve and sympathetic trunk were sectioned before measurement. Baroreflex responses to TBCO were eliminated by blockade with hexamethonium bromide (10 microg/kg). In HLU (denervated) mice, HR and MAP responses were reduced approximately 70% compared with DC mice. In part 2, myocardial contractile responses to TBCO were measured with a left ventricular micromanometer-conductance catheter. TBCO in DC mice increased the slope of the end-systolic pressure-volume relation (end-systolic elastance) by 86 +/- 13%. This inotropic response was attenuated (14 +/- 10%, P < 0.005) after HLU. In part 3, contractile responses to isoproterenol were impaired in myocytes isolated from HLU mice. In conclusion, selective carotid baroreceptor unloading stimulates HR, blood pressure, and myocardial contractility, and HLU attenuates each response. These findings have important implications for the management of OI in astronauts, the elderly, and individuals subjected to prolonged bed rest.

Modeling regulation of cardiac KATP and L-type Ca2+ currents by ATP, ADP, and Mg2+.

Changes in cytosolic free Mg(2+) and adenosine nucleotide phosphates affect cardiac excitability and contractility. To investigate how modulation by Mg(2+), ATP, and ADP of K(ATP) and L-type Ca(2+) channels influences excitation-contraction coupling, we incorporated equations for intracellular ATP and MgADP regulation of the K(ATP) current and MgATP regulation of the L-type Ca(2+) current in an ionic-metabolic model of the canine ventricular myocyte. The new model: 1), quantitatively reproduces a dose-response relationship for the effects of changes in ATP on K(ATP) current, 2), simulates effects of ADP in modulating ATP sensitivity of K(ATP) channel, 3), predicts activation of Ca(2+) current during rapid increase in MgATP, and 4), demonstrates that decreased ATP/ADP ratio with normal total Mg(2+) or increased free Mg(2+) with normal ATP and ADP activate K(ATP) current, shorten action potential, and alter ionic currents and intracellular Ca(2+) signals. The model predictions are in agreement with experimental data measured under normal and a variety of pathological conditions.

Neurovascular responses to mental stress.

The effects of mental stress (MS) on muscle sympathetic nerve activity (MSNA) and limb blood flows have been studied independently in the arm and leg, but they have not been studied collectively. Furthermore, the cardiovascular implications of postmental stress responses have not been thoroughly addressed. The purpose of the current investigation was to comprehensively examine concurrent neural and vascular responses during and after mental stress in both limbs. In Study 1, MSNA, blood flow (plethysmography), mean arterial pressure (MAP) and heart rate (HR) were measured in both the arm and leg in 12 healthy subjects during and after MS (5 min of mental arithmetic). MS significantly increased MAP (Delta15 +/- 3 mmHg; P < 0.01) and HR (Delta19 +/- 3 beats min(-1); P < 0.01), but did not change MSNA in the arm (14 +/- 3 to 16 +/- 3 bursts min(-1); n = 6) or leg (14 +/- 2 to 15 +/- 2 bursts min(-1); n = 8). MS decreased forearm vascular resistance (FVR) by -27 +/- 7% (P < 0.01; n = 8), while calf vascular resistance (CVR) did not change (-6 +/- 5%; n = 11). FVR returned to baseline during recovery, whereas MSNA significantly increased in the arm (21 +/- 3 bursts min(-1); P < 0.01) and leg (19 +/- 3 bursts min(-1); P < 0.03). In Study 2, forearm and calf blood flows were measured in an additional 10 subjects using Doppler ultrasound. MS decreased FVR (-27 +/- 10%; P < 0.02), but did not change CVR (5 +/- 14%) as in Study 1. These findings demonstrate differential vascular control of the arm and leg during MS that is not associated with muscle sympathetic outflow. Additionally, the robust increase in MSNA during recovery may have acute and chronic cardiovascular implications.

Proteolytic N-terminal truncation of cardiac troponin I enhances ventricular diastolic function.

Besides the core structure conserved in all troponin I isoforms, cardiac troponin I (cTnI) has an N-terminal extension that contains phosphorylation sites for protein kinase A under beta-adrenergic regulation. A restricted cleavage of this N-terminal regulatory domain occurs in normal cardiac muscle and is up-regulated during hemodynamic adaptation (Z.-B. Yu, L.-F. Zhang, and J.-P. Jin (2001) J. Biol. Chem. 276, 15753-15760). In the present study, we developed transgenic mice overexpressing the N-terminal truncated cTnI (cTnI-ND) in the heart to examine its biochemical and physiological significance. Ca(2+)-activated actomyosin ATPase activity showed that cTnI-ND myofibrils had lower affinity for Ca(2+) than controls, similar to the effect of isoproterenol treatment. In vivo and isolated working heart experiments revealed that cTnI-ND hearts had a significantly faster rate of relaxation and lower left ventricular end diastolic pressure compared with controls. The higher baseline relaxation rate of cTnI-ND hearts was at a level similar to that of wild type mouse hearts under beta-adrenergic stimulation. The decrease in cardiac output due to lowered preload was significantly smaller for cTnI-ND hearts compared with controls. These findings indicate that removal of the N-terminal extension of cTnI via restricted proteolysis enhances cardiac function by increasing the rate of myocardial relaxation and lowering left ventricular end diastolic pressure to facilitate ventricular filling, thus resulting in better utilization of the Frank-Starling mechanism.