Knowledge and perception of equine ticks and tick-borne diseases of Pennsylvania horse owners and caretakers.

There is limited data on current knowledge of Pennsylvania horse caretakers on tick-borne diseases (TBDs), tick identification, and tick management practices. This study aimed to determine tick knowledge, concern, and management among Pennsylvania equine caretakers using an online survey. Descriptive statistics and one-way ANOVA tests were used to analyze data. The survey received 894 responses (539 completed) from Pennsylvania equine owners and caretakers. The largest proportion of respondents cared for 3-5 horses (31 %), followed by 2 horses (27 %). Veterinarian-confirmed diagnosis rates of two TBDs, Lyme disease and anaplasmosis, were 38 % and 22 %, respectively. Most respondents (39 %) were moderately confident in recognizing Lyme disease, while most (44 %) were not confident at all in recognizing anaplasmosis. Most respondents (69 %) were either extremely or very concerned about their horses contracting any TBDs. Tick bite and TBD prevention methods used by equine caretakers included performing tick checks, using on-animal repellents, and conducting pasture/landscape management. Ten knowledge-based questions were asked, and the mean correct score was 3.97 ± 2.18 out of 10 possible points. There were significant positive associations between higher knowledge scores and previous veterinarian-confirmed equine Lyme disease diagnosis, higher concern level of TBDs, and higher frequency of tick checks. With increased equine TBD prevalence and high levels of horse owner concern about TBD, Extension educators should focus on teaching about TBDs and managing ticks on horses and farms.

[From the right to health to the responsibility for healthy aging: a new foundation for anti-aging medicine in Germany]. / Vom Recht auf Gesundheit zur Pflicht zum gesunden Alter(n): Die Neubegründung der Anti-Aging-Medizin in Deutschland.

This paper explores the problem of dealing with normalisation in public health concepts, using the example of the relaunching of anti-aging-medicine in Germany. The analysis mainly draws upon qualitative analyses of publications of different anti-aging-medicine organisations. The German branch of anti-aging-medicine's new concepts of the nature, the morality and the self-design of aging are delineated. These are the concepts of aging as a medically controllable health risk (nature), the emphasis of the moral duty to responsible personal risk control (morality) and the self-design through individual risk profiles and prevention programmes. The analysis shows that the proposed bio-political programme cannot only be induced from biologically, societally or medically given facts, but that it is - as all public health concepts - a normative concept. It is argued that the normative aspects of public health concepts cannot be avoided but should be explicated and negotiated. This paper therefore concludes with an exploration of what there is to negotiate concerning the German anti-aging-physicians' surprisingly uncontroversial plea for a shift of emphasis from the collective right to health to a new individual duty for health maintenance in old age.

Systematic review of tests to identify the disc, SIJ or facet joint as the source of low back pain.

Clinical practice guidelines state that the tissue source of low back pain cannot be specified in the majority of patients. However, there has been no systematic review of the accuracy of diagnostic tests used to identify the source of low back pain. The aim of this systematic review was therefore to determine the diagnostic accuracy of tests available to clinicians to identify the disc, facet joint or sacroiliac joint (SIJ) as the source of low back pain. MEDLINE, EMBASE and CINAHL were searched up to February 2006 with citation tracking of eligible studies. Eligible studies compared index tests with an appropriate reference test (discography, facet joint or SIJ blocks or medial branch blocks) in patients with low back pain. Positive likelihood ratios (+LR) > 2 or negative likelihood ratios (-LR) < 0.5 were considered informative. Forty-one studies of moderate quality were included; 28 investigated the disc, 8 the facet joint and 7 the SIJ. Various features observed on MRI (high intensity zone, endplate changes and disc degeneration) produced informative +LR (> 2) in the majority of studies increasing the probability of the disc being the low back pain source. However, heterogeneity of the data prevented pooling. +LR ranged from 1.5 to 5.9, 1.6 to 4.0, and 0.6 to 5.9 for high intensity zone, disc degeneration and endplate changes, respectively. Centralisation was the only clinical feature found to increase the likelihood of the disc as the source of pain: +LR = 2.8 (95%CI 1.4-5.3). Absence of degeneration on MRI was the only test found to reduce the likelihood of the disc as the source of pain: -LR = 0.21 (95%CI 0.12-0.35). While single manual tests of the SIJ were uninformative, their use in combination was informative with +LR of 3.2 (95%CI 2.3-4.4) and -LR of 0.29 (95%CI 0.12-0.35). None of the tests for facet joint pain were found to be informative. The results of this review demonstrate that tests do exist that change the probability of the disc or SIJ (but not the facet joint) as the source of low back pain. However, the changes in probability are usually small and at best moderate. The usefulness of these tests in clinical practice, particularly for guiding treatment selection, remains unclear.

Functional assessment of isolated right heart failure by high resolution in-vivo cardiovascular magnetic resonance in mice.

Precise and noninvasive characterization of the development of the cardiac phenotype in murine models of heart failure has been widely demanded in modern cardiovascular research. High-resolution cardiovascular magnetic resonance (CMR) has been proven to be a powerful tool for the accurate and reproducible assessment of LV and RV parameters in healthy mice. Whereas changes in LV parameters in models of heart failure have been thoroughly evaluated, RV dysfunction has not. Purpose of this study was to characterize a model of isolated RV failure induced by pulmonal banding by in vivo CMR at 7T. RV parameters differed significantly from those of normal mice in terms of RV end-diastolic volume (EDV: 85 +/- 14 microL vs. control 36 +/- 3 microL, p < 0.0001), RV end-systolic volume (ESV: 121 +/- 10 microL vs. control 84 +/- 4 microL, p < 0.005) and RV ejection fraction (EF: 31 +/- 6 % vs. control 57 +/- 2 %, p < 0.001). With regard to EDV, ESV, SV and EF LV parameters, there were no significant differences between pulmonary banded and control mice indicating overt isolated RV failure.

Field, coil, and echo-time influence on sensitivity and reproducibility of brain proton MR spectroscopy.

BACKGROUND AND PURPOSE: Clinical MR imaging scanners now offer many choices of hardware configurations that were not available in the first 25 years of their existence. Our goal was to assess the influence of coil technology, magnetic field strength, and echo time (TE) on the sensitivity, reflected by the signal intensity-to-noise-ratio (SNR) and reproducibility of proton MR spectroscopy (1H-MR spectroscopy). MATERIAL AND METHODS: The SNR, the intersubject reproducibility, and the intrasubject reproducibility of N-acetylaspartate (NAA), creatine (Cr), and choline (Cho) levels were compared at the common TEs of 30, 144, and 288 ms, by using 1H-MR spectroscopy in 6 volunteers at (1) 3T with a single-element quadrature (SEQ); (2) 1.5T with SEQ; and (3) 1.5T with a 12-channel phased-array (PA) head coil. RESULTS: In terms of sensitivity, the best SNR for all metabolites was obtained at the shortest TE (30 ms). It was comparable between the 3 and 1.5T with the PA, but approximately 35% better than the 1.5T with SEQ. This SNR difference declined <25% at TE of 144 ms and to equity among all imagers at TE of 288 ms. Reproducibility, reflected in the coefficient of variation (CV), was best for NAA at TE of 288 ms, 15%-50% better than at TE of 30 ms in either gray (GM) or white matter (WM). The CV for Cr was best, at TE of 288 ms for GM, but its WM results were independent of TE. Metabolite level reproducibility did not depend on coil technology or magnetic field strength. CONCLUSIONS: For the same coil type, the SNR of all major metabolites was approximately 35% better at 3T than at 1.5T. This advantage, however, was offset at 1.5T with a PA coil, making it a cost-effective upgrade for existing scanners. Surprisingly and counterintuitively, despite the lowest SNR, the best reproducibility was obtained at the longest TE (288 ms), regardless of field or coil.

[Living conditions of women 50plus in Europe - results of a secondary analysis in twelve Western European countries]. / Lebensbedingungen von Frauen 50plus in Europa - Ergebnisse einer Sekundäranalyse in zwölf westeuropäischen Ländern.

Within the framework of the research project MERI, we analyzed in twelve Western European countries which kind of studies and official statistics are available on the situation of women 50plus and how their situation is described by these data. On the one hand, thematic and country-specific knowledge and knowledge gaps were identified. Generally speaking the topics health and social integration are the focus of the examined studies. Detailed data were also found on issues relating to work and the material situation. Knowledge gaps are to be found with regard to the topics interest representation, education and violence/abuse. There are clear country-specific differences in the data. Partly there is a North-South divide with regard to the availability and the quality of data. On the other hand, characteristics of the living conditions of women 50plus were identified. Women 50plus are a very heterogeneous group which strongly differs among others with regard to social background, disability, illness, region and migration. At the same time there are, however, clear common problems in the examined areas health, social integration, education, work, material situation, interest representation and violence/abuse. From the research result recommendations are derived for future studies and the improvement of official statistics.

Failure of recombinant human growth hormone treatment to improve congestive heart failure in hypopituitarism.

Growth hormone (GH) deficiency decreases left ventricular (LV) contractility, induces LV chamber dilatation and promotes progression to congestive heart failure. It is, however, controversial, whether GH replacement therapy in addition to standard medical heart failure therapy should be considered as routine treatment in GH deficient patients with heart failure. In the present report of a 64-year-old GH deficient patient with heart failure, we demonstrate by using Doppler echocardiography, magnetic resonance imaging and 31P NMR spectroscopy that even a 12 month period of GH replacement therapy had no sustained effect on morphometric or functional parameters of LV performance nor on clinical signs or symptoms of heart failure. It is concluded that GH replacement therapy should currently not be regarded as standard heart failure therapy in patients with GH deficiency and should only be employed under careful monitoring including close follow-up in a standardized way.

A critical function of USF in HGF gene regulation mediated by a multiconsensus region.

Hepatocyte growth factor (HGF) is a multifunctional growth factor implicated in a variety of tissue restructuring processes. Since HGF acts as a highly potent mitogen, HGF expression is suggested to be under a well-defined transcriptional control. The 5' sequence of the HGF gene clusters a set of several binding sites for transcription factors in a so-called multiconsensus region (MCR) located between -230 and 260. Our studies demonstrate that a NF1-like element and the E(1)-box of the MCR form the main complexes with nuclear proteins and that both are involved in transcriptional silencing of the HGF gene in non-HGF expressing cell types. The E(1)-box of two tandemly arranged E-boxes was shown to be a binding site of high affinity interacting with the upstream stimulatory factor (USF). While recombinant expression of a wild-type USF did not affect gene expression, a USF variant lacking the DNA binding domain restored the MCR mediated transcriptional repression. In conclusion, our data provide evidence that USF is a central factor of cell-type specific HGF regulation, acting in cooperation with additional regulatory proteins as a bivalent mediator of transcriptional activation or repression.

Postpericardiotomy syndrome and cardiac tamponade as a late complication after pacemaker implantation.

In a 78-year old woman, pacemaker implantation was complicated by a transient perforation of the endocardial lead. The patient was in stable condition for up to 7 weeks after implantation, after which pericardial effusion and subacute cardiac tamponade developed and pericardiocentesis became necessary. This case illustrates that even after initially uneventful pacemaker lead perforation, careful, long-term follow-up is necessary to recognize the potential development of late postpericardiotomy syndrome.

Endogenous nitric oxide enhances coupling between O2 consumption and ATP synthesis in guinea pig hearts.

Endogenous nitric oxide (eNO) modulates tissue respiration. To test whether eNO modulates myocardial O2 consumption (MVO2), ATP synthesis, and metabolic efficiency, we used isolated isovolumic guinea pig hearts perfused at a constant flow. N(omega)-nitro-L-arginine (L-NNA; 5 x 10(-5) mol/l) was used to inhibit eNO production. MVO2 was measured at different levels of cardiac work, estimated as the rate-pressure product (RPP). ATP content and synthesis rate were determined using (31)P NMR and magnetization transfer during high cardiac work. L-NNA increased coronary vascular resistance (19 +/- 3%, P < 0.05) and MVO2 (12 +/- 3%, P < 0.05) without an increase in the RPP. In contrast, vehicle infusion resulted in insignificant changes in coronary vascular resistance (3 +/- 2%, P > 0.05) and MVO2 (-2 +/- 1%, P > 0.05). Compared with vehicle, L-NNA caused a higher MVO2 both during KCl arrest (L-NNA 5.6 +/- 0.5 vs. vehicle 3.0 +/- 0.4 micromol x min(-1) x mg x dry wt(-1), P < 0.05) and during increased cardiac work elicited by elevating perfusate Ca2+, indicating an upward shift in the relationship between contractile performance (measured as RPP) and MVO2. However, neither ATP contents nor ATP synthesis rates were different in the two groups during high cardiac work. Thus, because inhibition of eNO production by L-NNA increased MVO2 without a change in the ATP synthesis rate, these data suggest that eNO increases myocardial metabolic efficiency by reducing MVO2 in the heart.

Cardiac metabolism and function in patients with multiple sclerosis: a combined 31P-MR-spectroscopy and MRI study.

OBJECTIVE: Involvement of the autonomic system in multiple sclerosis (MS) may concur with dysfunction of the cardiovascular system. The introduction of potentially cardiotoxic immunosuppressive drugs like Mitoxantrone into the treatment of MS warrants proper assessment of preexisting heart disease. However, systematic analyses of functional and metabolic derangements in MS are missing. Using quantitative 31P-MR-spectroscopy (MRS) and MR-imaging (MRI) metabolic and functional parameters were analyzed in patients with MS in comparison to healthy volunteers. SUBJECTS/METHODS: 14/15 patients with MS could be included in the study, as the MRS examination of one patient had to be excluded from analysis due to movement during the examination. Using chemical shift imaging (CSI) and AMARES, phosphocreatine (PCr) to adenosine triphosphate (ATP) ratios, characterizing myocardial high-energy phosphate metabolism, were determined. Additionally, absolute concentrations of PCr and ATP were calculated by SLOOP (Spatial Localization with Optimal Pointspread Function). Analysis of functional changes was performed by Cine-MRI. 14 healthy volunteers matched for age and gender served as control. RESULTS: A significant decrease of absolute PCr concentration was observed in patients with MS compared to matched volunteers (p < 0.05), whereas ATP concentrations showed no significant changes (p = 0.27). Metabolite ratios calculated by SLOOP or AMARES showed a tendency to be reduced in patients, however, did not reach significance (p = 0.08, SLOOP; p = 0.47, AMARES). Using volunteers' mean values +/- 2 x SD as cut off value revealed PCr changes in 5 of 14 patients, whereas only 2 also had pathologic PCr/ATP ratios. Functional analysis by MRI depicted depressed left ventricular ejection fraction in 4 patients. CONCLUSIONS: The reduction in cardiac high-energy phosphates in some patients with MS points to a subclinical involvement of the heart. This may be important for treatment with potentially cardiotoxic drugs. Longitudinal studies are need to understand the clinical relevance of our findings.

Temporal fluctuations of myocardia high-energy phosphate metabolite with the cardiac cycle.

This review describes the temporal changes of high-energy phosphate metabolites during the cardiac cycle. Under baseline condition, the extent of cyclical changes ("cycling") of ATP, phosphocreatine and inorganic phosphate varies between 10-15%. Such energy oscillations are not augmented under various forms of metabolic stress including 1) inotropic stimulation, 2) acute hypoxia and 3) failing, chronically infarcted hearts. Thus, the concentrations of high-energy phosphates over the cardiac cycle are a tightly regulated entity, even when energetic needs are substantially augmented.

Phenotypical features of long Q-T syndrome in transgenic mice expressing human Na-K-ATPase alpha(3)-isoform in hearts.

To understand why the adult human heart expresses three isoforms of the sodium pump, we generated transgenic mice (TGM) with 2.3- to 5. 5-fold overexpression of the human alpha(3)-isoform of Na-K-ATPase in the heart. Hearts from the TGM had increased maximal Na-K-ATPase activity and ouabain affinity compared with control hearts, even though the density of Na-K-ATPase pump sites (of all isoforms) was similar to that of control mice. In perfused hearts, contractility both at baseline and in the presence of ouabain tended to be greater in TGM than in controls. Surface electrocardiograms in anesthetized TGM had a steeper dependence of Q-T on sinus cycle length, and Q-T intervals measured during atrial pacing were significantly longer in TGM. Q-T dispersion during sinus rhythm also tended to be longer in TGM. Thus TGM overexpressing human alpha(3)-isoform have several of the phenotypical features of human long Q-T syndrome, despite the absence of previously described mutations in Na(+) or K(+) channels.

Kinetic, thermodynamic, and developmental consequences of deleting creatine kinase isoenzymes from the heart. Reaction kinetics of the creatine kinase isoenzymes in the intact heart.

Creatine kinase (CK) exists as a family of isoenzymes in excitable tissue. We studied isolated perfused hearts from mice lacking genes for either the main muscle isoform of CK (M-CK) or both M-CK and the main mitochondrial isoform (Mt-CK) to determine 1) the biological significance of CK isoenzyme shifts, 2) the necessity of maintaining a high CK reaction rate, and 3) the role of CK isoenzymes in establishing the thermodynamics of ATP hydrolysis. (31)P NMR was used to measure [ATP], [PCr], [P(i)], [ADP], pH, as well as the unidirectional reaction rate of PCr--> [gamma-P]ATP. Developmental changes in the main fetal isoform of CK (BB-CK) were unaffected by loss of other CK isoenzymes. In hearts lacking both M- and Mt-CK, the rate of ATP synthesis from PCr was only 9% of the rate of ATP synthesis from oxidative phosphorylation demonstrating a lack of any high energy phosphate shuttle. We also found that the intrinsic activities of the BB-CK and the MM-CK isoenzymes were equivalent. Finally, combined loss of M- and Mt-CK (but not loss of only M-CK) prevented the amount of free energy released from ATP hydrolysis from increasing when pyruvate was provided as a substrate for oxidative phosphorylation.

Downregulation of the Na(+)-creatine cotransporter in failing human myocardium and in experimental heart failure.

BACKGROUND: The failing myocardium is characterized by depletion of phosphocreatine and of total creatine content. We hypothesized that this is due to loss of creatine transporter protein. METHODS AND RESULTS: Creatine transporter protein was quantified in nonfailing and failing human myocardium (explanted hearts with dilated cardiomyopathy [DCM; n=8] and healthy donor hearts [n=8]) as well as in experimental heart failure (residual intact left ventricular tissue, rats 2 months after left anterior descending coronary artery ligation [MI; n=8] or sham operation [sham; n=6]) by Western blotting. Total creatine content was determined by high-performance liquid chromatography. Donor and DCM hearts had total creatine contents of 136.4+/-6.1 and 68.7+/-4.6 nmol/mg protein, respectively (*P<0.05); creatine transporter protein was 25.4+/-2.2 optical density units in donor and 17.7+/-2.5 in DCM (*P<0.05). Total creatine was 87.5+/-4.2 nmol/mg protein in sham and 65.7+/-4.2 in MI rats (*P<0.05); creatine transporter protein was 139.0+/-8.7 optical density units in sham and 82.1+/-4.0 in MI (*P<0.05). CONCLUSIONS: Both in human and in experimental heart failure, creatine transporter protein content is reduced. This mechanism may contribute to the depletion of creatine compounds and thus to the reduced energy reserve in failing myocardium. This finding may have therapeutic implications, suggesting a search for treatment strategies targeted toward creatine transport.

Long-term expression of protein kinase C in adult mouse hearts improves postischemic recovery.

Activation of protein kinase C (PKC) protects the heart from ischemic injury; however, its mechanism of action is unknown, in part because no model for chronic activation of PKC has been available. To test whether chronic, mild elevation of PKC activity in adult mouse hearts results in myocardial protection during ischemia or reperfusion, hearts isolated from transgenic mice expressing a low level of activated PKCbeta throughout adulthood (beta-Tx) were compared with control hearts before ischemia, during 12 or 28 min of no-flow ischemia, and during reperfusion. Left-ventricular-developed pressure in isolated isovolumic hearts, normalized to heart weight, was similar in the two groups at baseline. However, recovery of contractile function was markedly improved in beta-Tx hearts after either 12 (97 +/- 3% vs. 69 +/- 4%) or 28 min of ischemia (76 +/- 8% vs. 48 +/- 3%). Chelerythrine, a PKC inhibitor, abolished the difference between the two groups, indicating that the beneficial effect was PKC-mediated. (31)P NMR spectroscopy was used to test whether modification of intracellular pH and/or preservation of high-energy phosphate levels during ischemia contributed to the cardioprotection in beta-Tx hearts. No difference in intracellular pH or high-energy phosphate levels was found between the beta-Tx and control hearts at baseline or during ischemia. Thus, long-term modest increase in PKC activity in adult mouse hearts did not alter baseline function but did lead to improved postischemic recovery. Furthermore, our results suggest that mechanisms other than reduced acidification and preservation of high-energy phosphate levels during ischemia contribute to the improved recovery.

Altered creatine kinase enzyme kinetics in diabetic cardiomyopathy. A(31)P NMR magnetization transfer study of the intact beating rat heart.

To determine whether the decreased contractile performance in diabetic hearts is associated with a reduced energy reserve due to decreased creatine kinase (CK) activity, we measured total CK activity (V(max)) in vitro and CK reaction velocity in vivo using(31)P NMR spectroscopy in isolated perfused rat hearts after 4 and 6 weeks of diabetes. After 4 weeks of diabetes, V(max)decreased by 22% with a larger decrease of CK MB than of CK MM and mitochondrial-CK isoenzymes. There was no further decrease in these parameters after 6 weeks of diabetes. Isovolumic contractile performance of 4 and 6 week diabetic hearts, estimated as rate-pressure product under identical perfusion and loading conditions (EDP set at 6-8 mmHg), was only 50% of that of control. ATP, PCr and total creatine concentrations were not different in control and 4 or 6 weeks diabetic rat hearts. After 4 weeks of diabetes, CK reaction velocity decreased by 22%. This was in proportion to the decline of V(max)and therefore predicted by the rate equation for the CK reaction. However, the further decline in the CK reaction velocity after 6 weeks of diabetes (45%) was greater than that predicted from the CK rate equation (17% decrease), and cannot be explained by substrate control of the enzyme. When hearts were inotropically stimulated by increasing perfusate calcium concentration, CK reaction velocity increased slightly (approximately 15%) in both control and diabetic hearts, thereby maintaining a constant ATP concentration. We conclude that in the diabetic myocardium, the CK reaction velocity decreases but does not limit the availability of high-energy phosphates for contraction over the range of workloads studied. We also conclude that a mechanism(s) in addition to substrate control regulates CK reaction velocity in the 6 week diabetic hearts.

Insulin-like growth factor-1 but not growth hormone augments mammalian myocardial contractility by sensitizing the myofilament to Ca2+ through a wortmannin-sensitive pathway: studies in rat and ferret isolated muscles.

A growing body of evidence has been accumulated recently suggesting that growth hormone (GH) and insulin-like growth factor-1 (IGF-1) affect cardiac function, but their mechanism(s) of action is unclear. In the present study, GH and IGF-1 were administered to isolated isovolumic aequorin-loaded rat whole hearts and ferret papillary muscles. Although GH had no effect on the indices of cardiac function, IGF-1 increased isovolumic developed pressure by 24% above baseline. The aequorin transients were abbreviated and demonstrated decreased amplitude. The positive inotropic effects of IGF-1 were not associated with increased intracellular Ca2+ availability to the contractile machinery but to a significant increase of myofilament Ca2+ sensitivity. Accordingly, the Ca2+-force relationship obtained under steady-state conditions in tetanized muscle was shifted significantly to the left (EC50, 0.44+/-0.02 versus 0.52+/-0.03 micromol/L with and without IGF-1 in the perfusate, respectively; P<0.05); maximal Ca2+-activated tetanic pressure was increased significantly by 12% (211+/-3 versus 235+/-2 mm Hg in controls and IGF-1-treated hearts, respectively; P<0.01). The positive inotropic actions of IGF-1 were not associated with changes in either pHi or high-energy phosphate content, as assessed by 31P nuclear magnetic resonance spectroscopy, and were blocked by the phosphatidylinositol 3-kinase inhibitor wortmannin. Concomitant administration of IGF binding protein-3 blocked IGF-1-positive inotropic action in ferret papillary muscles. In conclusion, IGF-1 is an endogenous peptide that through a wortmannin-sensitive pathway displays distinct positive inotropic properties by sensitizing the myofilaments to Ca2+ without increasing myocyte [Ca2+]i.

Diastolic dysfunction and altered energetics in the alphaMHC403/+ mouse model of familial hypertrophic cardiomyopathy.

An arginine to glutamine missense mutation at position 403 of the beta-cardiac myosin heavy chain causes familial hypertrophic cardiomyopathy. Here we study mice which have this same missense mutation (alphaMHC403/+) using an isolated, isovolumic heart preparation where cardiac performance is measured simultaneously with cardiac energetics using 31P nuclear magnetic resonance spectroscopy. We observed three major alterations in the physiology and bioenergetics of the alphaMHC403/+ mouse hearts. First, while there was no evidence of systolic dysfunction, diastolic function was impaired during inotropic stimulation. Diastolic dysfunction was manifest as both a decreased rate of left ventricular relaxation and an increase in end-diastolic pressure. Second, under baseline conditions alphaMHC403/+ hearts had lower phosphocreatine and increased inorganic phosphate contents resulting in a decrease in the calculated value for the free energy released from ATP hydrolysis. Third, hearts from alphaMHC403/+ hearts that were studied unpaced responded to increased perfusate calcium by decreasing heart rate approximately twice as much as wild types. We conclude that hearts from alphaMHC403/+ mice demonstrate work load-dependent diastolic dysfunction resembling the human form of familial hypertrophic cardiomyopathy. Changes in high-energy phosphate content suggest that an energy-requiring process may contribute to the observed diastolic dysfunction.