Stress and Heart in Remodeling Process: Multiple Stressors at the Same Time Kill.

Myocardial remodeling is developed by increased stress in acute or chronic pathophysiologies. Stressed heart morphology (SHM) is a new description representing basal septal hypertrophy (BSH) caused by emotional stress and chronic stress due to increased afterload in hypertension. Acute stress cardiomyopathy (ASC) and hypertension could be together in clinical practice. Therefore, there are some geometric and functional aspects regarding this specific location, septal base under acute and chronic stress stimuli. The findings by our and the other research groups support that hypertension-mediated myocardial involvement could be pre-existed in ASC cases. Beyond a frequently seen predominant base, hyperkinetic tissue response is detected in both hypertension and ASC. Furthermore, hypertension is the responsible factor in recurrent ASC. The most supportive prospective finding is BSH in which a hypercontractile base takes a longer time to exist morphologically than an acutely developed syndrome under both physiologic exercise and pressure overload by transaortic binding in small animals using microimaging. However, cardiac decompensation with apical ballooning could mask the possible underlying hypertensive disease. In fact, enough time for the assessment of previous hypertension history or segmental analysis could not be provided in an emergency unit, since ASC is accepted as an acute coronary syndrome during an acute episode. Additional supportive findings for SHM are increased stress scores in hypertensive BSH and the existence of similar tissue aspects in excessive sympathetic overdrive like pheochromocytoma which could result in both hypertensive disease and ASC. Exercise hypertension as the typical form of blood pressure variability is the sum of physiologic exercise and pathologic increased blood pressure and results in increased mortality. Hypertension is not rare in patients with a high stress score and leads to repetitive attacks in ASC supporting the important role of an emotional component as well as the potential danger due to multiple stressors at the same time. In the current review, the impact of multiple stressors on segmental or global myocardial remodeling and the hazardous potential of multiple stressors at the same time are discussed. As a result, incidentally determined segmental remodeling could be recalled in patients with multiple stressors and contribute to the early and combined management of both hypertension and chronic stress in the prevention of global remodeling and heart failure.

An optimized CT-dense agent perfusion and micro-CT imaging protocol for chick embryo developmental stages.

Compared to classical techniques of morphological analysis, micro-CT (µ-CT) has become an effective approach allowing rapid screening of morphological changes. In the present work, we aimed to provide an optimized micro-CT dense agent perfusion protocol and µ-CT guidelines for different stages of chick embryo cardiogenesis. Our study was conducted over a period of 10 embryonic days (Hamburger-Hamilton HH36) in chick embryo hearts. During the perfusion of the micro-CT dense agent at different developmental stages (HH19, HH24, HH27, HH29, HH31, HH34, HH35, and HH36), we demonstrated that durations and volumes of the injected contrast agent gradually increased with the heart developmental stages contrary to the flow rate that was unchanged during the whole experiment. Analysis of the CT imaging confirmed the efficiency of the optimized parameters of the heart perfusion.

Long-term stress induced cortisol downregulation, growth reduction and cardiac remodeling in Atlantic salmon.

Stress and elevated plasma cortisol in salmonids have been linked with pathological remodeling of the heart and deterioration of fitness and welfare. However, these associations were based on biomarkers that fail to provide a retrospective view of stress. This study is the first whereby the association of long-term stress, using scale cortisol as a chronic stress biomarker, with cardiac morphology and growth performance of wild Atlantic salmon (Salmo salar) is made. Growth, heart morphology, plasma and scale cortisol levels, and expression of genes involved in cortisol regulation of the hypothalamic-pituitary-interrenal axis of undisturbed fish (control) were compared with those of fish exposed daily to stress for 8 weeks. Though scale cortisol levels showed a time-dependent accumulation in both groups, plasma and scale cortisol levels of stress group fish were 29.1% and 25.0% lower than those of control fish, respectively. These results correlated with the overall upregulation of stress-axis genes involved in the systemic negative feedback of cortisol, and local feedback via 11ß-hydroxysteroid dehydrogenases, glucocorticoid and mineralocorticoid receptors in the stress treatment at the hypothalamus and pituitary level. These lower cortisol levels were, however, counterintuitive in terms of the growth performance as stress group fish grew 33.7% slower than control fish, which probably influenced the 8.4% increase in relative ventricle mass in the stress group. Though compact myocardium area between the treatments was comparable, these parameters showed significant linear correlations with scale cortisol levels, indicating the involvement of chronic stress in cardiac remodeling. These findings underscore the importance of scale cortisol as biomarker when associating chronic stress with long-term processes including cardiac remodeling.

Evaluation of the changes in cardiac morphology of fetuses with congenital heart disease using fetalHQ.

Objective: To evaluate the changes in cardiac morphology of fetuses with congenital heart disease (CHD) using the fetal heart quantitative technique (fetalHQ).Methods: A total of 20 normal pregnant women (control group) and 20 pregnant women suspected of fetal CHD (case group) were included in this study. The dynamic images of the four-chamber view of the fetal heart were recorded and analyzed using fetalHQ. The global sphericity index (GSI) and 24-segment SI of the two groups were compared. The differences in the left and right ventricular 24-segment SI for each group were investigated.Results: There was no statistically significant difference in the GSI between the two groups (p > 0.05). The difference in the SI values of left ventricular segments 1-2 between the case group and control group was statistically significant (all p < 0.05), while the intergroup difference in SI of left ventricular segments 3-24 was not significant (all p > 0.05). The SI of the 24 segments of the right ventricle showed no significant intergroup difference (all p > 0.05). The difference in the left and right ventricular 24-segment SI in the case group did not reach statistical significance (all p > 0.05). In the control group, the SI values between the left and right ventricles were significantly different in segments 18-24 (all p < 0.05), and no significant difference was found in segments 1-17 (all p > 0.05). There was a statistically significant intergroup difference in the percentage of unusual left ventricular SI, determined based on Z-score (p < 0.05), and the percentage of outliers for the right ventricle between the two groups showed no significant difference (p > 0.05).Conclusion: The fetalHQ is regarded as a straightforward and reliable approach for assessing the cardiac GSI and 24-segment SI of left and right ventricles in fetuses diagnosed with CHD. While CHD may not significantly impact the overall shape of the fetal heart or the geometric shape of the right ventricle, in this study, a notable increase in SI values for the left ventricular 1-2 segments was observed, indicating a more flattened ventricular chamber. Additionally, the morphological distinctions between the left and right ventricles in fetuses with CHD are no longer discernible.

Effect of Sex on Structural and Morphological Parameters of Rat Heart under Conditions of Combined Exposure to Hypokinesia and Cold.

We studied the combined effect of hypokinesia and external cooling on structural and morphological changes in the ventricular myocardium and parameters of homeostasis of the blood system in male and female WKY (normotensive) and SHR (hypertensive) rats. Simultaneous exposure to hypokinesia and cold caused destructive processes in the myocardium and high dynamics of heart remodeling with diverse structural and morphological changes in the left ventricle in rats of both sexes. The thickness of the left ventricular wall most rapidly decreased in male hypertensive SHR rats. The thickness of the wall of the right ventricle significantly increased in male and female rats of both strains. In WKY and SHR females, structural transformations in the heart were less pronounced than in males. The key role in different degree of morphological remodeling of the myocardium in male and female probably belongs to sex hormones.

Ultimate phases of hypertensive heart disease and stressed heart morphology by conventional and novel cardiac imaging.

Early recognition of hypertensive heart disease is needed to prevent macrovascular and microvascular damage. Hypertension (HTN) is a risk factor for coronary artery disease, and plays a prominent role in the development of adverse left ventricular (LV) remodeling and heart failure. Here, we review new knowledge on effects of HTN on cardiac geometry and function, obtained from multimodality cardiac imaging, including echocardiography, positron emission tomography and magnetic resonance imaging. Early recognition of changes in LV geometry and function induced by HTN could identify patients at risk for end-organ damage, who could be targeted for close monitoring and intensive therapy. Basal septal hypertrophy as the early imaging biomarker at the adaptive phase may be a specific aspect not only in hypertensive heart but stress-related conditions and called stressed heart morphology.

Right Heart Morphology and Its Association With Excessive and Deficient Cardiac Visceral Adipose Tissue.

Visceral adipose tissue is an independent risk factor for the development of atherosclerotic coronary disease, arterial hypertension, diabetes and metabolic syndrome. Right heart morphology often involves the presence of adipose tissue, which can be quantified by non-invasive imaging methods. The last decade brought a wealth of new insights into the function and morphology of adipose tissue, with great emphasis on its role in the pathogenesis of heart disease. Cardiac adipose tissue is involved in thermogenesis, mechanical protection of the heart and energy storage. However, it can also be an endocrine organ that synthesises numerous pro-inflammatory and anti-inflammatory cytokines, the effect of which is accomplished by paracrine and vasocrine mechanisms. Visceral adipose tissue has several compartments that differ in their embryological origin and vascularisation. Deficiency of cardiac adipose tissue, often due to chronic pathological conditions such as oncological diseases or chronic infectious diseases, predicts increased mortality and morbidity. To date, knowledge about the influence of visceral adipose tissue on cardiac morphology is limited, especially the effect on the morphology of the right heart in a state of excess or deficient visceral adipose tissue.

Effects of long-term right ventricular apex pacing on left ventricular dyssynchrony, morphology and systolic function.

BACKGROUND: Right ventricular apex (RVA) is still the most common implanted site in the world. There are a large number of RVA pacing population who have been carrying dual-chamber permanent pacemaker (PPM) over decades. Comparison of left ventricular dyssynchrony, morphology and systolic function between RVA pacing population and healthy population is unknown. METHOD: This case-control study enrolled 61 patients suffered from complete atrioventricular block (III°AVB) for replacement of dual-chamber PPM. Then, 61 healthy controls matched with PPM patients in gender, age, follow-up duration and complications were included. The lead impedance, pacing threshold and sensing were compared between at implantation and long-term follow-up. Left ventricular (LV) dyssynchrony, morphology and systolic function were compared between RVA pacing population (RVA group) and healthy population (healthy group) at implantation (baseline) and follow-up. And clarify the predictors of LV systolic function in RVA group at follow-up. RESULTS: After 112.44 ± 34.94 months of follow-up, comparing with parameters at implantation, atrial lead impedance decreased significantly (690 ± 2397 Ω vs 613 ± 2257 Ω， p = 0.048); atrial pacing threshold has a increased trend and P-wave amplitude has a decreased trend, but there was no statistical differences; while, RVA ventricular lead threshold increased significantly (0.50 ± 0.23 V vs 0.91 ± 0.47 V， p < 0.001), impedance (902 ± 397 Ω vs 680 ± 257 Ω，p < 0.001) and R-wave amplitude (11.71 ± 9.40mv vs 7.00 ± 6.91 mv， p < 0.001) decreased significantly. Compared with healthy group, long-term RVA pacing significantly increased ventricular dyssynchrony (mean QRS duration, 156.21 ± 29.80 ms vs 97.08 ± 15.70 ms， p < 0.001), left atrium diameter (LAD, 40.61 ± 6.15 mm vs 37.49 ± 4.80 mm，p = 0.002), left ventricular end-diastolic diameter (LVEDD, 49.15 ± 5.93 mm vs 46.41 ± 3.80 mm，p = 0.003), left ventricular hypertrophy (LVMI, 121.86 ± 41.52 g/m2 vs 98.41 ± 25.29 g/m2，p < 0.001), significantly deteriorated degree of tricuspid regurgitation (p < 0.001), and significantly decreased left ventricular ejection fraction (LVEF, 61.38 ± 8.10% vs 64.64 ± 5.85%, p = 0.012), but after long-term RVA pacing, the mean LVEF was still more than 50%. Long-term RVA group LVEF was negatively correlated with preimplantation LVMI (B = -0.055，t = -2.244，p = 0.029), LVMI at follow-up (B = -0.081，t = -3.864，p = 0.000) and tricuspid regurgitation at follow-up (B = -3.797，t = -3.599，p = 0.001). CONCLUSION: In conclusion, although long-term RVA pacing has significantly effects on left ventricular dyssynchrony, morphology and systolic function in III°AVB patients, the mean LVEF is still >50%. High preimplantation LVMI can predict the decline of LVEF.

Basal Septal Hypertrophy as the Early Imaging Biomarker for Adaptive Phase of Remodeling Prior to Heart Failure.

Hypertension plays a dominant role in the development of left ventricular (LV) remodeling and heart failure, in addition to being the main risk factor for coronary artery disease. In this review, we focus on the focal geometric and functional tissue aspects of the LV septal base, since basal septal hypertrophy (BSH), as the early imaging biomarker of LV remodeling due to hypertensive heart disease, is detected in cross-sectional clinic studies. In addition, the validation of BSH by animal studies using third generation microimaging and relevant clinical observations are also discussed in the report. Finally, an evaluation of both human and animal quantitative imaging studies and the importance of combined cardiac imaging methods and stress-induction in the separation of adaptive and maladaptive phases of the LV remodeling are pointed out. As a result, BSH, as the early imaging biomarker and quantitative follow-up of functional analysis in hypertension, could possibly contribute to early treatment in a timely fashion in the prevention of hypertensive disease progression to heart failure. A variety of stress stimuli in etiopathogenesis and the difficulty of diagnosing pure hemodynamic overload mediated BSH lead to an absence of the certain prevalence of this particular finding in the population.

The heart of the adult goldfish Carassius auratus as a target of Bisphenol A: a multifaceted analysis.

Bisphenol A (BPA) is a contaminant whose presence in aquatic environments is increasing. In fish embryos and larvae, it severely affects cardiac development; however, its influence on the heart function of adult fish has been scarcely analyzed. This study investigated the effects of the in vivo exposure to BPA on heart physiology, morphology, and oxidative balance in the goldfish Carassius auratus. Adult fish were exposed for 4 and 10 days to two BPA concentrations (10 µM and 25 µM). Ex vivo working heart preparations showed that high concentrations of BPA negatively affected cardiac hemodynamics, as revealed by an impaired Frank-Starling response. This was paralleled by increased cardio-somatic indices and by myocardial structural changes. An altered oxidative status and a modulation of stress (HSPs) and pro-apoptotic (Bax and Cytochrome C) proteins expression were also observed in the heart of animals exposed to BPA, with detrimental effects at the highest concentration and the longest exposure time. Results suggest that, in the adult goldfish, BPA may induce stressful conditions to the heart with time- and concentration-dependent deleterious morpho-functional alterations.

Disentangling the effects of sex, life history and genetic background in Atlantic salmon: growth, heart and liver under common garden conditions.

Livestock domestication has long been a part of agriculture, estimated to have first occurred approximately 10 000 years ago. Despite the plethora of traits studied, there is little understanding of the possible impacts domestication has had on internal organs, which are key determinants of survival. Moreover, the genetic basis of observed associated changes in artificial environments is still puzzling. Here we examine impacts of captivity on two organs in Atlantic salmon (Salar salar) that have been domesticated for approximately 50 years: heart and liver, in addition to growth. We studied multiple families of wild, domesticated, F1 and F2 hybrid, and backcrossed strains of S. salar in replicated common garden tanks during the freshwater and marine stages of development. Heart and liver weight were investigated, along with heart morphology metrics examined in just the wild, domesticated and F1 hybrid strains (heart height and width). Growth was positively linked with the proportion of the domesticated strain, and recombination in F2 hybrids (and the potential disruption of co-adapted gene complexes) did not influence growth. Despite the influence of domestication on growth, we found no evidence for domestication-driven divergence in heart or liver morphology. However, sexual dimorphism was detected in heart morphology, and after controlling for body size, females exhibited significantly larger heart weight and heart width when compared with males. Wild females also had an increased heart height when compared with wild males, and this was not observed in any other strain. Females sampled in saltwater showed significantly larger heart height with rounder hearts, than saltwater males. Collectively, these results demonstrate an additive basis of growth and, despite a strong influence of domestication on growth, no clear evidence of changes in heart or liver morphology associated with domestication was identified.

Combined Effects of Hypokinesia and Ambient Temperature on Heart Remodeling in Normotensive and Hypertensive Rats.

We studied the effect of hypokinesia combined with cold exposure on morphological parameters of the heart in Wistar-Kyoto rats and rats with spontaneous genetically determined hypertension (SHR). The pathological processes developing in the heart of white laboratory rats significantly affected cardiac function and manifested in the deterioration of the morphological structure of the heart: reduction of heart weight, thinning of the free wall of the left ventricle. These changes indicate transition to a lower energy level of functioning. At the same time, hypertrophy of the right free wall develops in both rat lines. Combined effect of hypokinesia and cold is probably a factor indirectly promoting the development of pulmonary heart.

Influence of hereditary haemochromatosis on left ventricular wall thickness: does iron overload exacerbate cardiac hypertrophy?

BACKGROUND: The left ventricular (LV) hypertrophy increases the risk of heart failure. Hypertension and infiltrative cardiomyopathies are the well-known reasons of LV hypertrophy. The growing interest of scientists in this issue affects hereditary haemochromatosis (HH), which is characterised by the excess deposition of iron mostly due to HFE gene mutation. The aim of our study was to investigate the possible influence of HH on LV parameters in patients with early-diagnosed (early HH) and long-lasting and long-treated (old HH) disease. MATERIALS AND METHODS: Thirty nine early HH and 19 old HH patients were prospectively enrolled in the study; age- and sex-matched healthy volunteers constituted the appropriate control groups. All participants had echocardiography performed (including three-dimension volume and mass analysis); the iron turnover parameters were measured at the time of enrolment in every HH patients. RESULTS: Echocardiographic parameters regarding to left atrium (LA), LV thickness, mass and long axis length were significantly higher, whereas LV ejection fraction was lower in early HH in comparison to healthy persons. In old HH patients the differences were similar to those mentioned before, except LV ejection fraction. The presence of hypertension in both HH groups did not influence echo parameters, as well as diabetes in old HH. The strongest correlation in all HH group was found between the time from HH diagnosis and LA, LV thickness and volumes parameters, but the correlations between iron turnover and echo parameters were non-existent. CONCLUSIONS: Hereditary haemochromatosis, not only long-lasting, but also early-diagnosed, could lead to exacerbation of LV wall thickness and cardiac hypertrophy. This effect is not simply connected with hypertension and diabetes that are frequent additional diseases in these patients, but with the time from HH diagnosis.

Clozapine, ziprasidone, and sertindole-induced morphological changes in the rat heart and their relationship to antioxidant enzymes function.

Atypical antipsychotics produce severe side effects including myocarditis that may be attributed to oxidative stress. The aim of this study was to investigate the influence of clozapine, ziprasidone, and sertindole on rat heart morphology and determine whether redox imbalane plays a role in development of histopathological changes. Adult 3-month-old male Wistar rats were treated with recommended daily dose for selected drugs. After 4 week treatment histopathological analysis of the heart was performed and expression and activity of antioxidant enzymes determined. All examined drugs induced histopathological changes that were characterized as toxic myocarditis. Degenerative changes in cardiomyocytes were accompanied by lymphocytic infiltration as well as pericardial histopathological alterations in all treated groups. The least prominent changes were observed in sertindole-treated animals, and most severe with clozapine. Clozapine increased superoxide dismutase 1 (SOD1) activity while ziprasidone reduced glutathione reductase (GR) activity. Sertindole exerted no marked effect on antioxidant enzyme function in the heart even though myocardial degeneration was noted. In conclusion, treatment with clozapine or ziprasidone induced pathophysiological alterations in rat heart, which appeared to be associated disturbances in antioxidant capacity. Abbreviation: AAP, Atypical antipsychotics; ROS, reactive oxygen species; SOD1, Copper-zinc superoxide dismutase; SOD2, Manganese superoxide dismutase; CAT, Catalase; GPx, Glutathione peroxidase; GR, Glutathione reductase; H&E, hematoxylin and eosin stain; TNF- α, tumor necrosis factor alpha.

The developmental origin of heart size and shape differences in Astyanax mexicanus populations.

Regulation of heart size and shape is one of the least understood processes in developmental biology. We have for the first time analysed the hearts of Astyanax mexicanus and identified several differences in heart morphology between the surface (epigean morph) and cave-dwelling (troglomorph) morphs. Examination of the adult revealed that the troglomorph possesses a smaller heart with a rounder ventricle in comparison to the epigean morph. The size differences identified appear to arise early in development, as early as 24 h post-fertilisation (hpf), while shape differences begin to appear at 2 days post-fertilisation. The heart of the first-generation cross between the cave-dwelling and river-dwelling morph shows uncoupling of different phenotypes observed in the parental populations and indicates that the cardiac differences have become embedded in the genome during evolution. The differences in heart morphology are accompanied by functional changes between the two morphs, with the cave-dwelling morph exhibiting a slower heart rate than the river-dwelling morph. The identification of morphological and functional differences in the A. mexicanus heart could allow us to gain more insight into how such parameters are regulated during cardiac development, with potential relevance to cardiac pathologies in humans.

hace1 Influences zebrafish cardiac development via ROS-dependent mechanisms.

BACKGROUND: In this study, we reveal a previously undescribed role of the HACE1 (HECT domain and Ankyrin repeat Containing E3 ubiquitin-protein ligase 1) tumor suppressor protein in normal vertebrate heart development using the zebrafish (Danio rerio) model. We examined the link between the cardiac phenotypes associated with hace1 loss of function to the expression of the Rho small family GTPase, rac1, which is a known target of HACE1 and promotes ROS production via its interaction with NADPH oxidase holoenzymes. RESULTS: We demonstrate that loss of hace1 in zebrafish via morpholino knockdown results in cardiac deformities, specifically a looping defect, where the heart is either tubular or "inverted". Whole-mount in situ hybridization of cardiac markers shows distinct abnormalities in ventricular morphology and atrioventricular valve formation in the hearts of these morphants, as well as increased expression of rac1. Importantly, this phenotype appears to be directly related to Nox enzyme-dependent ROS production, as both genetic inhibition by nox1 and nox2 morpholinos or pharmacologic rescue using ROS scavenging agents restores normal cardiac structure. CONCLUSIONS: Our study demonstrates that HACE1 is critical in the normal development and proper function of the vertebrate heart via a ROS-dependent mechanism. Developmental Dynamics 247:289-303, 2018. © 2017 Wiley Periodicals, Inc.

Effects of in ovo exposure to 3,3',4,4'-tetrachlorobiphenyl (PCB 77) on heart development in tree swallow (Tachycineta bicolor).

Tree swallow (Tachycineta bicolor) eggs from 2 uncontaminated sites, the Patuxent Research Refuge (Laurel, MD, USA) and the Cobleskill Reservoir (Cobleskill, NY, USA) were dosed with polychlorinated biphenyl (PCB) 77 to evaluate effects on the developing cardiovascular system. To ensure embryonic viability, treatments were administered into the air cell at embryonic day 2.5 including: untreated (control), vehicle (filtered sterilized fatty acid mixture), 100 ng/g and 1000 ng/g egg. Eggs were dosed in the field with 0.2 µL/egg, returned to the nest, collected at embryonic day 13, hatched in the laboratory, and necropsied. The PCB 77-treated hatchlings were compared with uninjected, vehicle-injected, and environmentally exposed hatchlings collected from a PCB-contaminated Upper Hudson River (NY, USA) site. The PCB 77-treated embryos showed no effects on hatching success or hatchling mortality, heart index, or morphological measures of 4 distinct heart layers (heart width, length, septal thickness, total and ventricular cavity area) compared with controls. Hatchlings that had received PCB 77 exhibited increased incidence of a cardiomyopathy and absence of the ventricular heart wall compact layer (Chi square test; p < 0.001); environmentally exposed embryos showed no apparent effects. The compact layer is essential in development and overall heart function for ventricular cardiomyocyte proliferation and normal heart contraction. The finding that in ovo exposure to PCB 77 resulted in distinct cardiomyopathy has implications for long-term individual fitness. Environ Toxicol Chem 2018;37:116-125. © 2017 SETAC.

Validating Candidate Congenital Heart Disease Genes in Drosophila.

Genomic sequencing efforts can implicate large numbers of genes and de novo mutations as potential disease risk factors. A high throughput in vivo model system to validate candidate gene association with pathology is therefore useful. We present such a system employing Drosophila to validate candidate congenital heart disease (CHD) genes. The protocols exploit comprehensive libraries of UAS-GeneX-RNAi fly strains that when crossed into a 4×Hand-Gal4 genetic background afford highly efficient cardiac-specific knockdown of endogenous fly orthologs of human genes. A panel of quantitative assays evaluates phenotypic severity across multiple cardiac parameters. These include developmental lethality, larva and adult heart morphology, and adult longevity. These protocols were recently used to evaluate more than 100 candidate CHD genes implicated by patient whole-exome sequencing (Zhu et al., 2017).

Cardiac Morphology and Function, and Blood Gas Transport in Aquaporin-1 Knockout Mice.

We have studied cardiac and respiratory functions of aquaporin-1-deficient mice by the Pressure-Volume-loop technique and by blood gas analysis. In addition, the morphological properties of the animals' hearts were analyzed. In anesthesia under maximal dobutamine stimulation, the mice exhibit a moderately elevated heart rate of < 600 min(-1) and an O2 consumption of ~0.6 ml/min/g, which is about twice the basal rate. In this state, which is similar to the resting state of the conscious animal, all cardiac functions including stroke volume and cardiac output exhibited resting values and were identical between deficient and wildtype animals. Likewise, pulmonary and peripheral exchange of O2 and CO2 were normal. In contrast, several morphological parameters of the heart tissue of deficient mice were altered: (1) left ventricular wall thickness was reduced by 12%, (2) left ventricular mass, normalized to tibia length, was reduced by 10-20%, (3) cardiac muscle fiber cross sectional area was decreased by 17%, and (4) capillary density was diminished by 10%. As the P-V-loop technique yielded normal end-diastolic and end-systolic left ventricular volumes, the deficient hearts are characterized by thin ventricular walls in combination with normal intraventricular volumes. The aquaporin-1-deficient heart thus seems to be at a disadvantage compared to the wild-type heart by a reduced left-ventricular wall thickness and an increased diffusion distance between blood capillaries and muscle mitochondria. While under the present quasi-resting conditions these morphological alterations have no consequences for cardiac function, we expect that the deficient hearts will show a reduced maximal cardiac output.