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Background— Genetically modified mice offer the unique opportunity to gain insight into the pathophysiology of pulmonary arterial hypertension. In mice, right heart catheterization is the only available technique to measure right ventricular systolic pressure (RVSP). However, it is a terminal procedure and does not allow for serial measurements. Our objective was to validate a noninvasive technique to assess RVSP in mice. Methods and Results— Right ventricle catheterization and echocardiography (30-MHz transducer) were simultaneously performed in mice with pulmonary hypertension induced acutely by infusion of a thromboxane analogue, U-46619, or chronically by lung-specific overexpression of interleukin-6. Pulmonary acceleration time (PAT) and ejection time (ET) were measured in the parasternal short-axis view by pulsed-wave Doppler of pulmonary artery flow. Infusion of U-46619 acutely increased RVSP, shortened PAT, and decreased PAT/ET. The pulmonary flow pattern changed from symmetrical at baseline to asymmetrical at higher RVSPs. In wild-type and interleukin-6–overexpressing mice, the PAT correlated linearly with RVSP ( r 2 =−0.67, P r 2 =−0.76, P 32 mm Hg) were 100% (7/7) and 86% (6/7), respectively, for both indices (cutoff values: PAT, Conclusions— Right ventricular systolic pressure can be estimated noninvasively in mice. Echocardiography is able to detect acute and chronic increases in RVSP with high sensitivity and specificity as well as to assess the effects of treatment on RVSP. This noninvasive technique may permit the characterization of the evolution of pulmonary arterial hypertension in genetically modified mice.

Altered cGMP signaling has been implicated in myocardial depression, morbidity, and mortality associated with sepsis. Previous studies, using inhibitors of soluble guanylate cyclase (sGC), suggested that cGMP generated by sGC contributed to the cardiac dysfunction and mortality associated with sepsis. We used sGCα1-deficient (sGCα1−/−) mice to unequivocally determine the role of sGCα1β1in the development of cardiac dysfunction and death associated with two models of inflammatory shock: endotoxin- and TNF-induced shock. At baseline, echocardiographic assessment and invasive hemodynamic measurements of left ventricular (LV) dimensions and function did not differ between wild-type (WT) mice and sGCα1−/−mice on the C57BL/6 background (sGCα1−/−B6mice). At 14 h after endotoxin challenge, cardiac dysfunction was more pronounced in sGCα1−/−B6than WT mice, as assessed using echocardiographic and hemodynamic indexes of LV function. Similarly, Ca2+handling and cell shortening were impaired to a greater extent in cardiomyocytes isolated from sGCα1−/−B6than WT mice after endotoxin challenge. Importantly, morbidity and mortality associated with inflammatory shock induced by endotoxin or TNF were increased in sGCα1−/−B6compared with WT mice. Together, these findings suggest that cGMP generated by sGCα1β1protects against cardiac dysfunction and mortality in murine inflammatory shock models.

Insulin resistance is an increasingly prevalent condition in humans that frequently clusters with disorders characterized by left ventricular (LV) pressure overload, such as systemic hypertension. To investigate the impact of insulin resistance on LV remodeling and functional response to pressure overload, C57BL6 male mice were fed a high-fat (HFD) or a standard diet (SD) for 9 days and then underwent transverse aortic constriction (TAC). LV size and function were assessed in SD- and HFD-fed mice using serial echocardiography before and 7, 21, and 28 days after TAC. Serial echocardiography was also performed on nonoperated SD- and HFD-fed mice over a period of 6 wk. LV perfusion was assessed before and 7 and 28 days after TAC. Nine days of HFD induced systemic and myocardial insulin resistance (assessed by myocardial 18F-fluorodeoxyglucose uptake), and myocardial perfusion response to acetylcholine was impaired. High-fat feeding for 28 days did not change LV size and function in nonbanded mice; however, TAC induced greater hypertrophy, more marked LV systolic and diastolic dysfunction, and decreased survival in HFD-fed compared with SD-fed mice. Compared with SD-fed mice, myocardial perfusion reserve was decreased 7 days after TAC, and capillary density was decreased 28 days after TAC in HFD-fed mice. A short duration of HFD induces insulin resistance in mice. These metabolic changes are accompanied by increased LV remodeling and dysfunction after TAC, highlighting the impact of insulin resistance in the development of pressure-overload-induced heart failure.

International audience; BACKGROUND: New therapeutic strategies aim to reduce the extent of myocardial infarction (MI) to decrease long-term left ventricular (LV) remodeling. These innovations are often developed on murine models of MI and have led to the need for a sensitive tool allowing follow-up. The aim of this study was to investigate by strain rate (SR) imaging early and long-term alteration in regional LV function occurring after MI in mice. METHODS: Echocardiography was serially performed during a 4-month follow-up period in 3 groups of C57BL6 male mice: 7 normal, 5 sham operated, and 27 with left coronary artery ligation (the MI group). In addition to conventional measurements, SR was obtained from short-axis views in the anterior wall and posterior wall (PW). Triphenyltetrazolium chloride staining allowed the localization and measurement of the transmural extent of MI. A transmural MI was defined as an extension > 75% of the wall thickness. RESULTS: In the MI group, LV ejection fractions significantly decreased, while LV dimensions and PW thicknesses increased from baseline to 4 months. On day 3, SR could differentiate transmural from nontransmural (1 +/- 1 vs 10 +/- 1 s(-1); P < .05) and noninfarcted myocardium (25 +/- 1 s(-1)). SR values did not significantly change between day 3 and month 4 and could still differentiate those segments at month 4. Wall thickening was not able to differentiate transmural from nontransmural infarcted segments at day 3 (16 +/- 3% vs 21 +/- 3%; P = NS) or at month 4. CONCLUSION: In this murine model of MI, SR was able to predict the transmural extent of MI as early as 3 days after MI, then remained stable and still differentiated them at 4 months.

Breathing hydrogen sulfide (H2S) has been reported to induce a suspended animation-like state with hypothermia and a concomitant metabolic reduction in rodents. However, the impact of H2S breathing on cardiovascular function remains incompletely understood. In this study, the authors investigated the cardiovascular and metabolic effects of inhaled H2S in a murine model.The impact of breathing H2S on cardiovascular function was examined using telemetry and echocardiography in awake mice. The effects of breathing H2S on carbon dioxide production and oxygen consumption were measured at room temperature and in a warmed environment.Breathing H2S at 80 parts per million by volume at 27 degrees C ambient temperature for 6 h markedly reduced heart rate, core body temperature, respiratory rate, and physical activity, whereas blood pressure remained unchanged. Echocardiography demonstrated that H2S exposure decreased both heart rate and cardiac output but preserved stroke volume. Breathing H2S for 6 h at 35 degrees C ambient temperature (to prevent hypothermia) decreased heart rate, physical activity, respiratory rate, and cardiac output without altering stroke volume or body temperature. H2S breathing seems to induce bradycardia by depressing sinus node activity. Breathing H2S for 30 min decreased whole body oxygen consumption and carbon dioxide production at either 27 degrees or 35 degrees C ambient temperature. Both parameters returned to baseline levels within 10 min after the cessation of H2S breathing.Inhalation of H2S at either 27 degrees or 35 degrees C reversibly depresses cardiovascular function without changing blood pressure in mice. Breathing H2S also induces a rapidly reversible reduction of metabolic rate at either body temperature.

Mice are increasingly used in cardiovascular research, and echocardiography is ideally suited to evaluate their cardiac phenotype. This review describes the current use of mice echocardiography and focuses on some of its applications in both basic and clinical science.

Background— Flavoprotein reductases are involved in the generation of reactive oxygen species by doxorubicin. The objective of the present study was to determine whether or not one flavoprotein reductase, endothelial nitric oxide synthase (nitric oxide synthase 3 [NOS3]), contributes to the cardiac dysfunction and injury seen after the administration of doxorubicin. Methods and Results— A single dose of doxorubicin (20 mg/kg) was administered to wild-type (WT) mice, NOS3-deficient mice (NOS3 −/− ), and mice with cardiomyocyte-specific overexpression of NOS3 (NOS3-TG). Cardiac function was assessed after 5 days with the use of echocardiography. Doxorubicin decreased left ventricular fractional shortening from 57±2% to 47±1% ( P −/− and less in NOS3-TG after doxorubicin (55±1% and 35±2%; P −/− and were more marked in NOS3-TG mice. Finally, WT and NOS3 −/− mice were treated with a lower dose of doxorubicin (4 mg/kg) administered weekly over 5 weeks. Sixteen weeks after beginning doxorubicin treatment, fractional shortening was greater in NOS3 −/− than in WT mice (45±2% versus 28±1%; P P Conclusions— These findings implicate NOS3 as a key mediator in the development of left ventricular dysfunction after administration of doxorubicin.

Genetically modified mice are used extensively in models of ischemia reperfusion (I/R) and nonreperfused myocardial infarction (MI) to gain insights into pathways involved in these pathologies. Echocardiography is an ideal noninvasive tool to serially monitor the cardiac murine phenotype. The present review details the surgical aspects of I/R and MI models and the measurement of MI size by pathology techniques and the input of echocardiographic techniques including the extent of wall motion abnormality and of perfusion defects using myocardial contrast echocardiography in the assessment of murine area at risk and MI size.

Anthracyclines and trastuzumab (Herceptin®) have led to significant improvements in breast cancer survival, but are associated with an increased risk of cardiotoxicity. Moreover, biomarker strategies to identify or predict which patients are at risk for cardiotoxicity remain poorly understood. Our

Myocardial dysfunction contributes to the high mortality of patients with endotoxemia. Although nitric oxide (NO) has been implicated in the pathogenesis of septic cardiovascular dysfunction, the role of myocardial NO synthase 3 (NOS3) remains incompletely defined. Here we show that mice with cardiomyocyte-specific NOS3 overexpression (NOS3TG) are protected from myocardial dysfunction and death associated with endotoxemia. Endotoxin induced more marked impairment of Ca 2+ transients and cellular contraction in wild-type than in NOS3TG cardiomyocytes, in part, because of greater total sarcoplasmic reticulum Ca 2+ load and myofilament sensitivity to Ca 2+ in the latter during endotoxemia. Endotoxin increased reactive oxygen species production in wild-type but not NOS3TG hearts, in part, because of increased xanthine oxidase activity. Inhibition of NOS by N G -nitro- l -arginine-methyl ester restored the ability of endotoxin to increase reactive oxygen species production and xanthine oxidase activity in NOS3TG hearts to the levels measured in endotoxin-challenged wild-type hearts. Allopurinol, a xanthine oxidase inhibitor, attenuated endotoxin-induced reactive oxygen species accumulation and myocardial dysfunction in wild-type mice. The protective effects of cardiomyocyte NOS3 on myocardial function and survival were further confirmed in a murine model of polymicrobial sepsis. These results suggest that increased myocardial NO levels attenuate endotoxin-induced reactive oxygen species production and increase total sarcoplasmic reticulum Ca 2+ load and myofilament sensitivity to Ca 2+ , thereby reducing myocardial dysfunction and mortality in murine models of septic shock.

Aims Currently available non-invasive imaging methods frequently fail to detect alterations in left ventricular (LV) function despite histological evidence of injury. Tissue Doppler imaging (TDI) can detect subtle LV dysfunction. The aim of this study was to investigate whether TDI indices can predict LV systolic dysfunction and mortality following exposure to doxorubicin (DOX) in mice. Methods and results TDI-derived peak endocardial systolic velocity ( V ENDO) and strain rate (SR), as well as M-mode and two-dimensional indices of LV systolic function, were measured serially in mice after receiving DOX as a single dose (20 mg/kg). Haemodynamic measurements were obtained invasively before and at 1, 2, 4, and 5 days after the single DOX dose. Cardiac apoptosis was measured before and at 1 day after DOX. V ENDO and SR decreased after 1 and 2 days, respectively, whereas changes in fractional shortening (FS) and LV ejection fraction (LVEF) were not detected before 5 days. The reduction in both V ENDO and SR correlated with the decrease in d P /d t MAX, and the change in V ENDO correlated with the early increase in cardiac cell apoptosis. In a subsequent experiment, DOX was administered at 4 mg/kg/week for 5 weeks, and LV function was followed serially for 16 weeks. In this chronic experiment, TDI indices decreased before FS and LVEF, correlated with late LV dysfunction, and predicted DOX-induced mortality. Conclusion In a murine model of DOX-induced cardiac injury, TDI detects LV dysfunction prior to alterations in conventional echocardiographic indices and predicts mortality. This study suggests that TDI may be a reliable tool to detect early subtle changes in DOX-induced cardiac dysfunction.

Nitric oxide synthase 2 (NOS2) has been reported to increase in hypertrophied cardiomyocytes; however, whether NOS2 plays a role in the development of hypertrophy is unknown. To investigate the relationship of NOS2 with left ventricular (LV) remodelling and hypertrophy following prolonged pressure overload, we studied 18 male wild-type (WT) and 20 male NOS2-deficient (NOS2-/-) mice before and 7, 14 and 28 days after transverse aortic constriction (TAC) using echocardiography. A subgroup of eight WT and eight NOS2-/- mice were studied 42 days after TAC. Haemodynamic measurements were obtained before killing. Left ventricular size and function were similar for both genotypes at baseline. After TAC for 28 days, both groups developed LV hypertrophy, with echo-derived LV mass increasing from 78 +/- 2 to 147 +/- 10 mg in WT and from 86 +/- 3 to 142 +/- 10 mg in NOS2-/- mice. Twenty-eight days after TAC, LV weight and cardiomyocyte width were also similar in both genotypes. Fractional shortening (FS) decreased on day 7 from 57 +/- 1 to 48 +/- 2% in WT and from 59 +/- 1 to 49 +/- 2% in NOS2-/- mice. Although this decrease in FS was transient in WT mice, it persisted in NOS2-/- mice. Invasively measured parameters of systolic and diastolic function, however, were similar in the two genotypes both 28 and 42 days after TAC. A load-independent index of contractility, Emax, was similar in both strains 42 days after TAC. In conclusion, NOS2 does not appear to have a critical role in the development of LV hypertrophy after chronic pressure overload.

To learn whether nitric oxide (NO) inhalation can decrease myocardial ischemia-reperfusion (I/R) injury, we studied a murine model of myocardial infarction (MI). Anesthetized mice underwent left anterior descending coronary artery ligation for 30, 60, or 120 min followed by reperfusion. Mice breathed NO beginning 20 min before reperfusion and continuing thereafter for 24 h. MI size and area at risk were measured, and left ventricular (LV) function was evaluated using echocardiography and invasive hemodynamic measurements. Inhalation of 40 or 80 ppm, but not 20 ppm, NO decreased the ratio of MI size to area at risk. NO inhalation improved LV systolic function, as assessed by echocardiography 24 h after reperfusion, and systolic and diastolic function, as evaluated by hemodynamic measurements 72 h after reperfusion. Myocardial neutrophil infiltration was reduced in mice breathing NO, and neutrophil depletion prevented inhaled NO from reducing myocardial I/R injury. NO inhalation increased arterial nitrite levels but did not change myocardial cGMP levels. Breathing 40 or 80 ppm NO markedly and significantly decreased MI size and improved LV function after ischemia and reperfusion in mice. NO inhalation may represent a novel method to salvage myocardium at risk of I/R injury.

Echocardiographic measurements were obtained before and 4 and 7 h after intraperitoneal challenge with endotoxin (Escherichia coli 0111:B4 lipopolysaccaride 50 mg/ kg) in wild-type C57BL6 mice (WT) and WT mice with myocyte-specific overexpression of NOS3 (TG), using a 13-MHz ultrasound probe (Sequoia, Acuson, Mountain View, CA). Invasive measurements of LV pressure and volume were obtained with a 1.4F pressure-volume catheter (SPR-839, Millar Instruments, Houston TX) (7 h after challenge with endotoxin or saline). At baseline, WT and TG mice had comparable measures of LV function. However, as assessed by echocardiography, the endotoxin-induced decrease in LV fractional shortening was attenuated in TG mice (from 54 ± 1 to 40 ± 1%) as compared to WT mice (from 56 ± 1 to 31 ± 2%). Invasive hemodynamics revealed that, compared to salinechallenged mice, dP/dtmax and cardiac output (CO) were markedly impaired in WT but not in TG 7 h after endotoxin challenge (Table 1).

Background— Tissue Doppler imaging (TDI) is a novel echocardiographic method to quantify regional myocardial function. The objective of this study was to assess whether myocardial velocities and strain rate (SR) could be obtained by TDI in mice and whether these indices accurately quantified alterations in left ventricular (LV) systolic function. Methods and Results— TDI was performed in 10 healthy mice to measure endocardial (v endo ) and epicardial systolic velocities and SR. In further experiments, TDI indices were compared with dP/dt max and with sonomicrometer-derived regional velocities, at rest and after administration of dobutamine or esmolol. TDI indices were also studied serially in 8 mice before and 4 and 7 hours after endotoxin challenge. Myocardial velocities and SR were obtained in all mice with low measurement variability. TDI indices increased with administration of dobutamine (v endo from 2.2±0.3 to 3.8±0.2 cm/s [ P −1 [ P endo 1.4±0.2 cm/s [ P −1 [ P max ( r 2 =0.79 for SR and r 2 = 0.69 for v endo ; both P max even after adjustment for the confounding effect of the other variables. V endo correlated closely with sonomicrometer-measured velocity ( r 2 =0.71, P endo and SR were detected before decreases in shortening fraction became manifest. Conclusions— Myocardial velocities and SR can be measured noninvasively in mice with the use of TDI. Both indices are sensitive markers for quantifying LV global and regional function in mice.

Cardiac catheterization and Doppler echocardiography are two methods used to measure transvalvular gradients and valve area in the assessment of aortic stenosis severity. Although both approaches are based on the same hemodynamic concepts and report data using the same units of measure, each method measures pressure drop or gradient at a different place; hence they produce fundamentally different quantities. Likewise, cardiac catheterization formulas for valve area attempt to obtain the anatomic area whereas the Doppler continuity equation reports the area to which flow is constricted. To use these two methods appropriately, it is necessary to understand the underlying hemodynamic principles and the effects of the methods of measurement on the values obtained. This article examines these variables and shows how they affect the reported gradients and valve areas and how differences can affect clinical application.

To investigate the role of endothelial nitric oxide synthase (NOS3) in left ventricular (LV) remodeling induced by chronic pressure overload, the impact of transverse aortic constriction (TAC) on LV structure and function was compared in wild-type (WT) and NOS3-deficient (NOS3–/–) mice. Before TAC, LV wall thickness, mass, and fractional shortening were similar in the two mouse strains. Twenty-eight days after TAC, both WT and NOS3–/– mice had increased LV wall thickness and mass as well as decreased fractional shortening. Although the pressure gradient across the TAC was similar in both strains of mice 28 days after TAC, LV mass and posterior wall thickness were greater in NOS3–/– than in WT mice, whereas fractional shortening and the maximum rate of developed LV pressure were less. Diastolic function, as measured by the time constant of isovolumic relaxation and the maximum rate of LV pressure decay, was impaired to a greater extent in NOS3–/– than in WT mice. The degree of myocyte hypertrophy and LV fibrosis was greater in NOS3–/– than in WT mice at 28 days after TAC. Mortality was greater in NOS3–/– than in WT mice 28 days after TAC. Long-term administration of hydralazine normalized the blood pressure and prevented the LV dilation in NOS3–/– mice but did not prevent the LV hypertrophy, dysfunction, and fibrosis associated with NOS3 deficiency after TAC. These results suggest that the absence of NOS3 augments LV dysfunction and remodeling in a murine model of chronic pressure overload.

Murine models are increasingly used to elucidate the molecular mechanisms contributing to left ventricular (LV) remodeling. Epidemiologic and animal studies have suggested that women undergo differing patterns of LV remodeling than men after myocardial infarction (MI). We, therefore, sought to compare LV remodeling after MI in male and female mice. Echocardiography was performed in male and female C57BL6 mice before and serially after MI. Two days after MI, end-diastolic LV internal diameter and shortening fraction were similar in males and females. Between days 2 and 28 after MI, LV internal diameter increased in male mice but remained unchanged in female mice. During this time period, shortening fraction declined in males, but not in females. Posterior wall thickness increased more in females than in males. The size of the MI and the LV mass/body weight were similar between the 2 sexes after MI. Echocardiography showed that after MI, female mice undergo less extensive LV remodeling than males, with less dilation and better preserved LV systolic function 28 days after MI. These sex differences should be taken into account when studying murine cardiac adaptation to MI.

Pulse inversion harmonic imaging (PIHI) is a new modality that increases the detection of harmonic echoes and myocardial contrast by cancelling linearly transmitted signals. We tested whether PIHI improved the detection of endocardial borders in noncontrast 2-dimensional echocardiography. We compared PIHI with tissue harmonic imaging (THI), which decreases linearly transmitted signals using filters. Fundamental mode (FM) was compared with THI and PIHI in 50 consecutive patients. The global and segmental endocardial visualization scores measured with FM were significantly improved by using either THI or PIHI. The improvement of the global score compared with FM was slightly higher using PIHI than THI, because of an improved visualization of the base and the anterior wall with the PIHI technique compared with THI. The ratio of myocardial-to-cavity signal was similarly increased from FM with THI and PIHI. PIHI, a new modality for detection of myocardial contrast, can also be used for endocardial border visualization. It provides an improvement relative to THI for specific regions of the endocardium.

In epidemiologic studies, obesity has been associated with reduced natriuretic peptide (NP) concentrations leading to the hypothesis that obesity is a state of relative “NP deficiency”. However, data from prior studies have been restricted to resting NP concentrations, which may not reflect how

Background To test whether deficiency in endothelial nitric oxide synthase (eNOS) affects atherosclerosis development, we compared lesion formation in apolipoprotein E (apoE)/eNOS-double knockout (DKO) and apoE-knockout (KO) control animals. Methods and Results After 16 weeks of “Western-type” diet, apoE/eNOS-DKO males and females showed significant increases in lesion area of 93.6% and 59.2% compared with apoE-KO mice. All apoE/eNOS-DKO animals studied developed peripheral coronary arteriosclerosis, associated with perivascular and myocardial fibrosis, whereas none of the apoE-KO mice did. Transthoracic echocardiography showed a significantly increased left ventricular wall thickness and decreased fractional shortening in DKO animals. Mean arterial pressure was increased in DKO mice and was comparable in degree to eNOS-KO animals. Male DKO animals developed atherosclerotic abdominal aneurysms and aortic dissection. Conclusions eNOS deficiency increases atherosclerosis in Western-type diet-fed apoE-KO animals and introduces coronary disease and an array of cardiovascular complications, including spontaneous aortic aneurysm and dissection. This phenotype constitutes the first murine model to demonstrate distal coronary arteriosclerosis associated with evidence of myocardial ischemia, infarction, and heart failure. Hypertrophy and reduced left ventricular function cannot be explained by increased blood pressure alone, because eNOS-KO animals do not develop these complications.

Background —Mechanistic insights from 3D echocardiography (echo) can guide therapy. In particular, ischemic mitral regurgitation (MR) is difficult to repair, often persisting despite annular reduction. We hypothesized that (1) in a chronic infarct model of progressive MR, regurgitation parallels 3D changes in the geometry of mitral leaflet attachments, causing increased leaflet tethering and restricting closure; therefore, (2) MR can be reduced by restoring tethering geometry toward normal, using a new ventricular remodeling approach based on 3D echo findings. Methods and Results —We studied 10 sheep by 3D echo just after circumflex marginal ligation and 8 weeks later. MR, at first absent, became moderate as the left ventricle (LV) dilated and the papillary muscles shifted posteriorly and mediolaterally, increasing the leaflet tethering distance from papillary muscle tips to the anterior mitral annulus ( P P r 2 =0.81). Conclusions —Ischemic MR in this model relates strongly to changes in 3D mitral leaflet attachment geometry. These insights from quantitative 3D echo allowed us to design an effective LV remodeling approach to reduce MR by relieving tethering.

Background —Currently, the reporting and archiving of echocardiographic data suffer from the difficulty of representing heart motion on printable 2-dimensional (2D) media. Methods and Results —We studied the capability of holography to integrate motion into 2D echocardiographic prints. Images of normal human hearts and of a variety of mitral valve function abnormalities (mitral valve prolapse, systolic anterior motion of the mitral leaflets, and obstruction of the mitral valve by a myxoma) were acquired digitally on standard echocardiographic machines. Images were processed into a data format suitable for holographic printing. Angularly multiplexed holograms were then printed on a prototype holographic “laser” printer, with integration of time in vertical parallax, so that heart motion became visible when the hologram was tilted up and down. The resulting holograms displayed the anatomy with the same resolution as the original acquisition and allowed detailed study of valve motion with side-by-side comparison of normal and abnormal findings. Comparison of standard echocardiographic measurements in original echo frames and corresponding hologram views showed an excellent correlation of both methods ( P r 2 =0.979, mean bias=2.76 mm). In this feasibility study, both 2D and 3D holographic images were produced. The equipment needed to view these holograms consists of only a simple point-light source. Conclusions —Holographic representation of myocardial and valve motion from echocardiographic data is feasible and allows the printing on a 2D medium of the complete heart cycle. Combined with the recent development of online holographic printing, this novel technique has the potential to improve reporting, visualization, and archiving of echocardiographic imaging.

Background —Noninvasive cardiac evaluation is of great importance in transgenic mice. Transthoracic echocardiography can visualize the left ventricle well but has not been as successful for the right ventricle (RV). We developed a method of transesophageal echocardiography (TEE) to evaluate murine RV size and function. Methods and Results —Normoxic and chronically hypoxic mice (F io 2 =0.11, 3 weeks) and agarose RV casts were scanned with a rotating 3.5F/30-MHz intravascular ultrasound probe. In vivo, the probe was inserted in the mouse esophagus and withdrawn to obtain contiguous horizontal planes at 1-mm intervals. In vitro, the probe was withdrawn along the left ventricular posterior wall of excised hearts. The borders of the RV were traced on each plane, allowing calculation of diastolic and systolic volumes, RV mass, RV ejection fraction, stroke volume, and cardiac output. RV wall thickness was measured. Echo volumes obtained in vitro were compared with cast volumes. Echo-derived cardiac output was compared with measurements of an ascending aortic Doppler flow probe. Echo-derived RV free wall mass was compared with true RV free wall weight. There was excellent agreement between cast and TEE volumes ( y =0.82 x +6.03, r =0.88, P y =1.00 x +0.45, r =0.99, P y =0.53 x +2.29, r =0.81, P P P Conclusions —TEE with an intravascular ultrasound catheter is a simple, accurate, and reproducible method to study RV size and function in mice.

Cigarette smoking increases the alveolar epithelial permeability to small solutes, as assessed by the pulmonary clearance of aerosolized 99mTc-labeled diethylenetriaminepentaacetate. The involvement of lipid peroxidation in this increased clearance was tested in eight asymptomatic young smokers by investigating the effects of a 3-wk supplementation with oral vitamin E (1,000 IU/day) on pulmonary clearance according to a protocol designed as a single-blind crossover study. Indexes of acute tobacco intoxication (exhaled CO, carboxyhemoglobin, and urinary cotinine) and lung function parameters [including Krogh factor (KCO)] were also studied. Under control conditions, pulmonary clearance was abnormally increased (2.93 +/- 0.78%/min), whereas KCO was in the normal range. Pulmonary clearance correlated strongly with expired CO (P < 0.04), HbCO (P < 0.005), urinary cotinine (P < 0.003), and KCO (P < 0.004). Supplementation with vitamin E, a highly efficient antioxidant, neither decreased the pulmonary clearance nor altered the above correlations. However, the strong correlations observed between pulmonary clearance and indexes of acute tobacco intoxication, which reflect the amount of inhaled smoke and the resultant oxidant stress, do not allow exclusion of the involvement of lipid peroxidation in the pulmonary clearance increase observed in smokers.

Whether angioplasty of occluded vessels after myocardial infarction may have beneficial effects on left ventricular function remains unknown. Patients with a first myocardial infarction and thrombolytic therapy who had an occluded infarct-related vessel at delayed coronary angiography were referred systematically for an elective coronary angioplasty performed between 3 and 4 weeks after the myocardial infarction. All patients underwent stress-redistribution-reinjection thallium-201 single-photon emission computed tomography for myocardial viability assessment. Prior angioplasty, a quantitative evaluation of global and regional left ventricular function, was performed. The study group consisted of 38 patients (aged 57 +/- 10 years); 18 had anterior wall infarctions and 20 inferior wall infarctions, but before angioplasty 3 had a patent artery and were excluded. Angioplasty was successful in 30 patients. At follow-up 13 patients (43%) had an occluded coronary artery. In contrast with patients with an occluded coronary artery at follow-up, those with a patent coronary artery had no left ventricular enlargement and had an improvement in both left ventricular ejection fraction (from 48 +/- 9% to 52 +/- 9.8%, p = 0.002) and regional wall motion index (delta = +0.95 SD, p0.01). In patients with a patent vessel at follow-up, there was a positive correlation between the number of myocardial viable segments and improvement of the infarct zone wall motion (r = 0.52; p = 0.035), and the number of necrotic segments at baseline was positively correlated to the 4-month changes in end-diastolic volume indexes (r = 0.6; p = 0.04). Thus, elective revascularization of occluded coronary arteries with viable myocardium after myocardial infarction improves left ventricular function and lessens remodeling if the artery remains patent during follow-up.

It has been observed that sustained exercise results in a prolonged increase in alveolar epithelial permeability, as assessed by the pulmonary clearance rate of aerosolized 99mTc-labeled diethylenetriaminepentaacetate (Lorino et al. J. Appl. Physiol. 67: 2055–2059, 1989). The involvement of lipid peroxidation in this increased permeability was tested in seven nonsmoking volunteers by comparing the exercise-induced increases in pulmonary 99mTc-diethylenetriaminepentaacetate clearance before and after a 3-wk supplementation with oral vitamin E (1,000 IU/day), according to a protocol designed as a single-blind crossover study. The 60-min exercise was performed on a treadmill at a constant load corresponding to 80% of maximal O2 uptake. Administration of vitamin E, a very important antioxidant, did not reduce the exercise-induced increase in lung clearance, suggesting that the exercise-induced increase in lung epithelial permeability does not primarily result from the occurrence of lipid peroxidation in the alveolar membrane. This result thus corroborates the hypothesis of an alteration of the intercellular tight junctions due to the mechanical effects of hyperventilation.

Background Genetically modified mice offer the unique opportunity to gain insights into the pathophysiology of pulmonary arterial hypertension (PAH). In mice, right heart catheterization is the only available technique to measure right ventricular systolic pressure (RVSP). However, it is a terminal procedure and does not allow serial follow-up. Our objective was to validate a non-invasive technique to assess RVSP in mice. Methods Right ventricle catheterization and echocardiography were simultaneously performed in mice with pulmonary hypertension induced acutely by infusion of a thromboxane analogue, U-46619 or chronically by lung-specific over-expression of interleukin 6 (IL-6). In a subgroup of mice, echocardiography was performed using light anesthesia before catheterization. Pulsed-Doppler of pulmonary artery flow was recorded in the parasternal short axis view. Pulmonary acceleration time (PAT), and ejection time (ET) were measured. Results Infusion of U-46619 acutely increased RVSP, shortened PAT and decreased PAT/ET. The pulmonary flow pattern changed from symmetric at baseline to asymmetric at higher RVSPs. Transgenic IL-6 mice had high RVSP measured by catheter (39±7 mmHg), short PAT (17±4 ms) and low PAT/ET ratio (31±8%). The PAT correlated linearly with RVSP (r2=–0.67; p 32 mmHg) were 100% (7/7) and 86% (6/7), respectively, for both indexes (cutoff values: PAT Conclusion Pulmonary artery systolic pressure can be estimated noninvasively in mice. Echocardiography allows to monitor acute changes of RVSP and to detect pulmonary hypertension. This technique enables to follow PAH evolution easily and repeatedly in mice. Download : Download full-size image

The lack of standardized reporting of the magnitude of ischemia on noninvasive imaging contributes to variability in translating the severity of ischemia across stress imaging modalities. We identified the risk of coronary artery disease (CAD) death or myocardial infarction (MI) associated with ≥10% ischemic myocardium on stress nuclear imaging as the risk threshold for stress echocardiography and cardiac magnetic resonance. A narrative review revealed that ≥10% ischemic myocardium on stress nuclear imaging was associated with a median rate of CAD death or MI of 4.9%/year (interquartile range: 3.75% to 5.3%). For stress echocardiography, ≥3 newly dysfunctional segments portend a median rate of CAD death or MI of 4.5%/year (interquartile range: 3.8% to 5.9%). Although imprecisely delineated, moderate-severe ischemia on cardiac magnetic resonance may be indicated by ≥4 of 32 stress perfusion defects or ≥3 dobutamine-induced dysfunctional segments. Risk-based thresholds can define equivalent amounts of ischemia across the stress imaging modalities, which will help to translate a common understanding of patient risk on which to guide subsequent management decisions.

Background: Stress echocardiography (SE) is dependent on subjective interpretations. As a prelude to the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) Trial, potential sites were required to submit two SE, one with moderate or severe left ventricular (LV) myocardial ischemia and one with mild ischemia. We evaluated the concordance of site and core lab interpretations. Methods: Eighty-one SE were submitted from 41 international sites. Ischemia was classified by the number of new or worsening segmental LV wall motion abnormalities (WMA): none, mild (1 or 2) or moderate or severe (3 or more) by the sites and the core lab. Results: Core lab classified 6 SE as no ischemia, 35 mild and 40 moderate or greater. There was agreement between the site and core in 66 of 81 total cases (81 %, weighted kappa coefficient [K] =0.635). Agreement was similar for SE type - 24 of 30 exercise (80 %, K = 0.571) vs. 41 of 49 pharmacologic (84 %, K = 0.685). The agreement between poor or fair image quality (27 of 36 cases, 75 %, K = 0.492) was not as good as for the good or excellent image quality cases (39 of 45 cases, 87 %, K = 0.755). Differences in concordance were noted for degree of ischemia with the majority of discordant interpretations (87 %) occurring in patients with no or mild LV myocardial ischemia. Conclusions: While site SE interpretations are largely concordant with core lab interpretations, this appears dependent on image quality and the extent of WMA. Thus core lab interpretations remain important in clinical trials where consistency of interpretation across a range of cases is critical. Trial registration: ClinicalTrials.gov NCT01471522

Conventional photon radiotherapy (RT) for breast cancer is cardiotoxic. The physical properties of protons is an alternative form of radiotherapy with much reduced radiation dosages, thus may be less cardiotoxic. Aim: To determine if proton therapy results in subclinical cardiac dysfunction in a