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Aims Determining which patients with pericardial effusion require urgent intervention can be challenging. We sought to develop a novel, simple risk prediction score for patients with pericardial effusion. Methods and results Adult patients admitted through the emergency department (ED) with pericardial effusion were retrospectively evaluated. The overall cohort was divided into a derivation and validation cohort for the generation and validation of a novel risk score using logistic regression. The primary outcome was a pericardial drainage procedure or death attributed to cardiac tamponade within 24 h of ED arrival. Among 195 eligible patients, 102 (52%) experienced the primary outcome. Four variables were selected for the novel score: systolic blood pressure 3 cm (2 points)], right ventricular diastolic collapse (2 points), and mitral inflow velocity variation > 25% (1 point). The need for pericardial drainage within 24 h was stratified as low ( Conclusion Among ED patients with pericardial effusion, a four-variable prediction score consisting of systolic blood pressure, effusion diameter, right ventricular collapse, and mitral inflow velocity variation can accurately predict the need for urgent pericardial drainage. Prospective validation of this novel score is warranted.

This chapter reviews the use of echocardiography in patients with heart failure, including heart failure with reduced and heart failure with preserved ejection fraction.

Echocardiography often visualizes cardiac masses which may comprise true tumors, thrombi, and vegetations. However, there are a variety of other structures that may often be misinterpreted to be significant pathology, when in fact they are not.

Tumors within the heart and pericardium are often initially detected by cardiac ultrasound. This chapter reviews the primary and secondary tumors of the heart. Their characteristics, benign versus malignant nature, locations, echocardiographic appearance, and effects on the heart and the patient are discussed.

Acute and subacute complications of myocardial infarction are often life-threatening and should be recognized by the astute sonographer. These include acute mitral valve disruption and consequent mitral regurgitation (flail mitral valve), ventricular septal defect, and free wall rupture (leading to either ventricular pseudoaneurysm, contained left ventricular rupture, or tamponade with hemopericardium). The echocardiographic manifestations of these emergencies are comprehensively covered in this chapter.

The primary aim of the present study was to identify the hemodynamic correlates of both steady and pulsatile blood pressure in community-dwelling older adults. In 3,762 adults aged 70–89 years, we observed that significant hemodynamic determinants of systolic blood pressure included arterial stiffness as measured by aortic pulse wave velocity, stroke volume (via echocardiography), arterial wave reflection, left ventricular ejection time, and upstroke time. The strongest influence was exerted by arterial stiffness. The steady state component of blood pressure, mean arterial pressure, was associated with both cardiac index and total peripheral resistance (TPR), but was more strongly associated with TPR. Results were similar when participants taking antihypertensive medications were excluded from analyses. The overall findings suggest that mean arterial pressure is associated strongly with TPR and that significant hemodynamic correlates of systolic blood pressure included arterial stiffness, stroke volume, and arterial wave reflection.

Background Appropriate use criteria (AUC) for transthoracic echocardiography (TTE) were developed to address concerns regarding inappropriate use of TTE. A previous pilot study suggests that an educational and feedback intervention can reduce inappropriate TTEs ordered by physicians in training. It is unknown if this type of intervention will be effective when targeted at attending level physicians in a variety of clinical settings. Aims The aim of this international, multicenter study is to evaluate the hypothesis that an AUC-based educational and feedback intervention will reduce the proportion of inappropriate echocardiograms ordered by attending physicians in the ambulatory environment. Methods In an ongoing multicentered, investigator-blinded, randomized controlled trial across Canada and the United States, cardiologists and primary care physicians practicing in the ambulatory setting will be enrolled. The intervention arm will receive (1) a lecture outlining the AUC and most recent available evidence highlighting appropriate use of TTE, (2) access to the American Society of Echocardiography mobile phone app, and (3) individualized feedback reports e-mailed monthly summarizing TTE ordering behavior including information on inappropriate TTEs and brief explanations of the inappropriate designation. The control group will receive no education on TTE appropriate use and order TTEs as usual practice. Conclusions The Echo WISELY (Will Inappropriate Scenarios for Echocardiography Lessen Significantly in an education RCT) study is the first multicenter randomized trial of an AUC-based educational intervention. The study will examine whether an education and feedback intervention will reduce the rate of outpatient inappropriate TTEs ordered by attending level cardiologists and primary care physicians (www.clinicaltrials.gov identifier NCT02038101).

Longstanding uncontrolled atherogenic risk factors may contribute to left atrial (LA) hypertension, LA enlargement (LAE) and coronary vascular dysfunction. Together they may better identify risk of major adverse cardiac events (MACE). The aim of this study was to test the hypothesis that chronic LA hypertension as assessed by LAE modifies the relationship between coronary vascular function and MACE.In 508 unselected subjects with a normal clinical (82)Rb PET/CT, ejection fraction ≥40 %, no prior coronary artery disease, valve disease or atrial fibrillation, LAE was determined based on LA volumes estimated from the hybrid perfusion and CT transmission scan images and indexed to body surface area. Absolute myocardial blood flow and global coronary flow reserve (CFR) were calculated. Subjects were systematically followed-up for the primary end-point - MACE - a composite of all-cause death, myocardial infarction, hospitalization for heart failure, stroke, coronary artery disease progression or revascularization.During a median follow-up of 862 days, 65 of the subjects experienced a composite event. Compared with subjects with normal LA size, subjects with LAE showed significantly lower CFR (2.25 ± 0.83 vs. 1.95 ± 0.80, p = 0.01). LAE independently and incrementally predicted MACE even after accounting for clinical risk factors, medication use, stress left ventricular ejection fraction, stress left ventricular end-diastolic volume index and CFR (chi-squared statistic increased from 30.9 to 48.3; p = 0.001). Among subjects with normal CFR, those with LAE had significantly worse event-free survival (risk adjusted HR 5.4, 95 % CI 2.3 - 12.8, p 0.0001).LAE and reduced CFR are related but distinct cardiovascular adaptations to atherogenic risk factors. LAE is a risk marker for MACE independent of clinical factors and left ventricular volumes; individuals with LAE may be at risk of MACE despite normal coronary vascular function.

Appropriate use criteria (AUC) have defined transthoracic echocardiogram (TTE) indications for which there is a clear lack of benefit as rarely appropriate (rA).This study sought to investigate the impact of an AUC-based educational intervention on outpatient TTE ordering by cardiologists and primary care providers.The authors conducted a prospective, investigator-blinded, multicenter, randomized controlled trial of an AUC-based educational intervention aimed at reducing rA outpatient TTEs. The study was conducted at 8 hospitals across 2 countries. The authors randomized cardiologists and primary care providers to receive either intervention or control (no intervention). The primary outcome measure was the proportion of rA TTEs.One hundred and ninety-six physicians were randomized, and 179 were included in the analysis. From December 2014 to April 2016, the authors assessed 14,697 TTEs for appropriateness, of which 99% were classifiable using the 2011 AUC. The mean proportion of rA TTEs was significantly lower in the intervention versus the control group (8.8% vs. 10.1%; odds ratio [OR]: 0.75; 95% confidence interval [CI]: 0.57 to 0.99; p = 0.039). In physicians who ordered, on average, at least 1 TTE per month, there was a significantly lower proportion of rA TTEs in the intervention versus the control group (8.6% vs. 11.1%; OR: 0.76; 95% CI: 0.57 to 0.99; p = 0.047). There was no difference in the TTE ordering volume between the intervention and control groups (mean 77.7 ± 89.3 vs. 85.4 ± 111.4; p = 0.83).An educational intervention reduced the number of rA TTEs ordered by attending physicians in a variety of ambulatory care environments. This may prove to be an effective strategy to improve the use of imaging. (A Multi-Centered Feedback and Education Intervention Designed to Reduce Inappropriate Transthoracic Echocardiograms [Echo WISELY]; NCT02038101).

BACKGROUND Proficiency and self-confidence in the physical examination is poor among internal medicine residents and interest in ultrasound technology has expanded.

Background— Heart failure is an important public health concern, particularly among persons >65 years of age. Women and blacks are critically understudied populations that carry a sizeable portion of the heart failure burden. Limited normative and prognostic data exist on measures of cardiac structure, diastolic function, and novel measures of systolic deformation in older adults living in the community. Methods and Results— The Atherosclerosis Risk in Communities (ARIC) study is a large, predominantly biracial, National Heart, Lung, and Blood Institute–sponsored epidemiological cohort study. Between 2011 and 2013, ≈6000 surviving participants, now in their seventh to ninth decade of life, are expected to return for a fifth study visit during which comprehensive 2-dimensional, Doppler, tissue Doppler, and speckle-tracking echocardiography will be performed uniformly in all cohort clinic visit participants. The following objectives will be addressed: (1) to characterize cardiac structural and functional abnormalities among the elderly and to determine how they differ by sex and race/ethnicity, (2) to determine the relationship between ventricular and vascular abnormalities, and (3) to prospectively examine the extent to which these noninvasive measures associate with incident heart failure. Conclusions— We describe the design, imaging acquisition and analysis methods, and quality assurance metrics for echocardiography in visit 5 of the ARIC cohort. A better understanding of the differences in cardiac structure and function through the spectrum of heart failure stages in elderly persons generally, and between sexes and racial/ethnic groups specifically, will deepen our understanding of the pathophysiology driving heart failure progression in these at-risk populations and may inform novel prevention or therapeutic strategies.

Objective Functional (or secondary) mitral regurgitation (FMR) is associated with greater morbidity and worse outcomes in patients with congestive heart failure (CHF) and cardiomyopathy. The Carillon® Mitral Contour System® is a coronary sinus-based percutaneous therapy to reduce FMR. We evaluated the safety and efficacy of a modified version of the Carillon device in the treatment of patients with cardiomyopathy and FMR. Methods 36 patients with CHF, depressed left ventricular function (ejection fraction

Aims Fabry disease is a rare X-linked deficiency of α-galactosidase A (αgal), which causes glycosphingolipid accumulation. This study analysed the cardiovascular manifestations of a cohort of Fabry patients, and sought to define relationships between disease severity, αgal activity, and cardiac abnormalities. Methods and results We prospectively analysed Fabry patients (139 subjects: 92 males and 47 females) undergoing screening for potential enzyme replacement therapy. Baseline echocardiograms, electrocardiograms, and exams were obtained as part of two multinational clinical trials. Cardiovascular symptoms were present in 60.4%. By echocardiography, the mean left ventricular mass index (LVMI) was increased at 165.5 ± 66.9 g/m2, and 84.8% of patients displayed concentric left ventricular hypertrophy (LVH). Electrocardiographic LVH was present in >50% of adult subjects. In females, log-corrected plasma αgal activity was inversely associated with LVMI ( r = −0.45, P < 0.040). Males with extremely low αgal activity and renal disease displayed the most LVH and cardiac symptoms, but LVH was prevalent even in females

Replacing a stenotic aortic valve with 19-mm bioprostheses remains controversial owing to potential patient-prosthesis mismatch concerns. We report a single-center 10 year experience with 19-mm bioprosthetic valves implanted in elderly patients. We hypothesized patients would have acceptable in-hospital and long-term outcomes.Between January 2002 and December 2011, 257 patients underwent aortic valve replacement with a 19-mm prosthesis, of whom 182 had available follow-up echocardiographic studies. Mean age was 77.4 ± 8.4 years, and 10 of 257 (4%) were male. Outcomes of interest included early and late mortality, peak and mean aortic valve gradients, and left ventricular mass regression.Operative mortality was 3.5% (9 of 257). Median postoperative echocardiographic time was 16 months. On follow-up echocardiography, mean peak aortic valve gradient decreased from 76 ± 27 mm Hg preoperatively to 32 ± 13 mm Hg and the mean gradient decreased from 46 ± 17 mm Hg to 18 ± 8 mm Hg (both p0.001) Mean left ventricular mass decreased from 191 g to 162 g (p0.001). Postoperative survival did not differ significantly between patients who met the criteria for patient-prosthesis mismatch and those who did not (p = 0.607).In a series of elderly patients with aortic stenosis who were implanted with 19-mm bioprosthetic valves, long-term follow-up showed significant left ventricular mass regression and peak and mean aortic valve gradient reductions. The use of 19-mm aortic valves is safe and efficacious for elderly patients with a small aortic root.

Increased nitric oxide (NO) production by inducible NO synthase (NOS2), an obligate homodimer, is implicated in the cardiovascular sequelae of sepsis. We tested the ability of a highly selective NOS2 dimerization inhibitor (BBS-2) to prevent endotoxin-induced systemic hypotension, myocardial dysfunction, and impaired hypoxic pulmonary vasoconstriction (HPV) in mice. Mice were challenged with Escherichia coli endotoxin before treatment with BBS-2 or vehicle. Systemic blood pressure was measured before and 4 and 7 h after endotoxin challenge, and echocardiographic parameters of myocardial function were measured before and 7 h after endotoxin challenge. The pulmonary vasoconstrictor response to left mainstem bronchus occlusion, which is a measure of HPV, was studied 22 h after endotoxin challenge. BBS-2 treatment alone did not alter baseline hemodynamics. BBS-2 treatment blocked NOS2 dimerization and completely inhibited the endotoxin-induced increase of plasma nitrate and nitrite levels. Treatment with BBS-2 after endotoxin administration prevented systemic hypotension and attenuated myocardial dysfunction. BBS-2 also prevented endotoxin-induced impairment of HPV. In contrast, treatment with NG-nitro-l-arginine methyl ester, which is an inhibitor of all three NOS isoforms, prevented the systemic hypotension but further aggravated the myocardial dysfunction associated with endotoxin challenge. Treatment with BBS-2 prevented endotoxin from causing key features of cardiovascular dysfunction in endotoxemic mice. Selective inhibition of NOS2 dimerization with BBS-2, while sparing the activities of other NOS isoforms, may prove to be a useful treatment strategy in sepsis.

The vertebrate heart differs from chordate ancestors both structurally and functionally. Genetic units of form, termed ‘modules’, are identifiable by mutation, both in zebrafish and mouse, and correspond to features recently acquired in evolution, such as the ventricular chamber or endothelial lining of the vessels and heart. Zebrafish (Danio rerio) genetic screens have provided a reasonably inclusive set of such genes. Normal cardiac function may also be disrupted by single–gene mutations in zebrafish. Individual mutations may perturb contractility or rhythm generation. The zebrafish mutations which principally disturb cardiac contractility fall into two broad phenotypic categories, ‘dilated’ and ‘hypertrophic’. Interestingly, these correspond to the two primary types of heart failure in humans. These disorders of early cardiac function provide candidate genes to be examined in complex human heart diseases, including arrhythmias and heart failure.

Cardiac masses may present themselves upon investigation of cardiovascular symptoms, systemic manifestations, or incidentally upon screening. The differential diagnosis, workup, and subsequent management are heavily dependent upon the presenting clinical setting and the individual patient. In the broadest terms, a mass may be a benign or malignant tumor, a degenerative or infectious process, a normal but prominent structure, or even merely an imaging artifact that has been misinterpreted.

The p53 gene is frequently mutated in human tumors; in hepatocellular carcinomas, there is a high frequency of a specific mutation at codon 249 in regions with significant aflatoxin exposure. To assess the role of this p53 mutation in the development of hepatocellular carcinoma, a mutant murine p53 gene, p53ser246, which corresponds to human codon 249, was transfected into a differentiated, nontransformed hepatocyte cell line AML12. Expression of p53ser246 in this line resulted in a growth advantage when compared with either a control vector (which contains a large p53 deletion) or with a different p53 mutant, val135, not found in hepatocellular carcinoma. Overall, there was a threefold increase in colony formation after transfection with p53ser246 as compared with the control or p53val135 vectors, and the p53ser246 plates developed consistently larger colonies. Whereas clones expressing the control or p53val135 constructs showed no significant morphological changes, clones expressing p53ser246 showed increased heterogeneity (large multinucleated cells and areas of small crowded cells) without focus formation. In addition, the ser246 mutation imparted a growth advantage in serum-free media, suggesting less dependence on specific factors present in serum. None of the mutant p53 or control lines were capable of growth in soft agar or tumor formation in nude mice. Thus in this model, in which endogenous wild-type p53 expression is retained, a high level of mutant p53 expression is not sufficient to transform hepatocytes. Our findings indicate that p53ser246 has effects on hepatocytes that may result in a clonal growth advantage and suggest that additional factors are required for the development of hepatocellular carcinoma.

Fabry disease is an X-linked deficiency of a-galsactosidase A, which leads to accumulation of glycosphingolipid in tissues and blood vessels. The extent to which Fabry disease is associated with cardiac dysfunction, even in the setting of a normal EF, is unknown. We studied 80 patients with Fabry

Background— Clinical observations of migraine headache symptoms in patients with a patent foramen ovale (PFO), both of which conditions are highly prevalent, have raised the question of a possible pathophysiological relationship. We sought to evaluate the assumption of an association between migraine headaches and the presence of PFO by use of a large case-control study. Methods and Results— We conducted a case-control study to assess the prevalence of PFO in subjects with and without migraine. Case subjects were those with a history of migraine (diagnosed by neurologists at a specialty academic headache clinic). Control subjects were healthy volunteers without migraine 1:1 matched on the basis of age and sex with case subjects. Presence of PFO was determined by transthoracic echocardiogram with second harmonic imaging and transcranial Doppler ultrasonography during a standardized procedure of infused agitated saline contrast with or without Valsalva maneuver and a review of the results by experts blinded to case-control status. PFO was considered present if both studies were positive. Odds ratios were calculated with conditional logistic regression in the matched cohort (n=288). In the matched analysis, the prevalence of PFO was similar in case and control subjects (26.4% versus 25.7%; odds ratio 1.04, 95% confidence interval 0.62 to 1.74, P =0.90). There was no difference in PFO prevalence in those with migraine with aura and those without (26.8% versus 26.1%; odds ratio 1.03, 95% confidence interval 0.48 to 2.21, P =0.93). Conclusions— We found no association between migraine headaches and the presence of PFO in this large case-control study.

Background— Functional mitral regurgitation (FMR), a well-recognized component of left ventricular remodeling, is associated with increased morbidity and mortality in heart failure patients. Percutaneous mitral annuloplasty has the potential to serve as a therapeutic adjunct to standard medical care. Methods and Results— Patients with dilated cardiomyopathy, moderate to severe FMR, an ejection fraction P P Conclusions— Percutaneous reduction in FMR with a novel coronary sinus–based mitral annuloplasty device is feasible in patients with heart failure, is associated with a low rate of major adverse events, and is associated with improvement in quality of life and exercise tolerance.

An embolus is an intravascular mass, which usually comprises a thrombus, atheromatous, or cellular matter that has entered the circulation and causes symptoms by lodging in end arteries and interrupting blood flow to the organs. Emboli from the venous system can enter the right side of the heart and cause pulmonary emboli, whereas those originating from the left side of the heart and great arteries can cause infarcts in the brain, kidneys, intestines, and skin. Although small strokes and transient ischemic attacks (TIAs) are often caused by atheromatous debris from the aorta or major cerebral arteries, an embolus large enough to occlude multiple major peripheral or visceral arteries is more likely to originate from the heart. A paradoxical embolus is a systemic infarct in which the source of the embolus is thought to be from the venous system, which has bypassed the pulmonary circulation by means of an intracardiac shunt, and crossed into the arterial circulation.

Masses in or around the heart are most often incidental findings on echocardiography. Less frequently, a tumor involving the heart causes direct symptoms that lead the clinician to suspect a cardiac abnormality.

Among the earliest detectable changes in myocardial ischemia or an acute MI are regional LV and potentially also right ventricular wall motion abnormalities. The LV can be divided into 17 anatomic segments, which can be viewed as a composite from the standard echocardiographic views, and have standardized nomenclature as recommended by the American Heart Association (AHA) (it see Chapter 5, Figs. 1 and 10). Normal wall motion (normally kinetic segments) is seen as wall thickening, caused by the contraction of individual myocardial fibers; on echocardiography, this is seen as the radial distance between the epi- and endocardial borders, which increases by at least 10–20% during systole. Abnormal wall motion owing to insufficient blood supply to the myocardium may be graded as hypokinetic (thickening, but less than normal), akinetic (no thickening), and dyskinetic or aneurysmal (no thickening, with outward movement of the segment during systole, owing to increased intraventricular pressure on a scarred and noncontractile area of myocardial fibrosis). In general, myocardium that is transmurally infarcted tends to have more severe dysfunction, with akinetic or dyskinetic motion.

The identification of ABCA1 as a key transporter responsible for cellular lipid efflux has led to considerable interest in defining its role in cholesterol metabolism and atherosclerosis. In this study, the effect of overexpressing ABCA1 in the liver of LDLr-KO mice was investigated. Compared with LDLr-KO mice, ABCA1-Tg x LDLr-KO (ABCA1-Tg) mice had significantly increased plasma cholesterol levels, mostly because of a 2.8-fold increase in cholesterol associated with a large pool of apoB-lipoproteins. ApoB synthesis was unchanged but the catabolism of (125)I-apoB-VLDL and -LDL were significantly delayed, accounting for the 1.35-fold increase in plasma apoB levels in ABCA1-Tg mice. We also found rapid in vivo transfer of free cholesterol from HDL to apoB-lipoproteins in ABCA1-Tg mice, associated with a significant 2.7-fold increase in the LCAT-derived cholesteryl linoleate content found primarily in apoB-lipoproteins. ABCA1-Tg mice had 1.4-fold increased hepatic cholesterol concentrations, leading to a compensatory 71% decrease in de novo hepatic cholesterol synthesis, as well as enhanced biliary cholesterol, and bile acid secretion. CAV-1, CYP2b10, and ABCG1 were significantly induced in ABCA1-overexpressing livers; however, no differences were observed in the hepatic expression of CYP7alpha1, CYP27alpha1, or ABCG5/G8 between ABCA1-Tg and control mice. As expected from the pro-atherogenic plasma lipid profile, aortic atherosclerosis was increased 10-fold in ABCA1-Tg mice. In summary, hepatic overexpression of ABCA1 in LDLr-KO mice leads to: 1) expansion of the pro-atherogenic apoB-lipoprotein cholesterol pool size via enhanced transfer of HDL-cholesterol to apoB-lipoproteins and delayed catabolism of cholesterol-enriched apoB-lipoproteins; 2) increased cholesterol concentration in the liver, resulting in up-regulated hepatobiliary sterol secretion; and 3) significantly enhanced aortic atherosclerotic lesions.

The ATP binding cassette (ABC) half-transporters ABCG5 and ABCG8 facilitate biliary and intestinal removal of neutral sterols. Here, we identify a binding site for the orphan nuclear receptor liver receptor homolog-1 (LRH-1) at nt 134-142 of the ABCG5/ABCG8 intergenic region necessary for the activity of both the ABCG5 and ABCG8 promoters. Mutating this LRH-1 binding site reduced promoter activity of the human ABCG5/ABCG8 intergenic region more than 7-fold in HepG2 and Caco2 cells. Electrophoretic mobility shift assays with HepG2 nuclear extracts demonstrated specific binding of LRH-1 to the LRH-1 binding motif in the human ABCG5/ABCG8 intergenic region. LRH-1 overexpression increased promoter activity up to 1.6-fold and 3-fold in Caco2 and 293 cells, respectively. Finally, deoxycholic acid repressed the ABCG5 and ABCG8 promoters, consistent with bile acid regulation via the farnesoid X receptor-small heterodimeric partner-LRH-1 pathway. These results demonstrate that LRH-1 is a positive transcription factor for ABCG5 and ABCG8 and, in conjunction with studies on LRH-1 activation of other promoters, identify LRH-1 as a "master regulator" for genes involved in sterol and bile acid secretion from liver and intestine.

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.

The serine-threonine kinase, Akt, inhibits cardiomyocyte apoptosis acutely both in vitro and in vivo. However, the effects of chronic Akt activation in the heart are unknown. To address this issue, we generated transgenic mice (TG+) with cardiac-specific expression of a constitutively active mutant of Akt (myr-Akt) driven by the myosin heavy chain-alpha promoter. Three TG+ founders (9-19 weeks) died suddenly with massive cardiac dilatation. Two viable TG+ lines (TG564 and TG20) derived from independent founders demonstrated cardiac-specific transgene expression as well as activation of Akt and p70S6 kinase. TG564 (n = 19) showed cardiac hypertrophy with a heart/body weight ratio 2.3-fold greater than littermates (n = 17, p < 0.005). TG20 (n = 18) had less marked cardiac hypertrophy with a heart/body weight ratio 1.6-fold greater than littermates (n = 17, p < 0.005). Isolated TG564 myocytes were also hypertrophic with surface areas 1.7-fold greater than littermates (p < 0.000001). Echocardiograms in both lines demonstrated concentric hypertrophy and preserved systolic function. After ischemia-reperfusion, TG+ had a 50% reduction in infarct size versus TG- (17 +/- 3% versus 34 +/- 4%, p < 0.001). Thus, chronic Akt activation is sufficient to cause a spectrum of phenotypes from moderate cardiac hypertrophy with preserved systolic function and cardioprotection to massive cardiac dilatation and sudden death.

Hepatocytes are extensively used in studies of gene regulation but cannot be maintained in long-term culture as replicating, differentiated cells while remaining nontumorigenic. We have derived two hepatocyte lines from livers of transgenic mice overexpressing transforming growth factor alpha, a potent hepatocyte mitogen, which overcome these limitations. The transgenic hepatocytes were maintained for > or = 2 months in serum-supplemented primary culture and gave rise to cell lines, of which two (AML12 and AML14) have been cultured for > 1.5 years (> 80 passages). Both lines have typical hepatocyte features such as peroxisomes and bile canalicular-like structures, do not grow in soft agar, and are nontumorigenic in nude mice. Like normal hepatocytes, AML cells express high levels of mRNA for serum (albumin, alpha 1-antitrypsin, and transferrin) and gap junction (connexins 26 and 32) proteins, secrete albumin, and contain solely isozyme 5 of lactate dehydrogenase. After extensive passaging, AML12 cells continue to strongly coexpress hepatocyte connexin mRNAs but do not display nonparenchymal cell markers. Although mRNA levels for some serum proteins progressively fall, high expression in late AML12 cultures may be regained by passage in serum-free medium. The AML14 line loses expression of both differentiated markers and transgene mRNA with extended passaging, and hepatocytic traits are only partially restored by passage in serum-free medium. These differentiated, nontumorigenic cell lines should serve as models in which to study hepatocyte growth and differentiation.