Relationship between the extent of non-viable myocardium and regional left ventricular function in chronic ischemic heart disease

Purpose. To define the relationship between left ventricular (LV) regional contractile function and the extent of myocardial scar in patients with chronic ischemic heart disease and multi-vessel coronary artery disease. Methods. Twenty-three patients with chronic ischemic heart disease and 5 healthy volunteers underwent magnetic resonance imaging (MRI). In patients, the relative area ( Percent Scar) and transmural extent (Transmurality) of myocardial infarction were computed from short-axis delayed enhancement images. In each image, myocardial segments were categorized based on the extent of infarction they contained, with 6 categories each for Percent Scar and Transmurality: normal, from healthy volunteers; and 0%; 1–25%, 26–50%, 51–75%, and \u3e 76% from patients. In patients and volunteers, regional LV function was quantified by absolute systolic wall thickening from cine images and midwall circumferential strain using tagged images. Results. Compared to normal segments, regional LV function in patients was significantly diminished in all scar extent intervals, with wall thickening=-8% for all categories. Systolic wall thickening was reduced significantly in all categories above 50% Percent Scar and above 25% Transmurality in patients, relative to corresponding 0% categories. Circumferential strain was significantly reduced above 25% Percent Scar and above 25% Transmurality. Conclusions. In patients with chronic ischemic heart disease and multivessel coronary artery disease, wall thickening was more sensitive to changes in scar Transmurality than to changes in Percent Scar. However, circumferential strain was equally sensitive to both indices. In general, circumferential strain was more sensitive than wall thickening to increases in scar extent

Relationship between the extent of non-viable myocardium and regional left ventricular function in chronic ischemic heart disease

Purpose. To define the relationship between left ventricular (LV) regional contractile function and the extent of myocardial scar in patients with chronic ischemic heart disease and multi-vessel coronary artery disease. Methods. Twenty-three patients with chronic ischemic heart disease and 5 healthy volunteers underwent magnetic resonance imaging (MRI). In patients, the relative area ( Percent Scar) and transmural extent (Transmurality) of myocardial infarction were computed from short-axis delayed enhancement images. In each image, myocardial segments were categorized based on the extent of infarction they contained, with 6 categories each for Percent Scar and Transmurality: normal, from healthy volunteers; and 0%; 1–25%, 26–50%, 51–75%, and \u3e 76% from patients. In patients and volunteers, regional LV function was quantified by absolute systolic wall thickening from cine images and midwall circumferential strain using tagged images. Results. Compared to normal segments, regional LV function in patients was significantly diminished in all scar extent intervals, with wall thickening=-8% for all categories. Systolic wall thickening was reduced significantly in all categories above 50% Percent Scar and above 25% Transmurality in patients, relative to corresponding 0% categories. Circumferential strain was significantly reduced above 25% Percent Scar and above 25% Transmurality. Conclusions. In patients with chronic ischemic heart disease and multivessel coronary artery disease, wall thickening was more sensitive to changes in scar Transmurality than to changes in Percent Scar. However, circumferential strain was equally sensitive to both indices. In general, circumferential strain was more sensitive than wall thickening to increases in scar extent

Extent of Thoracic Aortic Atheroma Burden and Long-Term Mortality After Cardiothoracic Surgery A Computed Tomography Study

ObjectivesWe hypothesized that the extent of aortic atheroma of the entire thoracic aorta, determined by pre-operative multidetector-row computed tomographic angiography (MDCTA), is associated with long-term mortality following nonaortic cardiothoracic surgery.BackgroundIn patients evaluated for cardiothoracic surgery, presence of severe aortic atheroma is associated with adverse short- and long-term post-operative outcome. However, the relationship between aortic plaque burden and mortality remains unknown.MethodsWe reviewed clinical and imaging data from all patients who underwent electrocardiographic-gated contrast-enhanced MDCTA prior to coronary bypass or valvular heart surgery at our institution between 2002 and 2008. MDCTA studies were analyzed for thickness and circumferential extent of aortic atheroma in 5 segments of the thoracic aorta. A semiquantitative total plaque-burden score (TPBS) was calculated by assigning a score of 1 to 3 to plaque thickness and to circumferential plaque extent. When combined, this resulted in a score of 0 to 6 for each of the 5 segments and, hence, an overall score from 0 to 30. The primary end point was all-cause mortality during long-term follow-up.ResultsA total of 862 patients (71% men, 67.8 years) were included and followed over a mean period of 25 ± 16 months. The mean TPBS was 8.6 (SD: ±6.0). The TPBS was a statistically significant predictor of mortality (p < 0.0001) while controlling for baseline demographics, cardiovascular risk factors, and type of surgery including reoperative status. The estimated hazard ratio for TPBS was 1.08 (95% confidence interval: 1.045 to 1.12). Other independent predictors of mortality were glomerular filtration rate (p = 0.015), type of surgery (p = 0.007), and peripheral artery disease (p = 0.03).ConclusionsExtent of thoracic aortic atheroma burden is independently associated with increased long-term mortality in patients following cardiothoracic surgery. Although our data do not provide definitive evidence, they suggest a relationship to the systemic atherosclerotic disease process and, therefore, have important implications for secondary prevention in post-operative rehabilitation programs

Therapeutic mitigation of measles-like immune amnesia and exacerbated disease after prior respiratory virus infections in ferrets

Measles cases have surged pre-COVID-19 and the pandemic has aggravated the problem. Most measles-associated morbidity and mortality arises from destruction of pre-existing immune memory by measles virus (MeV), a paramyxovirus of the morbillivirus genus. Therapeutic measles vaccination lacks efficacy, but little is known about preserving immune memory through antivirals and the effect of respiratory disease history on measles severity. We use a canine distemper virus (CDV)-ferret model as surrogate for measles and employ an orally efficacious paramyxovirus polymerase inhibitor to address these questions. A receptor tropism-intact recombinant CDV with low lethality reveals an 8-day advantage of antiviral treatment versus therapeutic vaccination in maintaining immune memory. Infection of female ferrets with influenza A virus (IAV) A/CA/07/2009 (H1N1) or respiratory syncytial virus (RSV) four weeks pre-CDV causes fatal hemorrhagic pneumonia with lung onslaught by commensal bacteria. RNAseq identifies CDV-induced overexpression of trefoil factor (TFF) peptides in the respiratory tract, which is absent in animals pre-infected with IAV. Severe outcomes of consecutive IAV/CDV infections are mitigated by oral antivirals even when initiated late. These findings validate the morbillivirus immune amnesia hypothesis, define measles treatment paradigms, and identify priming of the TFF axis through prior respiratory infections as risk factor for exacerbated morbillivirus disease.</p

Therapeutic mitigation of measles-like immune amnesia and exacerbated disease after prior respiratory virus infections in ferrets

Measles cases have surged pre-COVID-19 and the pandemic has aggravated the problem. Most measles-associated morbidity and mortality arises from destruction of pre-existing immune memory by measles virus (MeV), a paramyxovirus of the morbillivirus genus. Therapeutic measles vaccination lacks efficacy, but little is known about preserving immune memory through antivirals and the effect of respiratory disease history on measles severity. We use a canine distemper virus (CDV)-ferret model as surrogate for measles and employ an orally efficacious paramyxovirus polymerase inhibitor to address these questions. A receptor tropism-intact recombinant CDV with low lethality reveals an 8-day advantage of antiviral treatment versus therapeutic vaccination in maintaining immune memory. Infection of female ferrets with influenza A virus (IAV) A/CA/07/2009 (H1N1) or respiratory syncytial virus (RSV) four weeks pre-CDV causes fatal hemorrhagic pneumonia with lung onslaught by commensal bacteria. RNAseq identifies CDV-induced overexpression of trefoil factor (TFF) peptides in the respiratory tract, which is absent in animals pre-infected with IAV. Severe outcomes of consecutive IAV/CDV infections are mitigated by oral antivirals even when initiated late. These findings validate the morbillivirus immune amnesia hypothesis, define measles treatment paradigms, and identify priming of the TFF axis through prior respiratory infections as risk factor for exacerbated morbillivirus disease.</p

Real-Time Dynamic Imaging of Virus Distribution In Vivo

The distribution of viruses and gene therapy vectors is difficult to assess in a living organism. For instance, trafficking in murine models can usually only be assessed after sacrificing the animal for tissue sectioning or extraction. These assays are laborious requiring whole animal sectioning to ascertain tissue localization. They also obviate the ability to perform longitudinal or kinetic studies in one animal. To track viruses after systemic infection, we have labeled adenoviruses with a near-infrared (NIR) fluorophore and imaged these after intravenous injection in mice. Imaging was able to track and quantitate virus particles entering the jugular vein simultaneous with injection, appearing in the heart within 500 milliseconds, distributing in the bloodstream and throughout the animal within 7 seconds, and that the bulk of virus distribution was essentially complete within 3 minutes. These data provide the first in vivo real-time tracking of the rapid initial events of systemic virus infection

Growth hormone secretagogue increases muscle strength during immobilization after canine hindlimb immobilization

Summary: Twenty-two beagles were divided into two equal groups, and the right hindlimb of each animal was immobilized at 105&quot; of knee flexion by external fixation. After 10 weeks of fixation, the device was removed, allowing free mobility for the following 5 weeks. Each day throughout the 1. 5 weeks, one group received a growth hormone secretagogue (treatment) at a dose of 5 mg/kg, and the other received a lactose placebo (control). A t weeks 0, 10, and 15, strength as indicated by maximum isometric extension torque was measured in the right hindlimb, biopsies of the vastus lateralis muscle were taken, and the dogs were weighed. Weekly blood samples were analyzed for insulin-like growth factor-1, blood urea nitrogen, and creatine phosphokinase. Between weeks 0 and 10, tetanic torque declined by about 60% (p &lt; 0.001) in both groups, with no significant difference between the groups (p &gt; 0.7). Between weeks 10 and 15, tetanic torque in the treated group increased by 0.81 Nm; this was significantly greater than the increase of 0.25 Nm in the placebo group (p &lt; 0.05). The diameters of slow (type-1) and fast (type-2) fibers measured from the vastus lateralis muscle followed the same trend. At all time points, fiber diameter correlated strongly with torque; this argues against nonmuscular causes such as nerve injury for strength loss. The mean levels of insulin-like growth factor-1 increased 100% by week 4 in the treated group and remained elevated by about 60% throughout the experiment. Levels of insulin-like growth factor-1 in the placebo group decreased 30% within week 1 and remained depressed throughout the experiment. Our interpretation of these data suggests that the growth hormone secretagogue elevated levels of serum insulin-like growth factor-1, which in turn increased the size and strength of the quadriceps muscle during remobilization. These data may ultimately have therapeutic application to humans during rehabilitation after prolonged inactivity. - The strengthening of skeletal muscle after surgery or prolonged disuse remains a primary goal of rehabilitation. Many approaches -including electrical stimulation (lo), voluntary exercise (15), continuous passive motion (7), and hormone therapy (32) -have been used to strengthen atrophied muscles. In some cases, treatment modalities are limited by a patient&apos;s access to rehabilitation professionals or rehabilitation devices. Medical treatment of muscle atrophy with hormone therapy offers the advantage of requiring relatively little effort on the part of the patient to achieve the desired therapeutic result. There is ample evidence of hypertrophy of skeletal muscle in response to anabolic steroids. strong correlations were demonstrated between muscle strength and serum testosterone concentration in elderly men in whom a marked loss of muscle function was correlated with low testosterone levels relative to stronger age-matched controls (1). In related studies, the administration of testosterone to elderly men (to increase serum testosterone to a range observed in younger men) increased lean body mass (32) and grip strength (25). The effect of this hormone may be mediated, at least in part, by serum insulin-like growth factor-1 (IGF-1) (4). The anabolic effects on humans of I G F -1 administration have been well documented. For example, recombinant IGF-1 attenuated the catabolic effects of glucocorticoids (23) and increased muscle protein synthesis in young men (9). Similar results were obtained in vitro with other muscle growth factors such as fibroblast growth factor (FGF). At the cellular level, skeletal muscle myotubes grown in culture in the presence of FGF demonstrated a marked increase in protein synthesis. This effect was enhanced 51

Loss of FHL1 induces an age-dependent skeletal muscle myopathy associated with myofibrillar and intermyofibrillar disorganization in mice

Recent human genetic studies have provided evidences that sporadic or inherited missense mutations in four-and-a-half LIM domain protein 1 (FHL1), resulting in alterations in FHL1 protein expression, are associated with rare congenital myopathies, including reducing body myopathy and Emery–Dreifuss muscular dystrophy. However, it remains to be clarified whether mutations in FHL1 cause skeletal muscle remodeling owing to gain- or loss of FHL1 function. In this study, we used FHL1-null mice lacking global FHL1 expression to evaluate loss-of-function effects on skeletal muscle homeostasis. Histological and functional analyses of soleus, tibialis anterior and sternohyoideus muscles demonstrated that FHL1-null mice develop an age-dependent myopathy associated with myofibrillar and intermyofibrillar (mitochondrial and sarcoplasmic reticulum) disorganization, impaired muscle oxidative capacity and increased autophagic activity. A longitudinal study established decreased survival rates in FHL1-null mice, associated with age-dependent impairment of muscle contractile function and a significantly lower exercise capacity. Analysis of primary myoblasts isolated from FHL1-null muscles demonstrated early muscle fiber differentiation and maturation defects, which could be rescued by re-expression of the FHL1A isoform, highlighting that FHL1A is necessary for proper muscle fiber differentiation and maturation in vitro. Overall, our data show that loss of FHL1 function leads to myopathy in vivo and suggest that loss of function of FHL1 may be one of the mechanisms underlying muscle dystrophy in patients with FHL1 mutations

The Absence of MIST1 Leads to Increased Ethanol Sensitivity and Decreased Activity of the Unfolded Protein Response in Mouse Pancreatic Acinar Cells

Background: Alcohol abuse is a leading cause of pancreatitis in humans. However, rodent models suggest that alcohol only sensitizes the pancreas to subsequent insult, indicating that additional factors play a role in alcohol-induced pancreatic injury. The goal of this study was to determine if an absence of MIST1, a transcription factor required for complete differentiation of pancreatic acinar cells in mice, increased the sensitivity to alcohol. Methods: Two to four month-old mice lacking MIST1 (Mist1 2/2) or congenic C57 Bl6 mice were placed on a Lieber-DeCarli diet (36 % of total kcal from ethanol and fat), a control liquid diet (36 % kcal from fat) or a regular breeding chow diet (22% kcal from fat). After six weeks, pancreatic morphology was assessed. Biochemical and immunofluorescent analysis was used to assess mediators of the unfolded protein response (UPR). Results: Ethanol-fed Mist1 2/2 mice developed periductal accumulations of inflammatory cells that did not appear in wild type or control-fed Mist1 2/2 mice. Wild type mice fed diets high in ethanol or fat showed enhancement of the UPR based on increased accumulation of peIF2a and spliced XBP1. These increases were not observed in Mist1 2/2 pancreatic tissue, which had elevated levels of UPR activity prior to diet exposure. Indeed, exposure to ethanol resulted in a reduction of UPR activity in Mist1 2/2 mice. Conclusions: Our findings suggest that an absence of MIST1 increases the sensitivity to ethanol that correlated wit