Rare delayed cardiac tamponade in a pig after cardiac surgery.

OBJECTIVE: Delayed cardiac tamponade, a life-threatening complication of pericardial effusion in humans, has rarely been described in large animal models. We report here a pig with cardiac tamponade that developed 29 days after cardiac surgery. STUDY DESIGN: Case report. ANIMALS: One 45-kg domestic pig. METHODS: Open-chest surgery was performed on a pig to induce chronic heart failure. At 15 days after surgery, the pig's breathing appeared laboured; induced heart failure was considered the cause. Routine heart failure medications were administered. RESULTS: On day 28, the pig's status deteriorated. On day 29, echocardiography performed just before the pig's death showed a large pericardial effusion, mainly in the lateral and anterior walls of the right heart, with several fibre exudation bands. The right heart was severely compressed with an extremely small right ventricle. An emergency sternotomy was unsuccessful. Pathologic examination showed a severely thickened, fibrous pericardium. The pericardial sac was distended (up to 4.5 cm) and was full of dark brown, soft, friable material. Epicardial haemorrhage with a fresh, organised thrombus was noted in the pericardium. CONCLUSION: Delayed tamponade occurring at least 15 days after open-chest surgery is easy to misdiagnose or overlook in large animal models where attention is often focused on primary pathological model changes. To decrease mortality in animal models, researchers should be aware of potential complications and use the same level of follow-up monitoring of large animals as in clinical care.

Contribution of Increased Expression of Yin Yang 2 to Development of Cardiomyopathy.

Yin Yang 2 (YY2) is a member of the Yin Yang family of transcription factors. Although the bioactivity of YY2 has been previously studied, its role in cardiovascular diseases is not known. We observed the increased expression of YY2 in failing human hearts compared with control hearts, raising the question of whether YY2 is involved in the pathogenesis of cardiomyopathy. To investigate the potential contribution of YY2 to the development of cardiomyopathy, we crossed two independent transgenic (Tg) mouse lines, pCAG-YY2-Tg+and alpha-myosin heavy chain-cre (α-MHC-Cre), to generate two independent double transgenic (dTg) mouse lines in which the conditional cardiomyocyte-specific expression of YY2 driven by the α-MHC promoter was mediated by Cre recombinase, starting at embryonic day 9.0. In dTg mice, we observed partial embryonic lethality and hearts with defective cardiomyocyte proliferation. Surviving dTg mice from both lines developed cardiomyopathy and heart failure that occurred with aging, showing different degrees of severity that were associated with the level of transgene expression. The development of cardiomyopathy was accompanied by increased levels of cardiac disease markers, apoptosis, and cardiac fibrosis. Our studies further revealed that the Cre-mediated cardiomyocyte-specific increase in YY2 expression led to increased levels of Beclin 1 and LC3II, indicating that YY2 is involved in mediating autophagic activity in mouse hearts in vivo. Also, compared with control hearts, dTg mouse hearts showed increased JNK activity. Because autophagy and JNK activity are important for maintaining cardiac homeostasis, the dysregulation of these signaling pathways may contribute to YY2-induced cardiomyopathy and heart failure in vivo.

Clinicopathological manifestations of myocarditis in a heart failure population.

Myocarditis continues to present challenges in diagnosis and management. The goal of this study is to determine the occurrence and manifestations of myocarditis in a heart failure (HF) population. The analyzed patients had acute or persistent HF and were referred over a 6-year period to a quaternary HF center for advanced HF therapies including mechanical circulatory support, left ventricular assist device (LVAD) implantation, and/or heart transplantation. The histopathological diagnosis of myocarditis was made based on the presence of an inflammatory infiltrate of the myocardium, typically with associated cardiomyocyte (CMC) damage, combined as indicated with immunohistochemical and molecular biology characterization. The pathological findings were correlated with a panel of clinical parameters and clinical course of the patients. Myocarditis was identified in 36 patients, with initial diagnoses made in 10 (40%) of 25 by endomyocardial biopsy (EMB), 1 by atrial biopsy (maze procedure), 7 (2.1%) of 331 at LVAD implantation, and 18 (7.8%) of 229 in the explanted heart. There were 20 cases of lymphocytic myocarditis, 4 cases of giant cell myocarditis, 3 cases of eosinophilic myocarditis, and 9 cases of lymphohistocytic with granulomas myocarditis - cardiac sarcoidosis. EMB was performed in 25 patients and was positive in 10 (40%) of cases. Myocarditis was found in 23 explanted hearts including 18 cases de novo and 5 cases with a previously positive specimen. Of the 23 explanted hearts, 21 were nonischemic cardiomyopathy and 2 were ischemic cardiomyopathy. Our findings show that, in patients presenting to a quaternary medical center, myocarditis can be manifest as acute HF as well as a complicating factor in chronic HF.

Diet and Respiratory Health in Children from 11 Latin American Countries: Evidence from ISAAC Phase III.

BACKGROUND AND AIM: The burden of childhood asthma and its risk factors is an important but neglected public health challenge in Latin America. We investigated the association between allergic symptoms and dietary intake in children from this region. METHODS: As part of the International Study of Asthma and Allergies in Childhood (ISAAC) Phase III, questionnaire collected dietary intake was investigated in relation to risk of parental/child reported current wheeze (primary outcome) and rhino-conjunctivitis and eczema. Per-country adjusted logistic regressions were performed, and combined effect sizes were calculated with meta-analyses. RESULTS: 143,967 children from 11 countries had complete data. In children aged 6-7 years, current wheeze was negatively associated with higher fruit intake (adjusted odds ratio [aOR] 0.65; 95% CI 0.74, 0.97). Current rhino-conjunctivitis and eczema were statistically negatively associated with fruit intake (aOR 0.72; 95% CI 0.64, 0.82; and OR 0.64, 95% CI 0.56, 0.74, respectively). Vegetable intake was negatively associated with risk of symptoms in younger children, but these associations were attenuated in the 13-14 years old group. Fastfood/burger intake was positively associated with all three outcomes in the older children. CONCLUSION: A higher intake of fruits and vegetables was associated with a lower prevalence of allergic symptoms in Latin American children. Conversely, intake of fastfood was positively associated with a higher prevalence of wheeze in adolescents. Improved dietary habits in children might help reduce the epidemic of allergic symptoms in Latin America. Food interventions in asthmatic children are needed to evaluate the possible public health impact of a better diet on respiratory health.

Effect of botulinum toxin on inducibility and maintenance of atrial fibrillation in ovine myocardial tissue.

BACKGROUND: Aberrant vagal stimulation may promote the generation and propagation of atrial fibrillation (AF). Researchers have suggested that botulinum toxin (BTX), a neurotoxin that decreases neural vagal stimulation, may decrease the incidence of postoperative AF. The exact electrophysiologic mechanism underlying the observations and histopathologic alterations associated with BTX are unclear. OBJECTIVE: To investigate the electrophysiologic, functional, and histopathologic effects of BTX on fibrillation induction in ovine atria. METHODS: Eight sheep underwent BTX injections into their pulmonary veins, atrial fat pads, and ventricular walls. Electrophysiology with pacing was performed at baseline and 7 days after injection to evaluate the atrial effective refractory period (ERP) and vulnerability to AF with and without vagal stimulation. Echocardiography was performed at baseline and day 7. After euthanasia, histopathologic analysis was performed. RESULTS: Seven sheep completed the study. For both atria, there was significant shortening in the ERP with vagal stimulation versus no stimulation on day 0 but not on day 7. More aggressive pacing was required to induce AF in the left atrium on day 7 than on day 0. Echocardiography on day 7 showed no significant changes in ejection fraction or new wall-motion abnormalities of the left and right ventricle. Histopathologic analysis showed no significant adverse effects. CONCLUSION: The subacute BTX effect reduced the vulnerability of atrial tissue to AF induction and reduced the vagal influence on atrial ERP shortening compared to baseline levels. Direct BTX injection did not cause myocardial dysfunction or histologic adverse effects.

[Allergen immunotherapy: Mechanisms of action, and therapeutic and socioeconomic impact Consensus of the Asociación Colombiana de Alergia, Asma e Imunología].

Allergies comprise a set of highly prevalent diseases. When allergic processes are not controlled, they can endanger patients' health and lives, and have an important economic and social impact. The aim of this paper is to present a practical consensus of the scientific evidence on the use of immunotherapy in allergic diseases. A collaborative review made by various institutes and universities in Colombia was carried out upon request of the Asociación Colombiana de Alergia, Asma e Imunología, led by general practitioners, allergists, immunologists, internists and paediatricians with experience in the field of allergies. As a result, based on current national and international scientific evidence, we describe in detail what immunotherapy is about, its indications, contraindications and its economic and health benefits. Conclusions show immunotherapy as a clinically effective and safe treatment, which can substantially reduce the cost of the overall treatment of allergic patients.

Inmunoterapia con alérgenos: mecanismos de acción, impacto terapéutico y socioeconómico Consenso de la Asociación Colombiana de Alergias, Asma e Inmunología / Allergen immunotherapy: Mechanisms of action, and therapeutic and socioeconomic impact Consensus of the Asociación Colombiana de Alergia, Asma e Imunología

Las alergias constituyen un conjunto de enfermedades de gran prevalencia. Cuando los procesos alérgicos no se controlan, pueden poner en peligro la salud e, incluso, la vida de los pacientes y, además, su efecto económico y social es considerable. El objetivo de esta revisión es presentar un consenso práctico de la información científica disponible sobre el empleo de la inmunoterapia en las enfermedades alérgicas con la colaboración de varios institutos y universidades de Colombia, por solicitud de la Asociación Colombiana de Alergia, Asma e Inmunología. La revisión incluyó aspectos prácticos presentados desde el punto de vista de médicos generales, alergólogos, inmunólogos, internistas y pediatras con experiencia en el campo de las alergias. Con base en la evidencia científica actual a nivel nacional e internacional, se describió de forma detallada en qué consiste la inmunoterapia, sus indicaciones, contraindicaciones y sus beneficios para la salud, así como en el ámbito socioeconómico. Se concluyó que la inmunoterapia es efectiva y segura, y que, además, puede reducir sustancialmente el costo del tratamiento global de los pacientes alérgicos.

Allergies comprise a set of highly prevalent diseases. When allergic processes are not controlled, they can endanger patients´ health and lives, and have an important economic and social impact. The aim of this paper is to present a practical consensus of the scientific evidence on the use of immunotherapy in allergic diseases. A collaborative review made by various institutes and universities in Colombia was carried out upon request of the Asociación Colombiana de Alergia, Asma e Imunología , led by general practitioners, allergists, immunologists, internists and paediatricians with experience in the field of allergies. As a result, based on current national and international scientific evidence, we describe in detail what immunotherapy is about, its indications, contraindications and its economic and health benefits. Conclusions show immunotherapy as a clinically effective and safe treatment, which can substantially reduce the cost of the overall treatment of allergic patients.

Left ventricular noncompaction cardiomyopathy in end-stage heart failure patients undergoing orthotopic heart transplantation.

BACKGROUND: Previous studies reported that left ventricular noncompaction (LVNC) is a cardiomyopathy, familial or sporadic, arising from arrest of the normal process of trabecular remodeling during embryonic development. The diagnosis is usually made by echocardiography, but to date, there has been little research on the occurrence and clinicopathological features of LVNC in the explanted hearts of orthotopic heart transplant (OHT) recipients. DESIGN: The clinical, echocardiographic, and pathologic findings were reviewed for evidence of LVNC, diagnosed by echocardiographic criteria, in 105 patients with end-stage heart failure (HF) undergoing OHT. Analyses of multiple sections of the explanted hearts were carried out. The hearts were evaluated for grades (0, negative; 1, mild/occasional foci; 2, moderate/multiple foci; 3, severe/extensive, diffuse) of fibrosis, reactive and replacement, hypertrophy, myocytolysis in left ventricle, right ventricle, interventricular septum, and atria. Absolute measurements of noncompacted and compacted portions of the left ventricle wall and noncompacted/compacted ratios were calculated. RESULTS: Isolated LVNC was observed in 0 of 54 ischemic cardiomyopathy and in 4 of 51 (7.8%) nonischemic cardiomyopathy patients - 2 men and 2 women, with a mean age±SEM of 34.2±6.9years. The echocardiogram disclosed marked left ventricular dilatation, prominent trabeculations, and left ventricle ejection fraction <20%. Mural thrombi were seen in 3 of 4 (75%) patients. The heart weight mean±SEM was 468±55.3 g (range, 340-600g); noncompacted myocardium was 22±5.8mm, compacted myocardium was 13.2±3.5mm, and noncompacted/compacted ratio was 1.7/1±0.2. The total scores of hypetrophy, myocytolysis, and fibrosis were as follows: left ventricle, 7.7±0.2; right ventricle, 6.2±0.5; interventricular septum, 6.7±0.2; and atria, 7.5±0.3. CONCLUSIONS: LVNC is an unusual form of nonischemic cardiomyopathy in patients suffering from end-stage HF undergoing OHT. The variability in the noncompacted/compacted ratio and discordance between the echocardiographic and pathological findings points to the need for further clarification of diagnostic imaging and diagnostic criteria for LVNC. Further studies in larger series, correlating the anatomoclinical and genetic variables, also would improve our understanding of LVNC as a cause of advanced HF leading to OHT.

Comparative Efficacy of Nebivolol and Metoprolol to Prevent Tachycardia-Induced Cardiomyopathy in a Porcine Model.

Chronic tachycardia is a well-known cause of nonischemic cardiomyopathy. We hypothesized that nebivolol, a ß-blocker with nitric oxide activity, would be superior to a pure ß-blocker in preventing tachycardia-induced cardiomyopathy in a porcine model. Fifteen healthy Yucatan pigs were randomly assigned to receive nebivolol, metoprolol, or placebo once a day. All pigs underwent dual-chamber pacemaker implantation. The medication was started the day after the pacemaker implantation. On day 7 after implantation, each pacemaker was set at atrioventricular pace (rate, 170 beats/min), and the pigs were observed for another 7 weeks. Transthoracic echocardiograms, serum catecholamine levels, and blood chemistry data were obtained at baseline and at the end of the study. At the end of week 8, the pigs were euthanized, and complete histopathologic studies were performed. All the pigs developed left ventricular cardiomyopathy but remained hemodynamically stable and survived to the end of the study. The mean left ventricular ejection fraction decreased from baseline by 34%, 20%, and 20% in the nebivolol, metoprolol, and placebo groups, respectively. These changes did not differ significantly among the 3 groups (P =0.51). Histopathologic analysis revealed mild left ventricular perivascular fibrosis with cardiomyocyte hypertrophy in 14 of the 15 pigs. Both nebivolol and metoprolol failed to prevent cardiomyopathy in our animal model of persistent tachycardia and a high catecholamine state.

A Traditional Diet Is Associated with a Reduced Risk of Eczema and Wheeze in Colombian Children.

BACKGROUND: Diet might influence the risk of allergic diseases. Evidence from developing countries with high prevalence of childhood asthma is scant. METHODS: Information on wheeze, rhinitis, and eczema was collected from 3209 children aged 6-7 years in 2005, who were taking part in the International Study on Asthma and Allergy in Children (ISAAC) in Colombia. Intake frequency of twelve food groups was assessed. Associations between each food group and current wheeze, rhino-conjunctivitis, and eczema were investigated with multiple logistic regressions, adjusting for potential confounders. Simes' procedure was used to test for multiple comparisons. RESULTS: 14.9% of children reported wheeze in the last 12 months, 16% rhino-conjunctivitis, and 22% eczema. Eczema was negatively associated with consumption of fresh fruits and pulses three or more times per week (adjusted Odds ratio (aOR): 0.64; 95% Confidence Interval (CI): 0.49 to 0.83; p value = 0.004; and aOR: 0.62, 95% CI: 0.47 to 0.80; p value < 0.001, respectively). Current wheeze was negatively associated with intake of potatoes (aOR: 0.44, 95% CI: 0.31 to 0.62, p value = 0.005), whilst this outcome was positively associated with consumption of fast food (aOR: 1.76, 95% CI: 1.32 to 2.35, p value = 0.001). These associations remained statistically significant after controlling for multiple comparisons. CONCLUSIONS: A traditional diet might have a protective effect against eczema and wheeze in Colombian children, whilst intake of fast foods increases this risk.

Involvement of activated SUMO-2 conjugation in cardiomyopathy.

Sumoylation is a posttranslational modification that regulates a wide spectrum of cellular activities. Cardiomyopathy is the leading cause of heart failure. Whether sumoylation, particularly SUMO-2/3 conjugation, is involved in cardiomyopathy has not been investigated. We report here that SUMO-2/3 conjugation was elevated in the human failing hearts, and we investigated the impact of increased SUMO-2 conjugation on heart function by using the gain-of-function approach in mice, in which cardiac specific expression of constitutively active SUMO-2 was governed by alpha myosin heavy chain promoter (MHC-SUMO-2 transgenic, SUMO-2-Tg). Four of five independent SUMO-2-Tg mouse lines exhibited cardiomyopathy with various severities, ranging from acute heart failure leading to early death to the development of chronic cardiomyopathy with aging. We further revealed that SUMO-2 directly regulated apoptotic process by at least partially targeting calpain 2 and its natural inhibitor calpastatin. SUMO conjugation to calpain 2 promoted its enzymatic activity, and SUMO attachment to calpastatin mainly promoted its turnover and altered its subcellular distribution. Thus, enhanced SUMO-2 conjugation led to increased apoptosis and played a pathogenic role in the development of cardiomyopathy and heart failure.

Anthracycline treatment and ventricular remodeling in left ventricular assist device patients.

Nonischemic cardiomyopathy can complicate antineoplastic therapy and lead to irreversible heart failure. We evaluated structural changes at the time of left ventricular assist device implantation in heart failure patients who had been exposed to anthracycline, and we correlated those changes with clinical presentation. We retrospectively studied left ventricular core samples taken at implantation of the HeartMate II left ventricular assist device in 12 heart failure patients (mean age, 46 ± 16 yr) who had histories of anthracycline exposure. We evaluated those samples for hypertrophy, myocytolysis, and fibrosis. Histopathologic findings showed moderate-to-severe myocyte hypertrophy, moderate myocytolysis, and perivascular and interstitial fibrosis with areas of replacement fibrosis. Ultrastructural studies revealed marked decreases in myofibrils, diffuse mitochondrial swelling, and disorganization of the sarcoplasmic reticulum. The interval between anthracycline therapy and heart failure was a mean of 6.8 ± 5.7 years; duration of heart failure symptoms, 38 ± 47 months; and duration of device support, 414 ± 266 days. Four patients are continuing on device support, 3 have undergone transplantation, 3 have undergone device explantation, and 2 have died. The time of heart failure onset and the duration of symptoms did not correlate with the severity and extent of the histopathologic changes. The histopathologic findings and the clinical course varied in heart failure patients with anthracycline exposure. No correlation was observed between anthracycline therapy and the development or duration of heart failure symptoms, severity of histopathologic changes, or outcomes.

SENP5, a SUMO isopeptidase, induces apoptosis and cardiomyopathy.

Cardiomyopathy presents a major health issue and is a leading cause of heart failure. Although a subset of familial cardiomyopathy is associated with genetic mutations, over 50% of cardiomyopathy is defined as idiopathic, the mechanisms underlying which are under intensive investigation. SUMO conjugation is a dynamic posttranslational modification that can be readily reversed by the activity of sentrin-specific proteases (SENPs). However, whether SENPs are implicated in heart disease pathophysiology remains unexplored. We observed a significant increase in the level of SENP5, a SUMO isopeptidase, in human idiopathic failing hearts. To reveal whether it plays a role in the pathogenesis of cardiac muscle disorders, we used a gain-of-function approach to overexpress SENP5 in murine cardiomyocytes (SENP5 transgenic, SENP5-Tg). Overexpression of SENP5 led to cardiac dysfunction, accompanied by decreased cardiomyocyte proliferation and elevated apoptosis. The increase in apoptosis preceded other detectable pathological changes, suggesting its causal link to cardiomyopathy. Further examination of SENP5-Tg hearts unveiled a decrease in SUMO attachment to dynamin related protein (Drp1), a factor critical for mitochondrial fission. Correspondingly, the mitochondria of SENP5-Tg hearts at an early developmental stage were significantly larger compared with those in the control hearts, suggesting that desumoylation of Drp1 at least partially accounts for the cardiac phenotypes observed in the SENP5-Tg mice. Finally, overexpression of Bcl2 in SENP5-Tg hearts improved cardiac function of SENP5-Tg mice, further supporting the notion that SENP5 mainly targets mitochondrial function in vivo. Our findings demonstrate an important role of the desumoylation enzyme SENP5 in the development of cardiac muscle disorders, and point to the SUMO conjugation pathway as a potential target in the prevention/treatment of cardiomyopathy. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease".

Ventricular reconditioning and pump explantation in patients supported by continuous-flow left ventricular assist devices.

BACKGROUND: The potential for myocardial reconditioning and device explantation after long-term continuous-flow left ventricular assist device (LVAD) support presents an opportunity to delay or avoid transplantation in select patients. METHODS: Thirty of 657 patients with end-stage heart failure supported with continuous-flow LVADs were assessed for device explantation. Each patient underwent an individualized process of weaning focused on principles of ventricular unloading, gradual reconditioning, and transition to medical therapy. RESULTS: After varying reconditioning periods, 27 patients (16 men, 11 women; age, 39 ± 12 years) underwent LVAD explant, and 3 patients (2 men, 1 woman; age, 22 ± 6 years) were evaluated for explantation but could not be weaned. The duration of LVAD support was 533 ± 424 days (range, 42-1,937 days) for the explant cohort and 1,097 ± 424 days (range, 643-1,483) for the non-explant cohort. The LV end-diastolic dimension, LV ejection fraction, systolic pulmonary artery pressure, cardiac output, and cardiac index in the explant cohort were significantly improved at explantation (all, p < 0.05). Two late deaths occurred after LVAD explantation despite satisfactory native cardiac function, and 1 patient required resumption of LVAD support 2.7 years after device removal. The remaining explant patients remain in New York Heart Association classes I to II with medical management alone (mean survival post-explant, 1,172 ± 948 days). The 3 candidates who could not be weaned ultimately underwent transplantation. CONCLUSIONS: The potential for recovery of native LV function after long-term continuous-flow LVAD support should encourage a more aggressive approach to ventricular reconditioning with the goal of device explantation and a return to medical management, particularly in young patients with dilated cardiomyopathy.

Heart failure in remission for more than 13 years after removal of a left ventricular assist device.

Mechanical cardiac unloading with use of a left ventricular assist device (LVAD) is associated with substantial improvements in left ventricular function and enables subsequent LVAD explantation in some patients. We describe the case of a 35-year-old man with dilated nonischemic cardiomyopathy who was supported with an LVAD for 9 months. After the device was removed, he led a normal life for 13 years and 4 months. However, at 49 years of age, he presented with new signs and symptoms of heart failure, necessitating implantation of a 2nd LVAD. Afterwards, he has remained asymptomatic. This case is unique in that the patient lived a normal life for longer than a decade before renewed left ventricular decompensation necessitated repeat LVAD therapy. Histologic examination revealed few changes between the first device's removal in 1999 and the 2nd device's implantation in 2012.

HeartMate II left ventricular assist device implantation in patients with advanced hepatic dysfunction.

BACKGROUND: We sought to determine the outcomes for patients with advanced hepatic dysfunction undergoing HeartMate II left ventricular assist device (LVAD) implantation. METHODS: Between November 1, 2003 and December 1, 2012, we implanted the HeartMate II continuous-flow LVAD in 338 patients, either for bridging to heart transplantation or for destination therapy. Twenty-three of these patients (19 men and 4 women; mean age, 47 ± 16 years) had advanced hepatic dysfunction, as characterized by alanine aminotransferase (ALT) or aspartate transaminase (AST) levels five times normal; serum total bilirubin levels three times normal; and/or necessity for a liver biopsy before or during device implantation. Of this group, 17 patients received the LVAD as a bridge to transplantation, and six patients received it for destination therapy. RESULTS: Nine of the 23 patients required either a transjugular or a core liver biopsy during LVAD implantation. Three patients died within the first postoperative month; the 20 surviving patients had significant improvements in their hepatic parameters. The ALT decreased from 238 ± 296 to 27 ± 13 U/L (p = 0.022), AST decreased from 209 ± 199 to 29 ± 8 U/L (p = 0.009), and total bilirubin level decreased from 6.9 ± 6.0 to 0.6 ± 0.1 mg/dL (p = 0.044). The serum albumin level increased from 3.2 ± 0.6 to 4.3 ± 0.3 g/dL (p = 0.003), and creatinine clearance increased from 77.6 ± 35.2 to 110.2 ± 35.7 mL/min/1.73 m2 (p = 0.101). CONCLUSION: Continuous-flow LVAD support may significantly improve hepatic function, allowing patients with poor preimplant liver function to become better candidates for heart transplantation.

Variability in fibrosis in tissue samples obtained during diaphragmatic and apical LVAD implantation.

BACKGROUND: Histopathologic study of left ventricular (LV) tissue can provide structural data on the heart at the time of left ventricular assist device (LVAD) implantation. We assessed the effect of cannula placement site (apical/diaphragmatic) and cardiomyopathy etiology (ischemic/nonischemic) on cardiac histopathologic changes. METHODS: In 77 heart failure patients, tissue was obtained from the standard apical cannula insertion site or the diaphragmatic surface site during implantation of the HeartMate II (n=53) or HeartWare (n=24) LVAD. Fibrosis and hypertrophy (cytoplasmic and nuclear diameter) were evaluated by computerized morphometry. RESULTS: Thirty-two patients (27 men, 5 women; age, 57±15 years) underwent diaphragmatic implantation, and 45 (32 men, 13 women; age, 53±12 years) underwent apical implantation. The incidence of ischemic cardiomyopathy in the diaphragmatic and apical groups was 11/32 (34%) vs. 25/45 (56%) (P=.104). Overall, diaphragmatic tissue had less fibrosis than apical tissue (15.7±11.7% vs. 22.0±17.4%, P=.033), but both showed similar hypertrophic changes (cytoplasmic diameter, 39.0±10.3µm vs. 36.3±8.7µm, P=.141; nuclear diameter, 15.5±2.5µm vs. 14.8±3.0µm, P=.171). Likewise, in ischemic cardiomyopathy, apical samples showed more fibrosis than diaphragmatic samples (26.54±19.0% vs. 15.86±11.08%, P=.046) but similar hypertrophic changes (cytoplasmic diameter, 34.95±6.12µm vs. 37.48±12.07µm, P=.288; nuclear diameter, 14.66±2.69µm vs. 14.78±1.31µm, P=.451). CONCLUSION: Myocardial histology results at the time of LVAD placement and their prognostic implications may be affected by inlet placement site and cardiomyopathy etiology. In this study, LV samples from apical implantation in ischemic cardiomyopathy patients were the most fibrotic. Thus, sampling site and cardiomyopathy etiology should be considered when interpreting LV samples obtained during LVAD implantation.

Advanced atherosclerosis is associated with increased medial degeneration in sporadic ascending aortic aneurysms.

OBJECTIVE: The pathogenesis of non-familial, sporadic ascending aortic aneurysms (SAAA) is poorly understood, and the relationship between ascending aortic atherosclerosis and medial degeneration is unclear. We evaluated the prevalence and severity of aortic atherosclerosis and its association with medial degeneration in SAAA. METHODS AND RESULTS: Atherosclerosis was characterized in ascending aortic tissues collected from 68 SAAA patients (mean age, 62.9 ± 12.0 years) and 15 controls (mean age, 56.6 ± 11.4 years [P = 0.07]) by using a modified American Heart Association classification system. Upon histologic examination, 97% of SAAA patients and 73% of controls showed atherosclerotic changes. Most SAAA samples had intermediate (types 2 and 3, 35%) or advanced atherosclerosis (types ≥ 4; 40%), whereas most control samples showed minimal atherosclerosis (none or type 1, 80%; P < 0.001 after adjusting for age). In a separate analysis, we examined the total incidence and grade distribution of medial degenerative changes among SAAA samples according to atherosclerosis grade. Advanced atherosclerosis was associated with higher grades of smooth muscle cell depletion (P < 0.001), elastic fiber depletion (P = 0.02), elastic fiber fragmentation (P < 0.001), and mucopolysaccharide accumulation (P = 0.04). Aortic diameter was larger in SAAA patients with advanced atherosclerosis than in patients with minimal (P = 0.04) or intermediate atherosclerosis (P = 0.04). Immunostaining showed marked CD3+ T-cell and CD68+ macrophage infiltration, MMP-2 and MMP-9 production, and cryopyrin expression in the medial layer adjacent to atherosclerotic plaque. CONCLUSIONS: SAAA tissues exhibited advanced atherosclerosis that was associated with severe medial degeneration and increased aortic diameter. Our findings suggest a role for atherosclerosis in the progression of sporadic ascending aortic aneurysms.

Fibrosis and heart failure.

The extracellular matrix (ECM) is a living network of proteins that maintains the structural integrity of the myocardium and allows the transmission of electrical and mechanical forces between the myocytes for systole and diastole. During ventricular remodeling, as a result of iterations in the hemodynamic workload, collagen, the main component of the ECM, increases and occupies the areas between the myocytes and the vessels. The resultant fibrosis (reparative fibrosis) is initially a compensatory mechanism and may progress adversely influencing tissue stiffness and ventricular function. Replacement fibrosis appears at sites of previous cardiomyocyte necrosis to preserve the structural integrity of the myocardium, but with the subsequent formation of scar tissue and widespread distribution, it has adverse functional consequences. Continued accumulation of collagen impairs diastolic function and compromises systolic mechanics. Nevertheless, the development of fibrosis is a dynamic process wherein myofibroblasts, the principal cellular elements of fibrosis, are not only metabolically active and capable of the production and upregulation of cytokines but also have contractile properties. During the process of reverse remodeling with left ventricular assist device unloading, cellular, structural, and functional improvements are observed in terminal heart failure patients. With the advent of anti-fibrotic pharmacologic therapies, cellular therapy, and ventricular support devices, fibrosis has become an important therapeutic target in heart failure patients. Herein, we review the current concepts of fibrosis as a main component of ventricular remodeling in heart failure patients. Our aim is to integrate the histopathologic process of fibrosis with the neurohormonal, cytochemical, and molecular changes that lead to ventricular remodeling and its physiologic consequences in patients. The concept of fibrosis as living scar allows us to envision targeting this scar as a means of improving ventricular function in heart failure patients.