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Importance: Effective treatments for patients with severe COVID-19 are needed.Objective: To evaluate the efficacy of canakinumab, an anti-interleukin-1β antibody, in patients hospitalized with severe COVID-19.Design, Setting, and Participants: This randomized, double-blind, placebo-controlled phase 3 trial was conducted at 39 hospitals in Europe and the United States. A total of 454 hospitalized patients with COVID-19 pneumonia, hypoxia (not requiring invasive mechanical ventilation [IMV]), and systemic hyperinflammation defined by increased blood concentrations of C-reactive protein or ferritin were enrolled between April 30 and August 17, 2020, with the last assessment of the primary end point on September 22, 2020.Intervention: Patients were randomly assigned 1:1 to receive a single intravenous infusion of canakinumab (450 mg for body weight of 40-<60 kg, 600 mg for 60-80 kg, and 750 mg for >80 kg; n = 227) or placebo (n = 227).Main Outcomes and Measures: The primary outcome was survival without IMV from day 3 to day 29. Secondary outcomes were COVID-19-related mortality, measurements of biomarkers of systemic hyperinflammation, and safety evaluations.Results: Among 454 patients who were randomized (median age, 59 years; 187 women [41.2%]), 417 (91.9%) completed day 29 of the trial. Between days 3 and 29, 198 of 223 patients (88.8%) survived without requiring IMV in the canakinumab group and 191 of 223 (85.7%) in the placebo group, with a rate difference of 3.1% (95% CI, -3.1% to 9.3%) and an odds ratio of 1.39 (95% CI, 0.76 to 2.54; P = .29). COVID-19-related mortality occurred in 11 of 223 patients (4.9%) in the canakinumab group vs 16 of 222 (7.2%) in the placebo group, with a rate difference of -2.3% (95% CI, -6.7% to 2.2%) and an odds ratio of 0.67 (95% CI, 0.30 to 1.50). Serious adverse events were observed in 36 of 225 patients (16%) treated with canakinumab vs 46 of 223 (20.6%) who received placebo.Conclusions and Relevance: Among patients hospitalized with severe COVID-19, treatment with canakinumab, compared with placebo, did not significantly increase the likelihood of survival without IMV at day 29.Trial Registration: ClinicalTrials.gov Identifier: NCT04362813. [ABSTRACT FROM AUTHOR]

Immune-mediated myocardial injury following Severe Acute Respiratory Syndrome Coronavirys-2 (SARS-CoV2) infection has been described in adults and children. Cases of myocarditis following immunization for SARS-CoV2 have recently been documented, mostly associated with mild severity and spontaneous recovery. We herein report two cases of fulminant myocarditis following BNT162b2 mRNA Covid-19 vaccination associated with systemic hyperinflammatory syndrome and refractory shock requiring support with veno-arterial extracorporeal membrane oxygenation. • Fulminant myocarditis may occur following SARS-CoV2 mRNA vaccination requiring mechanical cardiac support. • It is important to recognize features of systemic hyperinflammatory syndrome following SARS-CoV2 mRNA vaccination. [ABSTRACT FROM AUTHOR]

Background: Marijuana is a commonly used recreational substance with purported analgesic and mood enhancing properties. Many people living with HIV identify marijuana as a palliative substance. However, through its main psychoactive component, tetrahydrocannabinol (THC), is known to influence the immune system. The effects of marijuana use in people with HIV are still controversial, with very scant literature in Black adults.Methods: The current study determined the differences in the lymphocyte count, specifically the number cluster differentiation 4 and 8 (CD4+ and CD8+), among patients who urine drug tested negative for THC (n = 70) and those who tested positive for THC (n = 25). The sample included 95 Black people living with HIV, 51% female, with a mean age of 46 ± 11 years. Participants provided a urine sample for substance use testing and a trained researcher extracted clinical data from clinical charts on the day of appointment.Results: After adjusting for demographic and HIV-related covariates, THC-positive patients had significantly higher CD4+ and CD8+ counts than their THC-negative counterparts.Conclusion: These results extend previous HIV-related immunity findings in an underrepresented group, and suggest that THC use does not reduce immune function as measured by CD count. Further research is warranted on the overall effects of THC on immune function in HIV positive patients. [ABSTRACT FROM AUTHOR]

The heart is extremely sensitive to ischaemic injury. During an acute myocardial infarction (AMI) event, the injury is initially caused by reduced blood supply to the tissues, which is then further exacerbated by an intense and highly specific inflammatory response that occurs during reperfusion. Numerous studies have highlighted the central role of the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome in this process. The inflammasome, an integral part of the innate immune system, is a macromolecular protein complex that finely regulates the activation of caspase 1 and the production and secretion of powerful pro-inflammatory cytokines such as IL-1β and IL-18. In this Review, we summarize evidence supporting the therapeutic value of NLRP3 inflammasome-targeted strategies in experimental models, and the data supporting the role of the NLRP3 inflammasome in AMI and its consequences on adverse cardiac remodelling, cytokine-mediated systolic dysfunction, and heart failure. [ABSTRACT FROM AUTHOR]

Interleukin-1 (IL-1) is the prototypical pro-inflammatory cytokine that occupies an apical place in the inflammatory cascade and also modulates cardiac function, functioning as a soluble cardiodepressant factor. Preclinical research over the past 4 decades has shown that blocking IL-1 processing or activity favorably affects cardiomyocyte survival and cardiac function in experimental animal models, paving the way for clinical studies in patients with heart disease. The promising results of phase II clinical trials of IL-1 blockade in patients with acute myocardial infarction and heart failure have been followed by a successful phase III trial in patients with prior acute myocardial infarction. Three IL-1 blockers with different mechanism of action are currently available for clinical use, although currently none have an indication for heart disease. We herein review the bench-to-bedside clinical translation of IL-1 targeting strategies and discuss the potential use of IL-1 blockade in patients with heart disease. [ABSTRACT FROM AUTHOR]

Background: Marijuana is a commonly used recreational substance with purported analgesic and mood enhancing properties. Many people living with HIV identify marijuana as a palliative substance. However, through its main psychoactive component, tetrahydrocannabinol (THC), is known to influence the immune system. The effects of marijuana use in people with HIV are still controversial, with very scant literature in Black adults.Methods: The current study determined the differences in the lymphocyte count, specifically the number cluster differentiation 4 and 8 (CD4+ and CD8+), among patients who urine drug tested negative for THC (n=70) and those who tested positive for THC (n=25). The sample included 95 Black people living with HIV, 51% female, with a mean age of 46±11years. Participants provided a urine sample for substance use testing and a trained researcher extracted clinical data from clinical charts on the day of appointment.Results: After adjusting for demographic and HIV-related covariates, THC-positive patients had significantly higher CD4+ and CD8+ counts than their THC-negative counterparts.Conclusion: These results extend previous HIV-related immunity findings in an underrepresented group, and suggest that THC use does not reduce immune function as measured by CD count. Further research is warranted on the overall effects of THC on immune function in HIV positive patients. [ABSTRACT FROM AUTHOR]

Right ventricular failure (RVF) is the main determinant of mortality in patients with pulmonary arterial hypertension (PAH). Although the exact pathophysiology underlying RVF remains unclear, inflammation may play an important role, as it does in left heart failure. Perivascular pulmonary artery and systemic inflammation is relatively well studied and known to contribute to the initiation and maintenance of the pulmonary vascular insult in PAH. However, less attention has been paid to the role of cardiac inflammation in RVF and PAH. Consistent with many other types of heart failure, cardiac inflammation, triggered by systemic and local stressors, has been shown in RVF patients as well as in RVF animal models. RV inflammation likely contributes to impaired RV contractility, maladaptive remodelling and a vicious circle between RV and pulmonary vascular injury. Although the potential to improve RV function through anti-inflammatory therapy has not been tested, this approach has been applied clinically in left ventricular failure patients, with variable success. Because inflammation plays a dual role in the development of both pulmonary vascular pathology and RVF, anti-inflammatory therapies may have a potential double benefit in patients with PAH and associated RVF. [ABSTRACT FROM AUTHOR]

Clinical decision-making requires synthesis of an often complex evidence base. Novel tools have been developed building upon the historical approach of reviewing the literature focusing on a specific topic. Stemming from qualitative reviews, systematic reviews of randomized clinical trials, typically encompassing statistical pooling with pairwise meta-analysis, have been devised and are now considered one of the uppermost ladders in the hierarchy of clinical evidence. In the last decade, the exponential growth in randomized trials and the introduction of original computational methods have created the novel opportunity to compare indirectly competing treatments, as well as combining effect estimates stemming from head-to-head trials with those obtained by indirect comparisons. These methods include adjusted indirect comparison meta-analysis, network meta-analysis, and mixed treatment comparison. While still the focus of intense research and debate, they represent a powerful tool for evidence synthesis and comparative effectiveness in cardiovascular research, and thus are likely to become increasingly popular and impactful in shaping research agenda and clinical practice. This is clearly highlighted by a number of recent landmark network meta-analyses on smoking cessation therapies, coronary stents, and management of patent foramen ovale in patients with history of cryptogenic stroke. [ABSTRACT FROM AUTHOR]

Two pilot studies of interleukin-1 (IL-1) blockade in ST-segment elevation myocardial infarction (STEMI) showed blunted acute inflammatory response and overall favorable outcomes at 3 months follow-up. We hereby present a patient-level pooled analysis with extended follow-up of 40 patients with clinically stable STEMI randomized to anakinra, a recombinant IL-1 receptor antagonist, 100 mg/day for 14 days or placebo in a doubleblinded fashion. End points included death, cardiac death, recurrent acute myocardial infarction (AMI), stroke, unstable angina, and symptomatic heart failure. Median follow-up was 28 (interquartile range 3 to 38) months. Sixteen patients (40%) had a total of 22 adverse cardiovascular events: 1 cardiac death, 4 recurrent AMI, 5 episodes of unstable angina pectoris requiring hospitalization and/or urgent revascularization, and 11 new diagnoses of heart failure. Treatment with anakinra was associated with a hazard ratio of 1.08 (95% confidence interval 0.31 to 3.74, p [ 0.90) for the combined end point of death, recurrent AMI, unstable angina pectoris, or stroke and a hazard ratio of 0.16 (95% confidence interval 0.03 to 0.76, p [ 0.008) for death or heart failure. In conclusion, IL-1 blockade with anakinra for 2 weeks appears, therefore, to have a neutral effect on recurrent ischemic events, whereas it may prevent new-onset heart failure long term after STEMI. [ABSTRACT FROM AUTHOR]

Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome of exercise intolerance and/or congestion, in the presence of a left ventricular (LV) ejection fraction within the normal limits (i.e. LVEF > 50%). Determining the presence of impaired LV relaxation and/or filling (diastolic dysfunction) in HFpEF is needed to pragmatically to distinguish it from other cardiac and non-cardiac conditions where symptoms are not due to HF. There are multiple mechanisms for diastolic dysfunction ranging from structural abnormalities to functional derangements in HFpEF yet tailored therapies are lacking. Treatments proven effective in HF with systolic dysfunction have failed to show significant benefit in patients with HFpEF, which prognosis remains poor. This review will discuss the challenges inherent to the use of diagnostic criteria for HFpEF, differential diagnosis, prognostic evaluation, and treatment, highlighting the need for more research in this field. [ABSTRACT FROM AUTHOR]

Alpha-1 antitrypsin (AAT) has broad anti-inflammatory and immunomodulating properties in addition to inhibiting serine proteases. Administration of human plasma-derived AAT is protective in models of acute myocardial infarction in mice. The objective of this study was to determine the safety and tolerability of human plasma-derived AAT and its effects on the acute inflammatory response in non-AAT deficient patients with ST-segment elevation myocardial infarction (STEMI). Ten patients with acute STEMI were enrolled in an open-label, single-arm treatment study of AAT at 60 mg/kg infused intravenously within 12 hours of admission and following standard of care treatment. C-reactive protein (CRP) and plasma AAT levels were determined at admission, 72 hours, and 14 days, and patients were followed clinically for 12 weeks for the occurrence of new onset heart failure, recurrent myocardial infarction, or death. Twenty patients with STEMI enrolled in previous randomized trials with identical inclusion and/or exclusion criteria, but who received placebo, served as historical controls. Prolastin C was well tolerated and there were no in-hospital adverse events. Compared with historical controls, the area under the curve of CRP levels was significantly lower 14 days after admission in the Prolastin C group (75.9 [31.4 to 147.8] vs 205.6 [78.8 to 410.9] mg/l, p = 0.048), primarily due to a significant blunting of the increase occurring between admission and 72 hours (delta CRP +1.7 [0.2 to 9.4] vs +21.1 [3.1 to 38.0] mg/l, p = 0.007). Plasma AAT levels increased from admission (149 [116 to 189]) to 203 ([185 to 225] mg/dl) to 72 hours (p = 0.005). In conclusion, a single administration of Prolastin C in patients with STEMI is well tolerated and is associated with a blunted acute inflammatory response. [ABSTRACT FROM AUTHOR]

Amlodipine (AMLO) is a calcium channel blocker with vasodilating properties, in which the specific effects on the coronary circulation are not fully known. Coronary flow velocity–pressure (F/P) curves were obtained at rest and during administration of AMLO (10 mg to 20 mg iv) or adenosine (ADO, 1 mg ic) in 10 normal subjects (six women, age 48 ± 14 years). F/P curves were reproduced in a numerical simulator of systemic and coronary circulations (CARDIOSIM©) by adjustment of coronary resistance ( > or < 100 μm diameter vessels) and extravascular resistance applied to smaller vessels at endocardial (ENDO), middle and epicardial (EPI) myocardial layers. Best matching ofin silicotoin vivocurves was achieved by trial and error approach. ADO induced 170% and 250% increase in coronary flow velocity CFV and F/P diastolic slope as compared to 80% and 25–30% increase induced by AMLO, respectively. In the cardiovascular model, AMLO effects were predicted by progressive reduction of>100 μm vessels resistance from EPI to ENDO. ADO effects were mimicked by reducing resistance of both>100 μm and < 100 μm vessels, progressively from EPI to ENDO in the latter. Additional reduction in extravascular resistance avoided to impose a transmural gradient of vasodilating effect for both drugs. Numerical simulation predicts vasodilating effects of AMLO mainly on larger arteries and of ADO on both>and < 100 μm vessels.In vivoF/P loops could be completely reproducedin silicoby adding extravascular resistance reduction for both drugs. Numerical simulator is useful tool for exploring the coronary effects of cardioactive drugs. [ABSTRACT FROM AUTHOR]

A first pilot study of interleukin-1 blockade in ST-segment elevation acute myocardial infarction showed improved remodeling. In the present second pilot study, we enrolled 30 patients with clinically stable ST-segment elevation acute myocardial infarction randomized to anakinra, recombinant interleukin-1 receptor antagonist, 100 mg/day for 14 days or placebo in a double-blind fashion. The primary end point was the difference in the interval change in left ventricular (LV) end-systolic volume index between the 2 groups within 10 to 14 weeks. The secondary end points included changes in the LV end-diastolic volume index, LV ejection fraction, and C-reactive protein levels. No significant changes in endsystolic volume index, LV end-diastolic volume index, or LV ejection fraction were seen in the placebo group. Compared to placebo, treatment with anakinra led to no measurable differences in these parameters. Anakinra significantly blunted the increase in C-reactive protein between admission and 72 hours (D0.8 mg/dl, interquartile range L6.4 to D4.2, vs D21.1 mg/dl, interquartile range D8.7 to D36.6, p [ 0.002), which correlated with the changes in LV end-diastolic volume index and LV end-systolic volume index at 10 to 14 weeks (R [ D0.83, p [ 0.002, and R [ D0.55, p [ 0.077, respectively). One patient in the placebo group (7%) died. One patient (7%) in the anakinra group developed recurrent acute myocardial infarction. More patients were diagnosed with new-onset heart failure in the placebo group (4, 27%) than in the anakinra group (1, 7%; p [ 0.13). When the data were pooled with those from the first Virginia Commonwealth University- Anakinra Remodeling Trial (n [ 40), this difference reached statistical significance (30% vs 5%, p [ 0.035). In conclusion, interleukin-1 blockade with anakinra blunted the acute inflammatory response associated with ST-segment elevation acute myocardial infarction. Although it failed to show a statistically significant effect on LV end-systolic volume index, LV end-diastolic volume index, or LV ejection fraction in this cohort of clinically stable patients with near-normal LV dimensions and function, anakinra led to a numerically lower incidence of heart failure. [ABSTRACT FROM AUTHOR]

Background: The nitric oxide (NO)--soluble guanylate cyclase (sGC)--cyclic guanosine monophosphate (cGMP) signal- transduction pathway is impaired in many cardiovascular diseases, including pulmonary arterial hypertension (PAH). Riociguat (BAY 63-2521) is a stimulator of sGC that works both in synergy with and independently of NO to increase levels of cGMP. The aims of this study were to investigate the role of NO--sGC--cGMP signaling in a model of severe PAH and to evaluate the effects of sGC stimulation by riociguat and PDE5 inhibition by sildenafil on pulmonary hemodynamics and vascular remodeling in severe experimental PAH. Methods and Results: Severe angioproliferative PAH was induced in rats by combined exposure to the vascular endothelial growth factor receptor antagonist SU5416 and hypoxia (SUHx). Twenty-one days thereafter rats were randomized to receive either riociguat (10 mg/kg/day), sildenafil (50 mg/kg/day) or vehicle by oral gavage, for 14 days until the day of the terminal hemodynamic measurements. Administration of riociguat or sildenafil significantly decreased right ventricular systolic pressure (RVSP). Riociguat significantly decreased RV hypertrophy (RVH) (0.55±0.02, p<0.05), increased cardiac output (60.8±.8 mL/minute, p<0.05) and decreased total pulmonary resistance (4.03±0.3 mmHg min-1 ml-1 100 g BW, p<0.05), compared with sildenafil and vehicle. Both compounds significantly decreased the RV collagen content and improved RV function, but the effects of riociguat on tricuspid annular plane systolic excursion and RV myocardial performance were significantly better than those of sildenafil (p<0.05). The proportion of occluded arteries was significantly lower in animals receiving riociguat than in those receiving vehicle (p<0.05); furthermore, the neointima/media ratio was significantly lower in those receiving riociguat than in those receiving sildenafil or vehicle (p<0.05). Conclusion: Riociguat and sildenafil significantly reduced RVSP and RVH, and improved RV function compared with vehicle. Riociguat had a greater effect on hemodynamics and RVH than sildenafil. [ABSTRACT FROM AUTHOR]

The inflammatory hypothesis of atherosclerosis postulates that inflammation within the plaque promotes plaque progression and complications. Interleukin-1 (IL-1) is a key pro-inflammatory cytokine responsible for the amplification of the inflammatory response following injury. Animal studies show that IL-1 blockade is effective in limiting atherosclerosis and atherothrombosis and improving outcomes in acute myocardial infarction and ischemic stroke. Preliminary data in patients with acute myocardial infarction, ischemic stroke, and heart failure are promising. A large secondary prevention trial with canakinumab in patients with prior acute myocardial infarction is currently ongoing. Many unanswered questions remain regarding the optimal use of IL-1 blockade and the preferred agent. [ABSTRACT FROM AUTHOR]

Background: Healing after acute myocardial infarction (AMI) is characterized by an intense inflammatory response and increased Interleukin-1 (IL-1) tissue activity. Genetically engineered mice lacking the IL-1 receptor (IL-1R1-/-, not responsive to IL-1) or the IL-1 receptor antagonist (IL-1Ra, enhanced response to IL-1) have an altered IL-1/IL-1Ra balance that we hypothesize modulates infarct healing and cardiac remodeling after AMI. Methods: IL-1R1-/- and IL-1Ra-/- male mice and their correspondent wild-types (WT) were subjected to permanent coronary artery ligation or sham surgery. Infarct size (trichrome scar size), apoptotic cell death (TUNEL) and left ventricular (LV) dimensions and function (echocardiography) were measured prior to and 7 days after surgery. Results: When compared with the corresponding WT, IL-1R1-/- mice had significantly smaller infarcts (-25%), less cardiomyocyte apoptosis (-50%), and reduced LV enlargement (LV end-diastolic diameter increase [LVEDD], -20%) and dysfunction (LV ejection fraction [LVEF] decrease, -50%), whereas IL-1Ra-/- mice had significantly larger infarcts (+75%), more apoptosis (5-fold increase), and more severe LV enlargement (LVEDD increase,+30%) and dysfunction (LVEF decrease, +70%)(all P values <0.05). Conclusions: An imbalance in IL-1/IL-1Ra signaling at the IL-1R1 level modulates the severity of cardiac remodeling after AMI in the mouse, with reduced IL-1R1 signaling providing protection and unopposed IL-1R1 signaling providing harm. [ABSTRACT FROM AUTHOR]

In a previous study, we obtained histologic documentation of liver gas embolism in the rat model of rapid decompression. The aim of the study was to assess in the same model occurrence and time course of liver embolism using 2-D ultrasound imaging, and to explore by this means putative liver gas embolism in recreational scuba divers. Following 42 min compression at 7 ATA breathing air and 12 min decompression, eight surviving female rats were anesthetized and the liver imaged by ultrasound at 20 min intervals up to 120 min. A significant enhancement of echo signal was recorded from 60 to 120 min as compared to earlier post-decompression times. Enzymatic markers of liver damage (AST, ALT, and GGT) increased significantly at 24 h upon decompression. Twelve healthy experienced divers were studied basally and at 15-min intervals up to 60 min following a 30-min scuba dive at 30 msw depth. At 30 min upon surfacing echo images showed significant signal enhancement that progressed and reached plateau at 45 and 60 min. Total bilirubin at 24 h increased significantly (p = 0.02) with respect to basal values although within the reference range. In conclusion, 2-D ultrasound liver imaging allowed detection of gas embolism in the rat and defined the time course of gas accumulation. Its application to scuba divers revealed liver gas accumulation in all subjects in the absence of clear-cut evidence of liver damage or of any symptom. The clinical significance of our findings remains to be investigated. [ABSTRACT FROM AUTHOR]

Cirrhotic cardiomyopathy is a clinical syndrome in patients with liver cirrhosis characterized by an abnormal and blunted response to physiologic, pathologic, or pharmacologic stress but normal to increased cardiac output and contractility at rest. As many as 50% of cirrhotic patients undergoing liver transplantation show signs of cardiac dysfunction, and 7% to 21% of deaths after orthotopic liver transplantation result from overt heart failure. In this review, we critically evaluate the existing literature on the pathophysiology and clinical implications of cirrhotic cardiomyopathy. [ABSTRACT FROM AUTHOR]

Occurrence of liver gas embolism after rapid decompression was assessed in 31 female rats that were decompressed in 12 mm after 42 mm of compression at 7 ATA (protocol A). Sixteen rats died after decompression (group T). Of the surviving rats, seven were killed at 3 h (group IT), and eight at 24 h (group Ill). In group I, bubbles were visible in the right heart, aortic arch, liver, and mesenteric veins and on the intestinal surface. Histology showed perilobular microcavities in sinusoids, interstitial spaces, and hepatocytes. In group II, liver gas was visible in two rats. Perilobular vacuolization and significant plasma aminotransferase increase were present. In group III, liver edema was evident at gross examination in all cases. Histology showed perilobular cell swelling, vacuolization, or hydropic degeneration. Compared with basal, enzymatic markers of liver damage increased significantly. An additional 14 rats were decompressed twice (protocol B). Overall mortality was 93%. In addition to diffuse hydropic degeneration, centrilobular necrosis was frequently observed after the second decompression. Additionally, 10 rats were exposed to three decompression sessions (protocol C) with doubled decompression time. Their mortality rate decreased to 20%, but enzymatic markers still increased in surviving rats compared with predecompression, and perilobular cell swelling and vacuolization were present in five rats. Study challenges were 1) liver is not part of the pathophysiology of decompression in the existing paradigm, and 2) although significant cellular necrosis was observed in few animals, zonal or diffuse hepatocellular damage associated with liver dysfunction was frequently demonstrated. Liver participation in human decompression sickness should be looked for and clinically evaluated. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to a study about the low diagnostic yield of elective coronary angiography, which appeared in the March 11, 2010 issue.

The article discusses the acute myocardial infarction to prevent adverse cardiac remodelling following acute myocardial infarction in the mouse. It aims to test the effects of modulation using a newly genetically engineered mouse antibody. It states that the study has been supported in part by funds from an American Heart Association Beginning Grant-in-aid.

Acute myocarditis is an acute inflammatory syndrome characterized by acute myocardial damage and dysfunction followed by a variable recovery over time with some patients progressing toward severe dilated cardiomyopathy. Cardiomyocyte apoptosis, a key pathologic feature of heart failure, may play a critical role in functional recovery in patients with acute myocarditis. The aim of the study was to investigate whether apoptosis predicts functional recovery in patients with acute myocarditis. Sixteen patients with biopsy-documented acute myocarditis were followed for 1 year with serial transthoracic echocardiography. Functional recovery was defined as 12-month left ventricular ejection fraction >40%. Cardiomyocyte apoptosis, leukocyte infiltration, and cell proliferation was assessed in all samples. A group of cases in which the diagnosis of acute myocarditis was made after death was also selected for comparison, and morphologically normal hearts from patients who died from a noncardiac cause were selected as controls. Six patients (38%) had functional recovery at 12 months, whereas 10 (62%) did not. The 2 groups had similar characteristics except for lower baseline left ventricular ejection fraction in the group with functional recovery. Apoptotic rate was found to be significantly higher in patients with acute myocarditis than in control hearts, and, unexpectedly, patients with functional recovery had significantly higher apoptotic rates than patients without recovery (3.2% vs 0.5%, p = 0.001). None of the patients with apoptotic rates below the median had functional recovery versus 86% of patients with apoptotic rates above the median (p <0.001). In conclusion, higher rates of cardiomyocyte apoptosis in patients with acute myocarditis are associated with functional recovery at 1 year. [Copyright &y& Elsevier]

Cardiac remodeling after acute myocardial infarction (AMI) is characterized by molecular and cellular mechanisms involving both the left (LV) and right ventricular (RV) walls. Cardiomyoycte apoptosis in the peri-infarct and remote LV myocardium has a central role in cardiac remodeling. Whether apoptosis also occurs in the right ventricle of patients with ischemic heart disease has not been investigated. The aim of the present study was to investigate the presence of cardiomyocyte apoptosis in the right ventricle in patients with AMI. We assessed the number of apoptotic cardiomyocytes using multiple samplings in the LV and RV walls of 12 patients selected at autopsy who died 4 to 42 days after AMI. Five patients without cardiac disease were also selected at autopsy as controls. Apoptotic rates were calculated from the number of cardiomyocytes showing double positive staining for in situ end-labeling of DNA fragmentation (TUNEL) and for activated caspase-3. Potentially false-positive results (DNA synthesis and RNA splicing) were excluded from cell counts. The apoptotic rate in the right ventricle in patients with AMI was significantly higher than in control hearts (median 0.8%, interquartile range 0.3 to 1.0 vs median 0.01%, interquartile range 0.01 to 0.03, p <0.001). RV apoptosis significantly correlated with such parameters of global adverse remodeling as cardiac diameter to LV free wall thickness (R = +0.57, p = 0.050). RV apoptosis was significantly higher in five cases (42%) with infarct involving the ventricular septum and an adjacent small area of the RV walls (median 1.0%, interquartile range 0.8 to 2.2 vs median 0.5%, interquartile range 0.2 to 1.0, p = 0.048, p <0.001 vs controls). The association between apoptotic rate in the right ventricle and cardiac remodeling was apparent even after exclusion of cases with RV AMI involvement (R = +0.82, p = 0.023 for diameter to LV wall thickness ratio and R = −0.91, p = 0.002 for RV free wall thickness). In conclusion, patients with cardiac remodeling after AMI had a significant increase in RV apoptosis even when ischemic involvement of the RV wall was not apparent. [Copyright &y& Elsevier]

A letter to the editor is presented in response to the article "Drug Eluting Stents vs. Coronary Artery Bypass Grafting in Multivessel Coronary Disease" by E. L. Hannan, C. Wu and G. Walford in the January 24, 2008 issue.

Objectives: Our purpose was to perform a systematic review and meta-analysis of randomized trials comparing percutaneous coronary intervention (PCI) of the infarct-related artery (IRA) with medical therapy in patients randomized >12 h after acute myocardial infarction (AMI). Background: There is ongoing uncertainty about the risk–benefit ratio of late PCI in stable patients with AMI. Methods: PubMed, CENTRAL, and other databases were searched (July 2007). Studies were included if they compared PCI with medical management and randomized patients >12 h and up to 60 days after AMI, and were excluded if patients were hemodynamically unstable. Odds ratios (ORs) were pooled for dichotomous outcomes, with all-cause mortality as the primary end point. Left cardiac remodeling parameters were also pooled with generic inverse-variance weighting. Results: We retrieved 10 studies that enrolled 3,560 patients, with median time from AMI to randomization of 12 days (range 1 to 26 days), and follow-up of 2.8 years (42 days to 10 years). Randomization allocated 1,779 subjects to PCI and 1,781 to medical treatment. There were 112 (6.3%) and 149 (8.4%) deaths in the 2 groups, respectively, yielding significantly improved survival in the PCI group (OR 0.49 [95% confidence interval (CI) 0.26 to 0.94], p = 0.030). These benefits were associated with similarly favorable effects on cardiac remodeling, such as improved left ventricular ejection fraction in the PCI group (+4.4% change [95% CI 1.1 to 7.6], p = 0.009). Conclusions: Percutaneous coronary intervention of the IRA performed late (12 h to 60 days) after AMI is associated with significant improvements in cardiac function and survival. [Copyright &y& Elsevier]

We tested the hypothesis that chronic treatment with sildenafil attenuates myocardial infarction (MI)-induced heart failure. Sildenafil has potent protective effects against necrosis and apoptosis following ischemia-reperfusion in the intact heart and cardiomyocytes. ICR mice underwent MI by left anterior descending coronary artery ligation and were treated with sildenafil (0.71 mg/kg bid) or saline for 4 wk. Infarct size (IS) was measured 24 h postinfarction, and apoptosis was measured by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. Left ventricular end-diastolic diameter (LVEDD) and fractional shortening (FS) were measured by echocardiography. Sildenafil reduced IS (40.0 ± 4.6%) compared with that in saline (69.6 ± 4.1%, P < 0.05). NG-nitro-L-arginine methyl ester, a nitric oxide synthase (NOS) inhibitor (15 mg/kg bid), blocked the protective effect of sildenafil (IS, 60.2 ± 1.6%, P < 0.05 vs. sildenafil). Western blot analysis revealed a significant increase in endothelial NOS/inducible NOS proteins 24 h post-MI after treatment with sildenafil versus saline. Apoptosis decreased from 2.4 ± 0.3% with saline to 1.2 ± 0.1% with sildenafil (P < 0.05) on day 7 and from 2.0 ± 0.2% with saline to 1.2 ± 0.1% with sildenafil on day 28 (P < 0.05), which was associated with an early increase in the Bcl-2-to-Bax ratio. LVEDD increased from baseline value of 3.6 ± 0.1 to 5.2 ± 0.2 and to 5.5 ± 0.1 mm on days 7 and 28, respectively, with saline (P < 0.05) but was attenuated to 4.4 ± 0.2 and 4.4 ± 0.1 mm following sildenafil treatment on days 7 and 28, respectively (P > 0.05 vs. baseline). FS significantly improved post-MI with sildenafil. A marked decline in cardiac hypertrophy was observed with sildenafil, which paralleled a reduction in pulmonary edema. Survival rate was lower with saline (36%) compared with sildenafil (93%, P < 0.05). Sildenafil attenuates ischemic cardiomyopathy in mice by limiting necrosis and apoptosis and by preserving left ventricular function possibly through a nitric oxide-dependent pathway. [ABSTRACT FROM AUTHOR]

Transient reduction in coronary perfusion pressure in the isolated mouse heart increases microvascular resistance (paradoxical vasoconstriction) by an endothelium-mediated mechanism. To assess the presence and extent of paradoxical vasoconstriction in hearts from normal and diabetic rats and to determine whether increased heme oxygenase (HO)-1 expression and HO activity, using cobalt protoporphyrin (CoPP), attenuates coronary microvascular response, male Wistar rats were rendered diabetic with nicotinamide/streptozotocin for 2 wk and either CoPP or vehicle was administered by intraperitoneal injection weekly for 3 wk (0.5 mg/100 g body wt). The isolated beating nonworking heart was submitted to transient low perfusion pressure (20 mmHg), and coronary resistance (CR) was measured. During low perfusion pressure, CR increased and was associated with increased lactate release. In diabetic rats, CR was higher, HO-1 expression and endothelial nitric oxide synthase were downregulated, and inducible nitric oxide synthase and O2¯ were upregulated. After 3 wk of CoPP treatment, HO activity was significantly increased in the heart. Upregulation of HO-1 expression and HO activity by CoPP resulted in the abolition of paradoxical vasoconstriction and a reduction in oxidative ischemic damage. In addition, there was a marked increase in serum adiponectin. Elevated HO-1 expression was associated with increased expression of cardiac endothelial nitric oxide synthase, B-cell leukemia/lymphoma extra long, and phospho activator protein kinase levels and decreased levels of inducible nitric oxide synthase and malondialdehyde. These results suggest a critical role for HO-1 in microvascular tone control and myocardial protection during ischemia in both normal and mildly diabetic rats through the modulation of constitutive and inducible nitric oxide synthase expression and activity, and an increase in serum adiponectin. [ABSTRACT FROM AUTHOR]

While 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, also known as statins, have a well-established in role in the treatment and prevention of ischemic coronary artery disease, their utility in the setting of heart failure (HF) and left ventricular (LV) dysfunction remains under investigation. Although a reduction in LDL is the major effect of statin therapy, pleiotropic effects have been demonstrated, which could be responsible for the reduction in morbidity and mortality seen with statin use in patients with HE Patients with both ischemic and nonischemic HF have been shown to have improved survival with statin therapy, and patients receiving statin therapy are less likely to develop HF. Studies have demonstrated that statins reduce inflammation, improve endothelial function, decrease thrombogenicity, and improve LV and autonomic function. In this Review, we present the literature supporting the pleiotropic effects of statin therapy in patients with HF or LV dysfunction, and discuss the mechanisms by which statins might elicit the improvements in morbidity and mortality seen in these patients. [ABSTRACT FROM AUTHOR]

Abstract: Apoptosis is a key pathologic feature in acute myocardial infarction and heart failure. Experimental animal studies have shown beneficial effects of inhibiting apoptosis. Understanding the mechanisms involved in the apoptotic cascade may be useful in better understanding of heart failure and its management. Not only in vivo detection of apoptosis may prove clinically useful in the diagnosis and risk stratification of patients with ischemic heart disease, but anti-apoptotic treatments (specific and non-specific) may be effective in the prevention and treatment of post-infarction remodelling and heart failure. [Copyright &y& Elsevier]

Abstract: Background: Apoptosis plays a major role in the transition to heart failure (HF) in systemic hypertension although the underlying mechanisms are still unclear. The aim of this study was to determine the relationship between apoptosis, left ventricular remodeling, heart failure and the myocyte expression of survivin, an inhibitor of apoptosis. Methods: Spontaneously hypertensive rats (SHR) were used as a model of hypertensive cardiopathy, and Wistar Kyoto Stars rats (WKY) were used as controls. Animals were allowed to survive up to 18 months of age. The animals underwent echocardiography (EDD, ESD and FS were measured). The median section of the heart was processed for in situ end-labeling of DNA fragmentation (TUNEL) and for survivin expression by immunohistochemistry. Results: All SHR presented features of adverse cardiac remodeling. Apoptotic cells were increased in SHR compared with WKY, measured as apoptotic cells per high power field (1.08±0.43 vs. 0.27±0.15, P <0.001), and as apoptotic rate (0.16±0.06% vs. 0.04±0.02%, P <0.001). The incidence of apoptosis showed a positive correlation with unfavorable ventricular remodeling, assessed by echocardiogram. Survivin expression was found in all cases, but the survivin expression index was significantly lower in SHR vs. WKY (43±40% vs. 86±18%, respectively, P =0.014). Moreover the survivin expression index was inversely correlated with features of adverse remodeling (i.e., Heart Weight, R =−0.79, P <0.001) and with apoptosis (i.e., apoptotic rate, R =−0.52, P =0.050). Conclusion: Survivin myocardial expression in aging SHR is associated with reduced apoptosis and more favorable cardiac remodeling. Modulation of this pathway may prove beneficial in preventing pressure overload cardiac remodeling and heart failure. [Copyright &y& Elsevier]

Background: Depressed heart rate variability at acute myocardial infarction discharge is associated with poor long-term prognosis. However, its early (<48 h) predictive value has not been extensively investigated. Aim of this Multicenter Italian Study was to investigate, during acute myocardial infarction, in-hospital prognostic value of heart rate variability and its short-term evolution. Methods: Twenty-four hour ECG monitoring was prospectively obtained on admission in 413 patients with new-onset acute myocardial infarction and repeated in 349 at discharge. Heart rate variability statistical and frequency domain indices, peak creatine kinase, echocardiographic wall motion score index and risk factors were obtained. The occurrence of cardiac death and resuscitated ventricular fibrillation were the primary end-points; cardiogenic shock, ventricular tachycardia, post-infarction angina and heart failure the secondary end-points. Results: At admission, a marked reduction in heart rate variability indices was evident. Nine patients died during hospitalization and 13 were resuscitated from ventricular fibrillation. Secondary endpoints occurred in other 91 patients. At univariate analysis, low frequencies (LF), mean time interval between consecutive heart beats (RR), wall motion score index and family history of ischemic heart disease were predictive of combined primary and secondary end-points. At multivariate analysis, only LF and family history were predictive with a relative risk of 2.01 and 1.84, respectively (P<0.003). In survivors, heart rate variability indices significantly increased during hospitalization, still remaining below reference values. Conclusions: A depressed heart rate variability was present in the early phase of infarction and improved at discharge. LF power was an independent predictor of the combined unfavorable short-term events. [Copyright &y& Elsevier]

Background: Multivessel coronary disease after myocardial infarction is a major risk factor for unfavorable cardiac remodeling and death due to pump failure, but underlying pathophysiologic mechanisms are still uncompletely established. Post-infarction myocardial apoptosis has been recently implicated as a cause of ongoing cell loss leading to cardiac failure. Our aim was to assess the role of post-infarction myocardial apoptosis and pro-apoptotic factor expression in the non-infarcted remote myocardium of subjects with multivessel coronary disease. Methods: Twenty-one males dying after recent myocardial infarction with permanent occlusion of the infarct-related artery were selected at autopsy. Apoptosis was assessed at viable myocardial regions remote from infarction by co-staining for in situ end-labeling of DNA fragmentation and cleaved caspase-3. Expression of pro-apoptotic factor bax and hypoxia-induced factor-1alpha was evaluated by immunohistochemistry. Results: Subjects with multivessel disease (N=11) showed a significantly two-fold higher myocardial apoptosis in comparison to subjects with single vessel disease (N=10) (0.9% vs. 0.5%, p=0.013). Similarly, myocardial bax expression was increased in patients with multivessel disease (3.0% vs. 1.4%, p=0.029). Stratification for the number of diseased coronary vessels confirmed the association between extent of coronary disease and apoptotic rates (p=0.022). Even in subjects dying over 30 days after infarction multivessel disease remained predictive of enhanced myocardiocyte apoptosis at remote regions (p=0.033). Conclusions: Post-infarction myocardial apoptosis and bax expression in remote left ventricular regions are significantly increased in male patients with multivessel coronary disease in comparison to those with isolated infarct-related artery occlusion. These findings suggest that apoptotic cell loss in the viable non-infarcted myocardium, possibly due ongoing ischemia, may play a relevant role in the unfavorable clinical course typical of multivessel disease after myocardial infarction. [Copyright &y& Elsevier]

Cardiac surgery (CS), in particular cardiopulmonary bypass and cardioplegia, have been reported to trigger myocardial inflammation and apoptosis. This surgery-related inflammatory reaction appears to be of extreme complexity with regard to its molecular, cellular and tissue mechanisms. Both experimental and clinical studies have ascertained the role of several hormonal mediators, mitochondria, cardioplegia and extracorporeal circulation temperature, apoptosis and even genetic modulators of damage. However, the correlations between these factors in vivo and post-surgery outcome and prognosis have not yet been systematically investigated. In animal models of myocardial cardioplegia and/or ischemia–reperfusion, experimental drugs such as antioxidants have been documented to provide amelioration of post-intervention cardiac performance and reduction of apoptosis suggesting the possibility of new therapeutic strategies. However, these findings have been only partially confirmed in humans. Moreover, markers for the differential detection of early and late phases of apoptosis are subjects of intense investigations. This review will provide an overview of the major studies about the link between ischemia, myocardial inflammation and apoptosis during and after CS, with particular regard to the markers and methods for apoptosis detection. [Copyright &y& Elsevier]

The open-artery hypothesis states that myocardial reperfusion, even if late for myocardial salvage, provides benefits and prevents adverse cardiac remodeling. While observational data in humans regarding the deleterious impact of a permanent infarct-related artery occlusion and the benefits of spontaneous reperfusion are quite consistent, the reports regarding late revascularization are inconclusive in order to prove such a hypothesis. The observational studies tend to have selection biases, while randomized trials to date are too small to be conclusive. Moreover, the pathophysiological mechanisms underlying presumed benefits of reperfusion are still unclear. However, although the open-artery hypothesis remains unproven, the current evidence suggesting benefits calls for additional studies. Limitations of ischemic left ventricular dilatation and myopathy could markedly reduce cardiovascular morbidity and mortality after acute myocardial infarction. Copyright © 2003 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Vasopressin is currently recommended in the management of patients with cardiac arrest, but its efficacy is still incompletely established. We systematically reviewed randomized trials comparing vasopressin to control treatment in the management of cardiac arrest in humans and animals. Two human and 33 animal studies were retrieved. At pooled analysis vasopressin appeared equivalent to adrenaline (epinephrine) in the management of human cardiac arrest (N=240), with, respectively 63 (78/124) vs 59% (68/116) ROSC (P=0.43), and 16 (20/124) vs 14% (16/116) survival to hospital discharge (P=0.52). In animal trials (N=669) vasopressin appeared instead significantly superior to both placebo (ROSC, respectively 93 [98/105] vs 19% [14/72], P<0.001) or adrenaline (ROSC, respectively 84 [225/268] vs 52% [117/224], P<0.001). In conclusion, vasopressin is superior to both placebo or adrenaline in animal models of cardiopulmonary resuscitation. Evidence in humans is still limited and confidence intervals estimates too wide to reliably confirm or disprove results obtained in experimental animal settings. [Copyright &y& Elsevier]

Diabetes represents a major cause of cardiovascular morbidity and mortality in developed countries, and atherothrombosis accounts for most deaths among diabetics. Recent evidence has reliably shown the relevant etiopathogenetic role of inflammation in atherothrombotic disease. This review summarizes and discusses the possible synergistic effects of diabetes and inflammation in promoting atherothrombosis and its complications, as well as potential avenues for diagnostic, preventive, and therapeutic benefits in the modulation of inflammatory mechanisms in diabetic atherothrombotic disease. [Copyright &y& Elsevier]

: ObjectivesThe purpose of this study was to evaluate a potential correlation between apoptotic rate (AR), post-infarction left ventricular (LV) remodeling, and clinical characteristics in subjects who died late (≥10 days) after an acute myocardial infarction (AMI) with evidence of persistent occlusion of the infarct-related artery at autopsy.: BackgroundApoptosis contributes to myocardiocyte loss in cardiac disease and may have a pathophysiologic role in post-infarction LV remodeling.: MethodsThe AR was calculated at the site of infarction and in remote unaffected LV regions, using co-localization of in situ end labeling for deoxyribonucleic acid fragmentation and immunohistochemistry for caspase-3, in 14 subjects who died within two months after AMI. Correlation between AR and clinical characteristics such as age, site of AMI, transmural extension, multivessel coronary disease, and signs and/or symptoms of heart failure (HF), at the time of initial hospitalization for AMI or subsequently before death, was assessed using non-parametric statistical tests. Parameters of LV remodeling including diameters, free wall thickness, diameter-to-wall-thickness ratio, and mass were measured at gross examination at autopsy. Values are expressed as median (interquartile range).: ResultsAmong clinical variables, early symptomatic post-infarction HF (9 cases, 64%) was associated with nearly fourfold increased AR at the site of infarction (26.2% [24.5% to 28.8%] vs. 6.4% [1.9% to 13.3%], p = 0.001). Moreover, AR both at the site of infarction and in unaffected regions was significantly correlated with parameters of progressive LV remodeling (p < 0.05).: ConclusionsOur data show that in patients dying ≥10 days after AMI, myocardial apoptosis is strongly associated with and may be a major determinant of unfavorable LV remodeling and early symptomatic post-infarction HF. [Copyright &y& Elsevier]

Apoptosis is a common pathological feature in acute myocardial infarction (AMI), however, its role in the later phases (>10 days) of AMI and in post-infarction left ventricular remodeling has not been characterized. The aim of the study was to identify signs of ongoing cell apoptosis late post AMI. Sixteen hearts were collected at autopsy from subjects 12 to 62 days after the onset of AMI. In situ end-labeling of DNA fragmentation (TUNEL) and co-staining with caspase-3 were performed. Double-positive cells were defined as apoptotic and the apoptotic rate was calculated. Values are expressed as median and interquartile range. Co-stainings with muscle-actin, splicing factor (SC35), PCNA, bax and bcl-2 were also performed. Apoptotic rates at site of infarction [25.4% (17.0–28.4%)] were significantly higherv those at remote regions [0.7% (0.5–0.8%) P<0.001] and significantly correlated to left ventricular longitudinal and transverse diameters [ r=+0.70 (P=0.016) andr =+0.63 (P=0.004) respectively]. Moreover, in subjects with persistently occluded infarct-related artery (14 cases) there was a significantly higher apoptotic rate at the site of infarction compared to those (2 cases) with patent artery [26.0% (21.9–28.5%) v 4.5% (0.6% and 8,4%);P=0.033]. A significantly greater bax immuno-reactivity close to the infarction v remote areas was found (P<0.001). High grade apoptosis is present at sites of infarction in the later phases post AMI. This is more evident if the infarct-related artery is persistently occluded and signs of ventricular remodeling are present. These data may provide an explanation of progressive late left ventricular dysfunction. [ABSTRACT FROM AUTHOR]

Justifies the need to study coronary microcirculation. Hypothesis that coronary microvascular dysfunction can produce pathological manifestations in patients with coronary artery disease; Microvascular role in coronary heart disease and myocardial infarction; Emphasis on the need for understanding both coronary physiology and ischemic heart disease pathophysiology.

Editorial. Discusses the clinical importance of coronary microcirculation. Occurrence of coronary microvascular constriction in some patients during increases in oxygen consumption and attacks of angina; Effects of the dilation of the microcirculation on the severity of ischemia; Interventions aimed at treating the coronary microvasculature.

Virtually all types of cardiovascular diseases are associated with pathological activation of the innate immune system. The NACHT, leucine-rich repeat (LRR), and pyrin domain (PYD)-containing protein 3 (NLRP3) inflammasome is a protein complex that functions as a platform for rapid induction of the inflammatory response to infection or sterile injury. NLRP3 is an intracellular sensor that is sensitive to danger signals, such as ischemia and extracellular or intracellular alarmins during tissue injury. The NLRP3 inflammasome is regulated by the presence of damage-associated molecular patterns and initiates or amplifies inflammatory response through the production of interleukin-1β (IL-1β) and/or IL-18. NLRP3 activation regulates cell survival through the activity of caspase-1 and gasdermin-D. The development of NLRP3 inflammasome inhibitors has opened the possibility to targeting the deleterious effects of NLRP3. Here, we examine the scientific evidence supporting a role for NLRP3 and the effects of inhibitors in cardiovascular diseases. [ABSTRACT FROM AUTHOR]

The authors offer a perspective on the impact of cellular preservation therapy on acute myocardial infarction. Past studies on cardiac cell biology and pathophysiology has led researchers to developments in the field of cardiac regeneration. In relation, the authors explore the definitions of certain acute myocardial infarction such as ischemic necrosis.

Abstract: Apoptosis is a pathologic feature of cardiomyocytes in acute myocardial infarction (AMI) and heart failure. The temporal course of apoptosis in the peri-infarct area in the weeks following an AMI is still uncompletely defined. In order to study the time course of apoptosis after AMI, 16 rabbits underwent left coronary artery ligation and were sacrificed at 16, 26, 35, and 56 days after surgery. Increased apoptotic rate (AR) was observed at in the peri-infarct region than in remote myocardium (5.4% [2.5–9.6] vs 0.4% [0.1–0.9], respectively, P <0.001) and than in sham-operated cases (0.01% [0–0.02], P <0.001). A gradual decrease of AR in the peri-infarct region was observed over time with a 90% reduction at 8 weeks after coronary ligation. [Copyright &y& Elsevier]

Abstract: We report on a case of a fatal pulmonary embolism—an unexpected finding at autopsy of a 71-year-old man who had suffered from severe erosive gouty arthritis. Using morphological findings, medical history and histopathological results, we show the potentially devasting complications of this fairly common medical condition, occurring as a result of massive bone marrow erosion and detachment and finally leading to embolization of the lungs. [Copyright &y& Elsevier]