Shannon Mackey-Bojack

Cardiac Functional and Histopathologic Findings in Humans and Mice with Mucopolysaccharidosis Type I: Implications for Assessment of Therapeutic Interventions in Hurler Syndrome

Hurler syndrome (mucopolysaccharidosis type I [MPS I]) is a uniformly lethal autosomal recessive storage disease caused by absence of the enzyme α-l-iduronidase (IDUA), which is involved in lysosomal degradation of sulfated glycosaminoglycans (GAGs). Cardiomyopathy and valvar insufficiency occur as GAGs accumulate in the myocardium, spongiosa of cardiac valves, and myointima of coronary arteries. Here we report the functional, biochemical, and morphologic cardiac findings in the MPS I mouse. We compare the cardiac functional and histopathological findings in the mouse to human MPS I. In MPS I mice, we have noted aortic insufficiency, increased left ventricular size, and decreased ventricular function. Aortic and mitral valves are thickened and the aortic root is dilated. However, murine MPS I is not identical to human MPS I. Myointimal proliferation of epicardial coronary arteries is unique to human MPS I, whereas dilation of aortic root appears unique to murine MPS I. Despite the differences between murine and human MPS I, the murine model provides reliable in vivo outcome parameters, such as thickened and insufficient aortic valves and depressed cardiac function that can be followed to assess the impact of therapeutic interventions in preclinical studies in Hurler syndrome.

Patent foramen ovale: standards for a preclinical model of prevalence, structure, and histopathologic comparability to human hearts.

Background: This study evaluated and standardized a Patent Foramen Ovale (PFO) preclinical model in gross anatomic and histopathologic features. Methods: We examined 150 necropsy‐derived domestic porcine hearts, age 4–6 months for PFO prevalence, appearance, and size. Histopathologic preparations were standardized and processed identically to 24 post‐mortem human hearts aged 16–62 years. A measurement scheme was developed for PFO atrial openings, tunnel length, and histopathologic features to compare porcine and patient hearts. Results: PFO was found in 32 of the 150 porcine hearts (prevalence 21.3%). Twenty‐five porcine PFO underwent standard characterization by tunnel length, and right, and left atrial orifice diameters. Logarithmic regression analysis between porcine PFO tunnel length and left atrial orifice area demonstrated a significant positive relationship (P = 0.0162, R2 = 0.227). The porcine PFO tunnel length was significantly longer than in humans (12.0 ± 4.0 mm vs. 7.1 ± 3.1 mm respectively, P < 0.0001). Histopathologic comparison was made using serial sections perpendicular to the atrial septum and the tunnel long axis. Human and porcine PFO lesions demonstrated strong similarities in tissue cells, connective tissue, and matrix composition. Conclusions: PFO assessment was standardized in both macroscopically and histopathologically, with quantitative and qualitative comparisons feasible using a porcine preclinical model. PFO prevalence in domestic swine is identical to humans, and microscopic structures very similar to humans. The domestic swine PFO model appears useful to evaluate new interventional closure technologies due to comparability in microscopic features. Tunnel length should be carefully evaluated due to differences across pigs and patients.

Review of Pathologic Findings in Remnant Hearts Following Valve Donation

ABSTRACT: The failure of medical examiners/coroners (ME/C) to allow heart valve donation is a major problem encountered by tissue agencies. Even though many ME/C favor tissue donation they remain responsible for determination of cause and manner of death. In 2001, the Jesse E. Edwards Registry of Cardiovascular Disease was approached by one of the nations largest tissue procurement agencies (The American Red Cross—ARC) for the purpose of performing cardiovascular pathologic examinations following valve donation. The affiliation existed from October 2001 to January 2005. This study was undertaken to review all 593 postvalve recovery heart remnants received during that time period to tabulate the abnormalities identified and to determine whether donation interfered with the determination of cause of death. For each case, a preliminary cause of death was provided by the ARC. The decedents body height and weight were also provided. Using the preliminary cause of death, the 593 cases were divided into natural and nonnatural manner of death groups. This division of the cases resulted in 106 cases placed in the natural manner of death group and 487 cases in the nonnatural manner of death group. For each case, all cardiac findings including significant conditions, additional findings, incidental findings, and congenital abnormalities were tabulated. Within the natural manner of death group, 15 cases had a noncardiac cause of death and 91 cases had a cause of death suspected to be cardiac related. In the 91 cases, a total of 132 significant cardiac findings were identified and there were six structurally normal hearts including two infants. In the nonnatural manner of death group, 214 significant cardiac findings were identified and 222 cases had a structurally normal heart. In both natural and nonnatural groups, the most common cardiac abnormality was atherosclerotic coronary artery disease. Other frequently encountered conditions were also identified including 11 cases with acute angle of origin of a coronary artery (five cases natural group; six cases nonnatural group). An important feature of this review was the recognition of potentially inheritable conditions that were diagnosed in both natural and nonnatural manner of death groups. There were three cases of hypertrophic cardiomyopathy (one natural; two nonnatural), three cases of arrhythmogenic right ventricular cardiomyopathy (one natural; two nonnatural), and one case of mitral valve prolapse (natural). In reviewing these cases, we did not feel that valve donation severely impaired cardiac pathologic examination. The benefits of cardiovascular pathologic examination by a cardiac pathologist include the identification of significant and incidental findings and recognition of potentially inheritable conditions.

Establishing a Multidisciplinary Network for the Workup of Sudden Cardiac Death

Sudden cardiac death (SCD) often falls under the jurisdiction of the medical examiner (ME). A recent expert consensus statement recommends cardiac evaluation for all first degree blood relatives of an individual with SCD and supports the referral of these family members to a multidisciplinary inherited arrhythmia clinic; however, most MEs lack the appropriate clinical network for a specific referral and family members are often not followed up. In 2010, Minnesota MEs and cardiovascular pathologists began collaborating with a cardiology referral center specializing in familial cardiac conditions to form a regional Sudden Death Network (SDN). The cardiac pathologists and MEs have established protocols for appropriate specimen retention in accordance with the National Association of Medical Examiners position paper on postmortem deoxyribonucleic acid (DNA) collection and for referring families for clinical evaluation. The expertise of a genetic counselor has been essential to the evaluation of these families in coordinating appropriate genetic testing and assisting with the identification of at-risk family members in extended pedigrees. This SDN uses a multidisciplinary approach for referral of family members for screening and treatment of SCD risk and represents an important resource for MEs. Development of SDNs across the country would lead to a more uniform approach to SCD follow-up and a more efficient use of clinical resources. The MEs role is essential in consulting cardiac pathologists when needed, establishing the correct diagnosis, collecting and retaining appropriate specimens, and initiating the referral of at-risk family members to specialists.

Sudden Death Due to Atherosclerotic Coronary Artery Disease: A Review of Commonly Accepted Practices

Atherosclerotic coronary artery disease (ASCAD) is the most common cause of morbidity and mortality in the United States. Sudden deaths due to ASCAD often fall under the jurisdiction of the medical examiner. ASCAD is such a common part of daily practice that pathologists often take for granted the validity of both clinical and postmortem ASCAD diagnostic techniques. This paper provides a comprehensive review of the history, literature, and common practices regarding postmortem ASCAD diagnosis.

Histologic Examination of the Heart in the Forensic Autopsy

Histologic examination of the myocardium, valves, and cardiac blood vessels is often as important as the gross examination. The diagnostic features and categories of heart disease are many and varied, possibly more than any other organ. We present a review of the histologic features of forensically important heart disease.

CLINICAL AND PATHOLOGIC FINDINGS OF AORTIC DISSECTION AT AUTOPSY: REVIEW OF 338 CASES OVER 6 DECADES

Background: Aortic dissection (AD) is characterized by diverse clinical manifestations and as a result, diagnosis is often delayed or not recognized until autopsy. Despite significant advances in imaging and the knowledge from clinical registries such as IRAD, the diagnosis is often still missed.

Uhl’s anomaly: perspective of fetal echocardiography and histopathological correlation

We report a case of Uhls anomaly imaged at 19 weeks of gestation by fetal echocardiography with pathological confirmation by anatomical gross heart specimen and tissue histology. Uhls anomaly of the right ventricle is a rare cardiac disorder with isolated right ventricular enlargement with almost complete absence of the right ventricular myocardium.