Cardiovascular Manifestations and Complications of Pheochromocytomas and Paragangliomas

Pheochromocytomas and paragangliomas (PPGLs) are rare neuro-endocrine tumors. The catecholamine surge causes paroxysmal or chronic secondary hypertension. PPGLs may present as hypertensive- or PPGL-crisis with severe life-threatening cardiac and cerebrovascular complications. PPGLs-induced cardiac manifestations have been reported with diagnoses as PPGLs-induced electrocardiogram (ECG) changes “mimicking acute myocardial infarction”, arrhythmias, myocarditis, acute coronary syndrome, dilated cardiomyopathy, and lately as takotsubo syndrome. Critical analysis of these reports reveals that most of these cardiac manifestations have certain features in common. They have a dramatic clinical presentation and are reversible if the disease is treated with appropriate medical therapy and surgical resection of the PPGL tumor. They may have the same repolarization ECG changes irrespective of the clinical cardiac diagnosis, usually associated with mild to moderate elevations of myocardial biomarkers as troponins and normal coronary arteries. The histopathological findings are usually focal or multifocal in the form hypercontracted sarcomeres and contraction band necrosis (myofibrillar degeneration) with subsequent secondary mononuclear cell infiltration. Evidences argue the PPGL caused surge of catecholamines triggers hyperactivation of the sympathetic nervous system with cardiac sympathetic nerve terminal disruption with norepinephrine spillover causing the cardiac complications. A comprehensive review of various reported cardiovascular manifestations and complications of PPGLs are presented.

Abstract 5871: Chronic Organic Mitral Regurgitation Results in Myofibrillar Degeneration and Oxidative Stress with Post-Surgical Left Ventricular Impairment Despite Pre-Surgical Left Ventricular Ejection Fraction > 60%

Background: Current guidelines recommend valve repair for chronic organic mitral regurgitation (MR) if LVEF drops below 60% to preserve LV function and maximize outcome. Post-operative drop in LVEF is typical, and widely believed to be due to alteration in loading conditions. Here we address whether cardiomyocyte damage may contribute to postoperative dysfunction. Methods: Three-dimensional magnetic resonance imaging (3D-MRI) with tissue tagging was performed in 23 MR patients, prior to and six months following mitral valve repair. LV biopsy was obtained from all MR patients at time of surgery. Immunohistochemistry was performed to assess for signs of oxidative stress, specifically lipofuscin deposition, and presence and quantity of xanthine oxidase (XO). Plasma XO levels were measured before, and six months post-surgery. Results: MR patients (n=23) demonstrated decreased LVEF (62 ± 1 to 54 ± 2% p=0.0002) and LV end-diastolic volume (116 ± 5 to 79 ± 5 ml/m 2 p<0.0001) six months after mitral valve (MV) repair. LV circumferential and longitudinal strain rates decreased below normal (6.54 ± 0.21 vs. 5.24 ± 0.24 p=0.0001, and 6.56 ± 0.26 vs. 5.41 ± 0.27 p=0.0084) despite no change in blood pressure and 3-dimensional LV end-systolic radius/wall thickness ratios. LV biopsies demonstrated marked cardiomyocyte myofibrillar degeneration vs. normals (2.32 ± 1.09 vs. 1.25 ± 0.45, p=0.0016, mean degeneration grade [1–4]). Immunostaining for xanthine oxidase (XO), a prominent oxidative enzyme, was increased in MR vs. normals (88 ± 7 vs. 33 ± 4%, p <0.01), as plasma XO decreased post-MV repair (2.12 ± 0.46 to 0.49 ± 0.25 μU/mL, p=0.008). Lipofuscin deposition, a product of oxidative stress, was increased in cardiomyocytes of MR vs. normals (0.62 ± 0.04 vs. 0.33 ± 0.04%, p <0.01). Conclusions: Decreased LV strain rates 6 months post MV repair indicate myocyte contractile dysfunction in chronic MR patients despite pre-surgical LVEF >60%. This is supported by marked cardiomyocyte myofibrillar degeneration and oxidative damage at the time of surgery. While raising questions regarding timing of surgery for MR, these findings generate hypothesis concerning XO and oxidative stress-related myocyte damage in the pathophysiology of LV contractile dysfunction in MR.

Analysis of Myofibrillar Organization and Degeneration by Fluorescence Confocal Microscopy

Myofibrillar degeneration is an important pathological process in progressive cardiomyopathy leading to heart failure. Loss of myofibrils in vivo has been observed in both adaptive cardiac responses (i.e. hypertrophy) as well as in chemotherapeutic use of antitumor drugs with cardiotoxic side effects (i.e. doxorubicin). The molecular mechanism(s) of myofibrillar degeneration are poorly understood in comparison with the sequence of events involved in myofibrillar assembly and organization. Maintenance of myofibril integrity is dependent upon a variety of factors, including contractile protein stoichiometry and protein kinase activity.The repeating sarcomeric architecture of myofibrils is well suited to structural analysis, since disruption of normal organization is easily visualized by fluorescence microscopy. Many antibodies are available for use in observation of myofibril structure (see Table at right). Confocal microscopy provides advantages in studies of myofilament organization by allowing for direct and accurate measurement of distances to within 0.2 βm and the ability to perform vertical sectioning through individual cells. This vertical (Z-axis) sectioning can be used to select the focal plane within the cell for observation, resulting in higher resolution images by reducing fluorescent signals from above and below the plane. Image analysis software enables the user to create projections of optically sectioned cardiomyocytes which can be rotated to reveal interior structural relationships previously unobserved with single sections or conventional epifluorescence microscopy. Examples of image analysis will highlight useful features such as distance measurement, periodicity, pixel intensity, colocalization of dual labels, and three dimensional reconstruction.

Neuromuscular junction alterations in extraocular muscles of myotonic rats

Rats treated with 20,25-diazacholesterol manifest clinical as well as physiological signs characteristic of human myotonic dystrophy. The extraocular muscles (EOMs) of such myotonic rats were shewn in a prior study to exhibit by electromyography, prolonged insertion activity, high frequency bizzare discharges, and myotonic responses, which are comparable to that observed in skeletal muscle. Light and electron microscopy of the EOMs revealed numerous fiber alterations, i.e., dense bodies, atrophic and angulated fibers, cell vacuolization, dilation and proliferation of the sarcoplasmic reticulum, mu11ilamllar membranous bodies, atypical mitochondrial clusters and disruptions, mitochondrial inclusions, excessive lipid accumulations, and myofibrillar degeneration. Many of these changes have been reported in human myotonic peripheral musculature. The most susceptible fiber populations in the EOMs were found to be the pale, intermediate, and red singly-innervated fibers of the global region; the pale fibers were the most affected.

Peripheral nerve autografts increase soleos muscle hydrolase activity

A peripheral nerve autograft placed on the surface of a normally innervated muscle has been shown to induce acetylcholine hypersensitivity and myofibrillar degeneration. Using a similar preparation, we determined the acid protease, alkaline protease, and N-acetylglucosaminidase activity in rat soleus muscle and the effect of protease inhibitors on these enzymes. Three days after nerve transplant, the muscle showed a significant increase in all three enzymes assayed. The protease inhibitors leupeptin and pepstatin totally prevented the nerve-induced increase in hydrolase activity. Our data suggest that muscle degeneration is secondary to an inflammatory response induced by the nerve.