Jagdish Butany

Clinical and Pathophysiological Implications of a Bicuspid Aortic Valve

You are contacted by a concerned 34-year-old airline pilot with a leaky bicuspid aortic valve recently diagnosed by an echocardiogram that had been requested by his new employer as part of a routine medical assessment. He claims that he is perfectly healthy but is at risk of losing his job over his condition. He is concerned that his disease is hereditary and that his children may also be at risk. The patient, his attorney, and his insurance company have requested a statement from you as to the cause, possible complications, and treatment options associated with a congenital malformation of the aortic valve. The bicuspid aortic valve (BAV) is the most common congenital cardiac malformation, occurring in 1% to 2% of the population. The majority of BAV patients develop complications requiring treatment. Physicians are often challenged when asked to provide evidence-based advice about BAV disease because the pathogenesis and pathophysiology of this disease are not well understood. BAVs are the result of abnormal aortic cusp formation during valvulogenesis. Adjacent cusps fuse to form a single aberrant cusp, larger than its counterpart yet smaller than 2 normal cusps combined. BAVs are likely the result of a complex developmental process, not simply the fusion of 2 normal cusps. In fact, congenital aortic valve malformations may reflect a phenotypic continuum of unicuspid valves (severe form), bicuspid valves (moderate form), tricuspid valves (normal), and the rare quadricuspid forms1 (Figure 1). Figure 1. A, Normal tricuspid aortic valve. The cusps (arrowheads) and the 3 commissures (arrows) are clearly seen. Three sinuses of Valsalva are also seen. The cusps coapt normally to give a functionally normal valve. B, Congenitally bicuspid aortic valve, with one cusp larger (asterisk) than the other. The cusps show thickening due to fibrosis. Two commissures (arrows) are seen. One raphe (arrowhead) is …

Histologic abnormalities of the ascending aorta and pulmonary trunk in patients with bicuspid aortic valve disease: Clinical relevance to the ross procedure

OBJECTIVE Bicuspid aortic valve disease is often associated with dilation of the aortic root and ascending aorta. This study examines the histologic features of the ascending aorta and main pulmonary artery of patients with and without aortic valve disease. METHODS Samples from ascending aorta and main pulmonary artery were obtained at the time of the operation from 20 patients with bicuspid aortic valve and 11 patients with tricuspid aortic valve disease. In addition, samples were also obtained from autopsy cases with normal aortic valve. The histologic changes were graded from 1 to 3 according to severity of degenerative changes. RESULTS In the ascending aorta, the severity of cystic medial necrosis (P =.001), elastic fragmentation (P =.002), and changes in the smooth muscle cell orientation (P =.002) were significantly more severe in patients with bicuspid than in those with tricuspid aortic valve disease. In the pulmonary trunk specimens, those 3 histologic features were also significantly more severe in patients with bicuspid than those with tricuspid valves (P =.001, P =.01, and P =.04, respectively). Seventy-five percent of patients with bicuspid aortic valve disease had grade 3 degenerative changes, whereas only 14% of those patients with tricuspid aortic valve disease had similar degrees of degenerative changes. CONCLUSION Patients with bicuspid aortic valve disease have more severe degenerative changes in the media of the ascending aorta and main pulmonary artery than patients with tricuspid aortic valve disease. These findings may explain root and ascending aortic dilation in patients with bicuspid aortic valve disease and pulmonary autograft dilation in certain patients after the Ross procedure.

Myocardial fibrosis in hypertrophic cardiomyopathy: accurate reflection of histopathological findings by CMR.

OBJECTIVES In this study we sought to explore the relationship between cardiac magnetic resonance (CMR) with late gadolinium enhancement (LGE) and histopathological parameters including interstitial fibrosis and replacement fibrosis (scar) in patients with hypertrophic cardiomyopathy (HCM). BACKGROUND CMR-LGE is a well-established tool for the assessment of scar in ischemic heart disease. Its role in HCM has evolved in recent years, and an association with nonsustained ventricular tachycardia has been demonstrated. METHODS HCM patients who underwent septal myectomy during the period 2004 through 2010 and had undergone CMR-LGE no more than 6 months before surgery were selected. Histopathological assessment of the myectomy specimens included quantitative digital analysis (interstitial and replacement fibrosis) and semiquantitative assessment (small intramural coronary arteriole dysplasia and disarray). Correlations between CMR-LGE measured with various techniques, SD above the signal intensity for the normal remote myocardium (2, 4, 5, 6, and 10 SD) and the full width at half maximum (FWHM) technique, at the myectomy site, and interstitial fibrosis, replacement fibrosis (scar), and their sum (fibrosis + scar) were evaluated. RESULTS Twenty-nine patients were included. Statistically significant correlations between CMR-LGE (at 2, 4, 5, 6, 10 SD and by the FWHM technique), and both interstitial fibrosis and the combined interstitial and replacement fibrosis were found. The strongest correlation was between combined interstitial and replacement fibrosis and CMR-LGE measured at 5 SD (r = 0.78, p < 0.0001). LGE measured at 10 SD demonstrated the best correlation with replacement fibrosis (r = 0.42, p = 0.02). Bland-Altman analysis revealed optimum agreement between the combined interstitial and replacement fibrosis found at pathology and LGE measured at 4 SD. In addition, moderate and severe small intramural coronary artery dysplasia showed a statistically significant correlation with replacement fibrosis (p = 0.01) and CMR-LGE at 10 SD (p = 0.04). CONCLUSIONS CMR-LGE measured at 4 SD and 5 SD yields the closest approximation to the extent of total fibrosis measured by the histopathological standard of reference. These findings have implications for future investigations of CMR-LGE and its association with important clinical endpoints in HCM, including sudden cardiac death.

Time Course and Cellular Localization of SARS-CoV Nucleoprotein and RNA in Lungs from Fatal Cases of SARS

Background Cellular localization of severe acute respiratory syndrome coronavirus (SARS-CoV) in the lungs of patients with SARS is important in confirming the etiological association of the virus with disease as well as in understanding the pathogenesis of the disease. To our knowledge, there have been no comprehensive studies investigating viral infection at the cellular level in humans. Methods and Findings We collected the largest series of fatal cases of SARS with autopsy material to date by merging the pathological material from two regions involved in the 2003 worldwide SARS outbreak in Hong Kong, China, and Toronto, Canada. We developed a monoclonal antibody against the SARS-CoV nucleoprotein and used it together with in situ hybridization (ISH) to analyze the autopsy lung tissues of 32 patients with SARS from Hong Kong and Toronto. We compared the results of these assays with the pulmonary pathologies and the clinical course of illness for each patient. SARS-CoV nucleoprotein and RNA were detected by immunohistochemistry and ISH, respectively, primarily in alveolar pneumocytes and, less frequently, in macrophages. Such localization was detected in four of the seven patients who died within two weeks of illness onset, and in none of the 25 patients who died later than two weeks after symptom onset. Conclusions The pulmonary alveolar epithelium is the chief target of SARS-CoV, with macrophages infected subsequently. Viral replication appears to be limited to the first two weeks after symptom onset, with little evidence of continued widespread replication after this period. If antiviral therapy is considered for future treatment, it should be focused on this two-week period of acute clinical disease.

Amiodarone an inhibitor of phospholipase activity a comparative study of the inhibitory effects of amiodarone chloroquine and chlorpromazine

Amiodarone, an antiarrhythmic drug, like chloroquine and chlorpromazine, is a tertiary amine with amphiphilic properties. Chloroquine and chlorpromazine are known inhibitors of phospholipases. All three drugs produce characteristic microcorneal deposits consistent with lysosomal accumulations of phospholipid. Similar lysosomal bodies were found in leukocytes of 15 patients on chronic amiodarone treatment as well as 3 patients each on chloroquine and chlorpromazine, suggestive of widespread systemic inhibition of lysosomal phospholipases. These lysosomal inclusions were similar in morphology, irrespective of the drug given, and were of four types: multilamellar, amorphous dense, amorphous light, or a combination of 2 or more of the preceding types. There was no simple relationship between the number of inclusion bodies per cell and the cumulative dose of amiodarone (r=0.02) or amiodarone serum levels (r=0.11). An in vitro assay was used to compare the effects of the three drugs on Ca2+-dependent phospholipase A and C activities. Phospholipase A2 activity was inhibited in a dose-dependent fashion (1–8 mg/assay) by all three drugs in the order: chlorpromazine > amiodarone > chloroquine. The inhibitory effect on phospholipase C was more pronounced with all three drugs, producing almost total inhibition at 8 mg/assay. In a Ca2+-independent lysosomal phospholipase A system, amiodarone had a greater effect, producing 85% inhibition at 1.2 mg/assay. These observations suggest that amiodarone, like other cationic amphiphiles, induces a generalized phospholipidosis by inhibiting phospholipid catabolism. Its therapeutic and toxic effects may be due to its ability to modulate both Ca2+-dependent membrane phospholipases and Ca2+-independent acid phospholipases.

Innate Response Activator B Cells Aggravate Atherosclerosis by Stimulating T Helper-1 Adaptive Immunity

Background— Atherosclerotic lesions grow via the accumulation of leukocytes and oxidized lipoproteins in the vessel wall. Leukocytes can attenuate or augment atherosclerosis through the release of cytokines, chemokines, and other mediators. Deciphering how leukocytes develop, oppose, and complement each other’s function and shape the course of disease can illuminate our understanding of atherosclerosis. Innate response activator (IRA) B cells are a recently described population of granulocyte macrophage colony-stimulating factor–secreting cells of hitherto unknown function in atherosclerosis. Methods and Results— Here, we show that IRA B cells arise during atherosclerosis in mice and humans. In response to a high-cholesterol diet, IRA B cell numbers increase preferentially in secondary lymphoid organs via Myd88-dependent signaling. Mixed chimeric mice lacking B cell–derived granulocyte macrophage colony-stimulating factor develop smaller lesions with fewer macrophages and effector T cells. Mechanistically, IRA B cells promote the expansion of classic dendritic cells, which then generate interferon &ggr;–producing T helper-1 cells. This IRA B cell–dependent T helper-1 skewing manifests in an IgG1-to-IgG2c isotype switch in the immunoglobulin response against oxidized lipoproteins. Conclusions— Granulocyte macrophage colony-stimulating factor–producing IRA B cells alter adaptive immune processes and shift the leukocyte response toward a T helper-1–associated milieu that aggravates atherosclerosis.

Bicuspid aortic valve disease: recent insights in pathophysiology and treatment

Bicuspid aortic valve is a common congenital cardiac malformation with a broad spectrum of clinical outcomes. Bicuspid aortic valve may go undetected throughout an individual’s lifetime or, alternatively, they may have devastating clinical consequences, resulting in death. Both clinicians and medical scientists have taken a renewed interest in the development, pathophysiology and treatment options for this subtle but often substantial clinical entity. Evidence is mounting to suggest that an underlying disease of the aorta is inherited with bicuspid aortic valve, although considerable controversy surrounds this theory. Novel molecular mechanisms underlying the valve and vascular pathologies, as well as new surgical therapies for these patients have been proposed in the past 10 years.

Recommendations for processing cardiovascular surgical pathology specimens: a consensus statement from the Standards and Definitions Committee of the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology

With the advent of molecular subclassification of diseases, much consideration should be given to the proper processing of cardiovascular surgical pathology specimens to maximize patient care. Such specimens include endomyocardial biopsies, cardiac myectomy specimens, cardiac apical core segments, resected cardiac valves, pericardial biopsies, resected segments of aorta, cardiac tumors, vascular stents, vascular grafts, cardiac devices, resected veins, arterial biopsies including temporal artery biopsies and hearts removed during cardiac transplantation. In this report, the Standards and Definitions Committee of the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology present consensus guidelines for the gross description, sectioning, processing, and staining of these specimens. This report is presented to aid pathologists, pathology assistants, and clinicians in maximizing the diagnostic utility of cardiovascular surgical pathology specimens for enhanced patient care.

An approach to endomyocardial biopsy interpretation

The endomyocardial biopsy (EMB) remains the gold standard mode of investigation for diagnosing many primary and secondary cardiac conditions. Through a percutaneous and transvenous route, tissue fragments are generally procured from the right ventricular septum, with very few complications. Widespread use of EMB followed the development of heart transplantation as a means to follow allograft rejection. It has since been useful in helping to diagnose conditions affecting the heart, including cardiomyopathies, myocarditis, infiltrative lesions, arrhythmias, and drug toxicities. The procedure has also been used as a research tool to investigate the natural history of disease and the cardiotoxicity of new medications. This review presents an approach to the evaluation of the EMB, which is particularly directed towards those who may be asked to interpret such biopsies, but are not dedicated cardiovascular pathologists. Through a systematic evaluation of the endocardium, myocardium, interstitium, and intramural vessels, in the context of a complete clinical history, enough information can be deduced to diagnose or exclude specific conditions of clinical value.

Intraabdominal hemorrhage as a result of segmental mediolytic arteritis of an omental artery: Case report *

This article describes the fifth reported case of segmental mediolytic arteritis and the second in a survivor. The patient had intraabdominal bleeding as a result of a ruptured omental artery. The pathologic and arteriographic findings are described. The pathology is characterized by segmental disruption of the medial smooth muscle cells and the initiation of mediolysis. Mediolysis is associated with marked segmental thinning of the vessel wall, often with only the adventitia intact. Fibrin is deposited at the adventitial and medial surfaces, and hemorrhage into the media may occur. As in this reported case, lysis of the adventitia leads to sudden, often catastrophic intraabdominal hemorrhage. Little associated adventitial inflammation occurred. Segmental mediolytic arteritis seems to involve the intra-abdominal muscular arteries in elderly patients with nonspecific abdominal symptoms. An angiogram showed patchy areas of narrowing involving ileal, gastroduodenal, and renal arteries that correlated with the pathologic findings observed in the excised omental arteries.