Small Intramyocardial Vessels Research Articles

Pathomorphology of the heart in COVID-19

Cardiovascular system is a significant target for SARS-CoV-2.The objective was to study morphological changes in the heart in patients who died from COVID-19.Materials and methods. Autopsy material of the heart of those who died from COVID-19 (700 autopsies) was analyzed. The analysis of autopsy protocols was carried out, macroscopic changes were assessed, histological preparations stained with hematoxylin and eosin, van Gieson stain, Schiff’s reagent, the results of immunohistochemistry with antibodies to CD68, CD3, CD4, CD8, CD45 were analyzed.Results. The leading pathomorphological changes in the heart in COVID-19 are acute discirculatory changes with predominant disorders in small intramyocardial vessels. Lymphocytic myocarditis was confirmed in 1 % of cases.Conclusion. Damage to cardiomyocytes in COVID-19 is multifactorial and associated with manifestations of the underlying cardiovascular pathology, changes in intramyocardial vessels due to the action of SARS-CoV-2, and hypoxia due to progressive lung damage.

Transplant Vasculopathy Versus Native Atherosclerosis: Similarities and Differences.

Cardiac allograft vasculopathy (CAV) is one of the leading causes of graft failure and death after heart transplantation. Alloimmune-dependent and -independent factors trigger the pathogenesis of CAV through activation of the recipients' (and to a lesser extent donor-derived) immune system. Early diagnosis of CAV is complicated by the lack of clinical symptoms for ischemia in the denervated heart, by the impact of early functional coronary alterations, by the insensitivity of coronary angiography, and by the involvement of small intramyocardial vessels. CAV in general is a panarterial disease confined to the allograft and characterized by diffuse concentric longitudinal intimal hyperplasia in the epicardial coronary arteries and concentric medial disease in the microvasculature. Plaque composition in CAV may include early fibrous and fibrofatty tissue and late atheromatous calcification. In contrast, native coronary atherosclerosis usually develops over decades, is focal, noncircumferential, and typically diminishes proximal parts of the epicardial vessels. The rapid and early development of CAV has an adverse prognostic impact, and current prevention and treatment strategies are of limited efficacy compared with established strategies in native atherosclerosis. Following acute coronary syndromes, patients after heart transplantation were more likely to have accompanying cardiogenic shock and higher mortality compared with acute coronary syndromes patients with native hearts.

Effects of neuropeptide Y on coronary artery vasomotion in patients with microvascular angina

BackgroundPatients with microvascular angina (exertional angina, positive exercise tests and normal coronary arteriograms) usually have a reduced coronary blood flow reserve. Neuropeptide Y (NPY) is a potent endogenous vasoconstrictor involved in modulation of coronary vasomotor tone and may play a role in microvascular angina. MethodsWe compared the effects of NPY (0.2–1.0pmol/kg, intracoronary) on the vasomotor response of proximal and distal segments of the coronary arteries in 7 patients with microvascular angina, 9 with chronic stable angina, and 9 control individuals. The coronary response to the administration of ergonovine was also assessed in 9 other patients with microvascular angina. Computerized coronary artery diameter measurements were carried out before (baseline) and after the administration of the vasoactive agents. ResultsMean baseline coronary lumen diameters were similar in control, microvascular angina, and coronary artery disease patients. NPY constricted proximal coronary segments by 8±2%, 5±2% and 6±3% and distal segments by 14±2%, 11±2% and 10±2% in control, microvascular angina, and coronary artery disease patients, respectively (p=NS between groups). In patients with microvascular angina, ergonovine constricted proximal coronary segments by 7±1.5% and distal segments by 12.5±3% (p=NS vs. NPY). During NPY administration four microvascular angina patients developed chest pain, ST segment depression, and a marked lengthening of the contrast medium run off, in the absence of epicardial coronary artery spasm. Control individuals and coronary artery disease patients did not experience chest pain, ST segment shifts, or lengthening of the run off during NPY administration. Ergonovine administration caused chest pain and lengthening of the contrast run-off, in the absence of epicardial coronary artery spasm, in one microvascular angina patient. ConclusionsExogenous NPY causes mild epicardial coronary artery constriction which is similar in patients with non-cardiac chest pain, microvascular angina and coronary artery disease. Myocardial ischemia and marked lengthening of the contrast run off in response to NPY occurred in microvascular angina patients but not in control or coronary artery disease patients. An abnormal constrictor response to NPY at the microcirculation level could be the mechanism underlying the ischemic manifestations observed in patients with microvascular angina. Condensed abstract (table of contents)The vasomotor response of proximal and distal coronary artery segments was studied in twenty five patients: 7 microvascular angina, 9 chronic stable angina, and 9 control subjects. Computerized measurements of coronary diameters were carried out before and after the intracoronary administration of neuropeptide Y (NPY) and ergonovine. Constriction of epicardial arteries in response to NPY was mild and not significantly different in control, microvascular angina and coronary artery disease patients. Ergonovine-induced epicardial coronary artery constriction was similar to that of NPY. However, NPY caused transient myocardial ischemia in patients with microvascular angina (probably through constriction of the small intramyocardial vessels), but not in control subjects or coronary artery disease patients.

OC10_01 Analysis of Small Intramyocardial Vessels of the Heart in Chronic Cocaine Users After Sudden Death

OC10_01 Analysis of Small Intramyocardial Vessels of the Heart in Chronic Cocaine Users After Sudden Death

A Translational Approach to Hypertensive Heart Disease

The spectrum of the cardiac complications of arterial hypertension includes heart failure (HF), sudden death, and cardiac dysrhythmias, as well as the exacerbation of coincidental diseases (ie, atherosclerosis and chronic renal disease).1 However, knowledge of the cardiac impact of chronic elevation of arterial pressure has so evolved that hypertensive heart disease (HHD) may be thought as those consequences derived from left ventricular (LV) responses to fundamental disease mechanisms triggered by mechanical overload and neurohumoral stimuli.2 For instance, the long-held views are that LV hypertrophy (LVH), as the result of cardiomyocyte growth in response to pressure overload, serves to restore heart muscle economy back to normal and to preserve LV function.3 However, a number of alterations of the cardiomyocyte and the noncardiomyocyte components of the myocardium (including apoptosis, fibrosis, and changes in the microcirculation) also develop in HHD that lead to pathological myocardial remodeling not only in the left ventricle but also the left atrium and right ventricle.2 These alterations may explain the overall risk of LVH and its associated cardiac and noncardiac complications in hypertensive patients.4 Although LVH may be detected early and accurately in hypertensive patients by electrocardiography and echocardiography, newer cardiac imaging methods and the monitoring of several circulating biomarkers hold promise as noninvasive tools for the diagnosis of myocardial remodeling. Numerous clinical studies have shown that effective long-term antihypertensive treatment may be associated with a decreased LV mass (LVM), which has been attributed to diminished risk. However, no large study (or meta-analysis) has demonstrated that diminished risk from the contemporary reduction of arterial pressure by virtue of its a priori design. Therefore, because overall risk remains unacceptably high, especially from HF, new therapeutic strategies aimed not only to decrease arterial pressure and LVM but also to repair and even prevent myocardial remodeling …

N ε -(Carboxymethyl)lysine Depositions in Intramyocardial Blood Vessels in Human and Rat Acute Myocardial Infarction

Advanced glycation end products (AGEs), such as N(epsilon)-(carboxymethyl)lysine (CML), are implicated in vascular disease. We previously reported increased CML accumulation in small intramyocardial blood vessels in diabetes patients. Diabetes patients have an increased risk for acute myocardial infarction (AMI). Here, we examined a putative relationship between CML and AMI. Heart tissue was stained for CML, myeloperoxidase, and E-selectin in AMI patients (n=26), myocarditis patients (n=17), and control patients (n=15). In AMI patients, CML depositions were 3-fold increased compared with controls in the small intramyocardial blood vessels and predominantly colocalized with activated endothelium (E-selectin-positive) both in infarction and noninfarction areas. A trend of increased CML positivity of the intima of epicardial coronary arteries did not reach significance in AMI patients. In the rat heart AMI model, CML depositions were undetectable after 24 hours of reperfusion, but became clearly visible after 5 days of reperfusion. In line with an inflammatory contribution, human myocarditis was also accompanied by accumulation of CML on the endothelium of intramyocardial blood vessels. CML, present predominantly on activated endothelium in small intramyocardial blood vessels in patients with AMI, might reflect an increased risk for AMI rather than being a result of AMI.

Myocardial infarction as an uncommon clinical manifestation of intravascular large cell lymphoma

Intravascular large cell lymphoma (IVL) is a very rare variant of non-Hodgkin`s lymphoma presenting with puzzling clinical manifestations.There is a predilection for the central nervous system, but the tumour often affects also skin, lung, and kidneys while lymphadenopathy and hepatosplenomegaly are usually absent. Myocardial infarction due to IVL has not been reported so far.We here report on a 56-year-old patient who was admitted to our hospital with fever and clinical signs of erysipelas. He had a 6-month history of “collagen vasculitic disease” treated with prednisolon and azathioprin. He received antibiotic treatment, but after transient improvement fever recurred with generalized seizures and myocardial infarction, which required transfer to the intensive care unit where the patient died with signs of an acute cardiogenic shock. Autopsy revealed a generalized highgrade B cell lymphoma of IVL type affecting and obstructing small vessels of a variety of tissues including heart, brain and lungs.The tumorous obliteration of small intramyocardial vessels had led to an acute ischaemia with infarction and subsequent signs of myocardial insufficiency.To the best of the authors’ knowledge myocardial infarction as a leading symptom of IVL has not been described.

Early Morphologic Changes Following Microwave Endocardial Ablation for Treatment of Chronic Atrial Fibrillation During Mitral Valve Surgery

The aim of this study was to investigate the early qualitative and quantitative structural changes in the left atrial wall after endocardial microwave ablation in patients with chronic atrial fibrillation (AF) undergoing mitral surgery. Seven patients with chronic AF of for at least 6 months underwent surgical microwave energy ablation. Linear isolation of pulmonary veins was performed in all patients by microwave energy applications to the endocardial surface delivered by catheter at 65-W constant power for 45 seconds. Biopsies were obtained from a selected site (below the right lower pulmonary vein) of the left atrial posterior wall before and after the ablation procedure in all patients. Control tissues from the same sites were obtained at autopsy from patients with noncardiac causes of death. Light and electron microscopy was used to examine qualitative and quantitative changes in tissue morphology. Tissues after endocardial ablation procedure showed significantly increased loss of contractile material. Electron microscopy of atrial tissue demonstrated loss of profile of perinuclear and plasma membranes of myocytes, disruption of the endothelial cells of capillary vessels, and presence of macrophages. Lesions created by endocardial microwave energy ablation revealed a transmural effect on the left atrial wall without a significant reduction in thickness but a significant increase in the myolytic areas involving the entire cytosol and occlusion of the small intramyocardial vessels within the ablative lesion.

Intramural coronary vasculature prevents transmural radiofrequency lesion formation: implications for linear ablation.

Blood flow near a radiofrequency (RF) lesion can reduce lesion size by convective cooling. It is unknown whether blood flow through small vasculature within an RF lesion can prevent transmural lesion formation. In 40 rabbit right ventricle preparations, 2 epicardial RF lesions were created straddling a selectively perfused (0 to 12 mL/min) marginal artery (diameter, 0.34+/-0.1 mm). RF lesions were created at either 60 degrees C or 80 degrees C and delivered either sequentially or simultaneously. Conduction through the lesion area was measured. The lesions were analyzed histologically. At a perfusion rate of 0 mL/min, all RF lesions were transmural and without conduction. As little as 1 mL of flow through the artery during RF delivery could prevent transmural lesion formation by preserving a cuff of tissue along the length of the vessel. High-energy delivery (45 W) and very high tissue temperatures (93 degrees C) were needed to overcome the protective effect of vascular perfusion at 12 mL/min. The volume of preserved myocardium was related to arterial perfusion rate, artery diameter, and lesion temperature but not to the sequence of RF delivery (sequential versus simultaneous). Conduction persisted through the RF lesion in 20 experiments. Conduction through the lesion was related to the arterial perfusion rate and volume or cross-sectional area of preserved myocardium. Flow through even small intramyocardial vessels can prevent transmural lesion formation and preserve conduction through an RF lesion. These findings may represent an unrecognized obstacle to the creation of linear RF lesions in the clinical setting.

Microvascular coronary arterial vasculopathy--predictive value of endomyocardial biopsy.

Graft arteriosclerosis (GA) is characterized as a diffuse, usually concentric, proliferative lesion of uncertain pathogenesis that occurs in the coronary arteries of cardiac allografts involving both the microvasculature and epicardial vessels, and represents the major limitation to long-term recipient survival. The whole length of the vessel is affected, including small distal intramyocardial branches, which precludes optimal treatment with routine revascularization procedures. The prevalence of GA at 5 years after transplantation is high. Early diagnosis of GA is limited by the lack of clinical symptoms for ischemia in the denervated allogaft, by the insensitivity of coronary angiography, which frequently underestimates the extent and severity of the disease, and by the exclusive or predominant involvement of small intramyocardial vessels in some cases. The introduction of intracoronary ultrasound imaging supports earlier pathological data indicating that coronary angiography underestimates the severity of the disease. The use of intracoronary ultrasound has improved the early diagnosis of large vessel disease, but it lacks accessibility to distal lesions; thus, the extent of intramyocardial small artery disease remains relatively unexplored. Although it has been proposed that EMB could provide useful information on the diagnosis and development of allograft vasculopathy, less attention has been focused on the small intramyocardial vessels, as they appear in the endomyocardial biopsy (EMB), nor on the significance of the myocardial pathology resulting from the perfusion defects caused by GA. The aim of this paper is to briefly review some of the pathogenic mechanisms responsible for the development of GA, and the pathological findings observed in the microvasculature of the myocardium with special attention to the lesions that can be noticed in EMBs.

Abnormalities in intramyocardial arteries detected in cardiac transplant biopsy specimens and lack of correlation with abnormal intracoronary ultrasound or endothelial dysfunction in large epicardial coronary arteries

We sought to determine whether abnormalities in small intramyocardial vessels could be detected on routine cardiac transplant biopsy specimens and whether these features correlate with intimal thickening by intracoronary ultrasound and endothelial dysfunction in large epicardial vessels. Variability in clinical presentation of allograft vasculopathy suggests differential involvement of large and small vessels. Intracoronary ultrasound and endothelial function studies detect large-vessel abnormalities but may not reflect changes in small intramyocardial arteries. The latter could be detected in routine cardiac biopsy specimens by histologic and immunohistochemical studies. Thirty-nine cardiac transplant recipients underwent intracoronary ultrasound and acetylcholine studies 5 to 7 days after endomyocardial biopsy. Biopsy tissue was evaluated for coronary artery endothelial plumping and intimal thickening and increased immunostaining for fibronectin, tumor necrosis factor-alpha and receptor for hyaluronan-mediated motility. Large-vessel disease was assessed by calculating an average intimal index from intracoronary ultrasound of the left anterior descending coronary artery. Endothelial function was determined by quantitative coronary analysis after acetylcholine challenge. Coronary arteries were found in the biopsy tissue of 30 (76%) of the 39 patients who formed the study group. Fourteen of 30 patients had abnormal histologic findings. Immunohistochemical analysis for fibronectin, possible in 20 of 30 patients, was positive in 14 (70%) of 20 and correlated with abnormal histologic findings (p = 0.01). Immunostaining was positive for tumor necrosis factor-alpha and receptor for hyaluronan-mediated motility in 12 (40%) and 13 (43%) of 30 patients, respectively. All patients had intimal thickening by intracoronary ultrasound, but intimal index did not correlate significantly with small-artery disease by histologic or immunohistochemical analysis. Large-vessel endothelial dysfunction in 13 patients (43%) did not correlate with either abnormal ultrasound findings or small-vessel disease. Intramyocardial arteries are readily observed in biopsy specimens from cardiac transplant recipients and provide useful information about allograft vasculopathy. Lack of correlation between intramyocardial and epicardial vessel disease suggests discordant progression of allograft vasculopathy.

Cytomegalovirus infection-associated generalized immune activation in heart allograft recipients: a study of cellular events in peripheral blood and endomyocardial biopsy specimens.

An association between cytomegalovirus (CMV) infection, heart allograft rejection, and arteriosclerosis has been reported. To investigate the mechanisms of this association, the cellular immune response in peripheral blood and the inflammation in heart allografts during antigenemia were studied. CMV antigenemia occurred in 13 recipients. In recipients with severe CMV infection, a significantly weaker immune response was recorded in peripheral blood: fewer lymphoid blast cells (max. 2.4% +/- 0.4%) and large granular lymphocytes (LGL; max. 9.3% +/- 1.4%) were seen than in patients with mild or asymptomatic CMV infection (lymphoid blast cells max. 6.5% +/- 0.8% P < 0.01 and LGLs max. 20% +/- 2.3%, P < 0.05). Thus, a strong immune response with lymphoid activation was associated with clinically good outcome of CMV infection. In heart allograft histology, subendothelial inflammation of small intramyocardial vessels was a characteristic finding during CMV antigenemia compared to CMV-free recipients (at the peak P < 0.01). However, no difference in this mild and short-lived inflammatory response was observed between clinically mild or severe CMV infection. The CMV-linked generalized immune activation and inflammation of the vascular structures might contribute to the initiation of allograft vasculopathy and to the pathogenesis of chronic heart allograft rejection.

Determinants of Ventricular Arrhythmias in Cardiac Hypertrophy

Ventricular arrhythmias occur with increased frequency in both experimental and human cardiac hypertrophy. Although the process of hypertrophy itself may be arrhythmogenic, other factors may contribute to the high prevalence of arrhythmias in hypertensive patients with left ventricular hypertrophy (LVH). Disease of the large epicardial coronary arteries or of the small intramyocardial vessels (coronary microangiopathy) may lead to myocardial ischemia and thus predispose to arrhythmia. Myocardial fibrosis, a common sequelae of cardiac hypertrophy, has also been shown to be associated with ventricular arrhythmias in experimental models. Other possible determinants of ventricular arrhythmias in this group of patients include metabolic abnormalities; studies relating to the importance of hypokalemia in particular have yielded conflicting results. Thus a number of factors may combine to explain the high prevalence of ventricular arrhythmias in hypertensive patients with LVH.

Spectrum and Diagnosis of Myocardial Rejection

Right ventricular endomyocardial biopsy has become the mainstay for the diagnosis of acute cardiac rejection. The intelligent inerpretation of endomyocardial biopsy specimens requires knowledge of the artifacts inherent to the procedure as well as specific rejection and nonrejection pathology. Myocardial contraction bands, artifactual tissue spreading, and prior biopsy site changes should not be misinterpreted as evidence of myocyte damage, interstitial edema, or rejection, respectively. The Billingham criteria for acute cardiac rejection (mild, moderate, and severe) are still the most widely utilized, although other schemes for rejection have also shown clinical usefulness. Additionally, there is increasing evidence that some patients may develop a vascular or humoral rejection that may be more difficult to diagnose by endomyocardial biopsy without utilization of special techniques--for example, immunofluorescence. Nonrejection pathology frequently seen post-transplantation includes ischemia or catecholamine effect, interstitial fibrosis, myocardial calcification, cyclosporine-associated endocardial infiltrates (Quilty effect), myocyte hypertrophy, and infections (CMV, toxoplasmosis). Coronary artery disease continues to be the most significant threat to long-term survival. The spectrum of pathologic changes in the vessels range from mild intimal thickening to severe concentric intimal fibrosis involving extramural, as well as intramural, coronaries to lesions virtually identical to native atherosclerosis. Patients with diffuse narrowing involving large and small intramyocardial vessels appear to be at greater risk for myocardial infarction, death, or retransplantation than patients with other types of coronary pathology. Although important, these large vessel changes are rarely identified by endomyocardial biopsy.

The Correlation of Various Features of Rejection in Myocardial Biopsies after Human Heart Transplantation

1571 specimens taken at 493 occasions for endomyocardial biopsy in 30 selected heart transplant patients were reexamined in order to assess (a) the difference between conventional (steroid, azathioprine and antithymocyte globulin) and cyclosporine with low-dose steroid immunosuppression regimes, and (b) the relationship of myocardial rejection to endocardial infiltrates, the Quilty lesion, and changes in the small intramyocardial blood vessels. The incidence of all histological changes discussed were related to the severity of the myocardial rejection and therefore the endocardial and vascular changes may be used as adjuvants to make good any technical deficiencies in the myocardial part of the biopsy. Cyclosporine therapy is associated with the Quilty effect and with changes in small vessels.

Intramyocardial platelet aggregation in patients with unstable angina suffering sudden ischemic cardiac death.

A specific search for intramyocardial platelet aggregates was made in 90 patients who died suddenly of ischemic heart disease. Platelet aggregates in small intramyocardial vessels were found in 27 (30%). There was a significant difference (p less than .05) in the incidence of platelet aggregates in patients with chest pain of recent onset (unstable angina) before death (16/36, 44.4%) and that in those without it (11/54, 20.4%). Multifocal microscopic necrosis with involvement of the full thickness of the ventricular wall, including the subpericardial zone, was significantly more common (p = less than .005) in the patients with platelet emboli (55.6% vs 12.7%). With one exception, aggregates were confined to the segment of myocardium immediately downstream of a major epicardial coronary artery containing an atheromatous plaque that had undergone fissuring and on which mural thrombus had developed. The results support the view that platelet aggregates in the myocardium represent an embolic phenomenon and are a potential cause of unstable angina. The association of myocardial necrosis with such emboli could precipitate sudden death from ventricular fibrillation.

Hepatitis B virus and myocarditis

Myocarditis may be a serious extrahepatic complication of hepatitis. In this fatal case of serologically documented hepatitis B viral hepatitis, acute myocarditis was present, with histologic features consistent with a viral pathogenesis. Hepatitis B surface antigen was demonstrated by immunoperoxidase methods in small intramyocardial vessels, suggesting that hepatitis B virus infected the heart. The resulting inflammatory heart disease may have been caused either directly, by virus infecting the myocardium, or indirectly, by an immune-mediated mechanism.

Endocardial fibroelastosis: Myocardial and vascular alterations associated with viral-like nuclear particles

Although clinical, immunologic, and experimental evidence exists implicating in utero viral infection of the myocardium in the development of primary endocardial fibroelastosis, the infectious etiology of this condition remains somewhat controversial. To date, specific features of viral myocarditis and morphological demonstration of viral particles have not been described in EFE. The present case is the first in which extensive light microscopic and ultrastructural analysis of the myocardium revealed abnormalities consistent with a primary viral myocarditis associated with typical EFE. These alterations consisted of chronic myocardial inflammation, extensive interstitial fibrosis, severe degenerative changes in myocardial cells, and a marked proliferation of endothelial cells in large and small intramyocardial vessels leading to vascular occlusions. In support of the infectious etiology of this disease, similar features were noted in skeletal muscle. Most interestingly, viral-like particles were observed in many myocardial and endothelial nuclei. Although we are not absolutely certain of the viral nature of these particles, their appearance suggests viral associated material. We propose that the presence of these particles in this case in association with the other morphological alterations is support for the viral etiology of EFE. The prominent vascular occlusion observed in the myocardium may be an important clue to the pathogenesis of fibroelastosis as either a primary or secondary disease.

Adriamycin cardiotoxicity

Endomyocardial biopsies were examined in 12 patients receiving total doses of Adriamycin from 90 to 445 mg/M2. These patients had also received previous mediastinal irradiation (from less than 600 to 5700 rad) over periods varying from 6 months to 14 years prior to the endomyocardial biopsy. Severity of pathological change in these 12 patients was compared with that of dose-matched control patients who had not received mediastinal radiation. The severity of the histopathologic changes was scored on a scale from 0 (normal) to 3 (marked abnormality). The mean score of the group receiving irradiation (2.0 +/- 0.89) was significantly higher than the score in those not irradiated (1.18 +/- 0.23) (p less than 0.001). Morphological demonstration of a "recall phenomenon" of latent radiation changes by Adriamycin was demonstrated in small intramyocardial vessels. This study indicates that radiation, even if remote, enhances Adriamycin-induced cardiomyopathy. Therefore, Adriamycin must be given cautiously in patients who have received previous mediastinal radiotherapy.