Aggressive systemic mastocytosis with the co-occurrence of PRKG2::PDGFRB, KAT6A::NCOA2, and RXRA::NOTCH1 fusion transcripts and a heterozygous RUNX1 frameshift mutation.

Systemic mastocytosis (SM) is a myeloproliferative neoplasm displaying abnormal mast cell proliferation. It is subdivided into different forms, including aggressive systemic mastocytosis (ASM) and systemic mastocytosis with an associated hematologic neoplasm (SM-AHN). Oncogenic genetic alterations include point mutations, mainly the KIT D816V, conferring poor prognosis and therapy resistance, and fusion genes, with those involving PDGFRA/PDGFRB as the most recurrent events. We here describe an ASM case negative to the KIT D816V and JAK2 V617F alterations but showing a RUNX1 frameshift heterozygous mutation and the co-occurrence of three fusion transcripts. The first one, PRKG2::PDGFRB, was generated by a balanced t(4;5)(q24;q32) translocation as the sole abnormality. Other two novel chimeras, KAT6A::NCOA2 and RXRA::NOTCH1, originated from cryptic intra-chromosomal abnormalities. The patient rapidly evolved towards SM-AHN, characterized by the persistence of the PRKG2::PDGFRB chimera, due to the presence of an extra copy of the der(5)t(4;5)(q24;q34) chromosome and an increase in the RUNX1 mutation allelic frequency. The results indicated that the transcriptional landscape and the mutational profile of SM deserve attention to predict the evolution and prognosis of this complex disease, whose classification criteria are still a matter of debate.

Minimal changes of thyroid axis activity influence brain functions in young females affected by subclinical hypothyroidism.

There is evidence of an association between thyroid hormones (TH) alterations and mental dysfunctions related to procedural and working memory functions, but the physiological link between these domains is still under debate, also for the presence of age as a confounding factor. Thus, we investigated the TH tuning of cerebral functions in young females affected by the borderline condition of subclinical hypothyroidism (SH) and in euthyroid females of the same age. The experiment consisted in the characterization of the affective state and cognitive abilities of the subjects by means of specific neuropsychological questionnaires, and of brain activity (EEG) in resting state and during the passive viewing of emotional video-clips. We found that SH had i) increased anxiety for Physical Danger; ii) better scores for both Mental Control and no-working-memory-related functions; iii) association between anxiety for Physical Danger and fT4 levels. Thus, in young adults, SH increases inward attention and paradoxically improves some cognitive functions. In addition, self-assessed questionnaires showed that SH had a greater susceptibility to unpleasant emotional stimulation. As for EEG data, SH compared to controls showed: i) reduction of alpha activity and of gamma left lateralization in resting state; ii) increased, and lateralized to the right, beta2 activity during stimulations. Both results indicated that SH have higher levels of arousal and greater susceptibility to negative emotion than controls. In conclusion, our study indicates that minimal changes in TH levels produce subtle but well-defined mental changes, thus encouraging further studies for the prediction of pathology evolution.

Apolipoprotein A-I mimetic peptide L-4F prevents myocardial and coronary dysfunction in diabetic mice.

Diabetes is a major health problem associated with adverse cardiovascular outcomes. The apolipoprotein A-I mimetic peptide L-4F is a putative anti-diabetic drug, has antioxidant and anti-inflammatory proprieties and improves endothelial function. In obese mice L-4F increases adiponectin levels, improving insulin sensitivity, and reducing visceral adiposity. We hypothesized that the pleiotropic actions of L-4F can prevent heart and coronary dysfunction in a mouse model of genetically induced Type II diabetes. We treated db/db mice with either L-4F or vehicle for 8 weeks. Trans-thoracic echocardiography was performed; thereafter, isolated hearts were subjected to ischemia/reperfusion (IR). Glucose, insulin, adiponectin, and pro-inflammatory cytokines (IL-1ß, TNF-α, MCP-1) were measured in plasma and HO-1, pAMPK, peNOS, iNOS, adiponectin, and superoxide in cardiac tissue. In db/db mice L-4F decreased accumulation of subcutaneous and total fat, and increased insulin sensitivity and adiponectin levels while lowering inflammatory cytokines (P < 0.05). L-4F normalized in vivo left ventricular (LV) function of db/db mice, increasing (P < 0.05) fractional shortening and decreasing (P < 0.05) LV dimensions. In I/R experiments, L-4F prevented coronary microvascular resistance from increasing and LV function from deteriorating in the db/db mice. These changes were associated with increased cardiac expression of HO-1, pAMPK, peNOS, and adiponectin and decreased levels of superoxide and iNOS (P < 0.01). In the present study we showed that L-4F prevented myocardial and coronary functional abnormalities in db/db mice. These effects were associated with stimulation of HO-1 resulting in increased levels of anti-inflammatory, anti-oxidative, and vasodilatatory action through a mechanism involving increased levels of adiponectin, pAMPK, and peNOS.

Isolation, proliferation, cytogenetic, and molecular characterization and in vitro differentiation potency of canine stem cells from foetal adnexa: a comparative study of amniotic fluid, amnion, and umbilical cord matrix.

The possibility to isolate canine mesenchymal stem cells (MSCs) from foetal adnexa is interesting since several canine genetic disorders are reported to resemble similar dysfunctions in humans. In this study, we successfully isolated, cytogenetically and molecularly characterized, and followed the differentiation potency of canine MSCs from foetal adnexa, such as amniotic fluid (AF), amniotic membrane (AM), and umbilical cord matrix (UCM). In the three types of cell lines, the morphology of proliferating cells typically appeared fibroblast-like, and the population doubling time (DT) significantly increased with passage number. For AF- and AM-MSCs, cell viability did not change with passages. In UCM-MSCs, cell viability remained at approximately constant levels up to P6 and significantly decreased from P7 (P < 0.05). Amnion and UCM-MSCs expressed embryonic and MSC markers, such as Oct-4 CD44, CD184, and CD29, whereas AF-MSCs expressed Oct-4, CD44. Expression of the hematopoietic markers CD34 and CD45 was not found. Dog leucocyte antigens (DLA-DRA1 and DLA-79) were expressed only in AF-MSCs at P1. Isolated cells of the three cell lines at P3 showed multipotent capacity, and differentiated in vitro into neurocyte, adipocyte, osteocyte, and chondrocyte, as demonstrated by specific stains and expression of molecular markers. Cells at P4 showed normal chromosomal number, structure, and telomerase activity. These results demonstrate that, in dog, MSCs can be successfully isolated from foetal adnexa and grown in vitro. Their proven stemness and chromosomal stability indicated that MSCs could be used as a model to study stem cell biology and have an application in therapeutic programs.

Thyroid hormone, amiodarone therapy, and prognosis in left ventricular systolic dysfunction.

BACKGROUND: Amiodarone protects patients with left ventricular systolic dysfunction (LVSD) against serious arrhythmias, but it also has numerous side effects on non-cardiac organs, such as the thyroid. Indeed, amiodarone may inhibit the peripheral conversion of T4 into T3. Pathologically reduced serum levels of T3 - the so-called "low T3 syndrome" (LOWT3) - increase mortality in patients with LVSD and not on amiodarone. AIM: The aim of the study was to examine the relationship between thyroid hormone status, amiodarone therapy, and outcome in a population with LVSD. MATERIAL/ SUBJECTS AND METHODS: A total of 2344 patients with LVSD and free of overt hyper- and hypothyroidism were enrolled. The population was divided into 4 groups: group 1 (LOWT3 and amiodarone therapy, no.=126), group 2 (isolated amiodarone therapy, no.=74), group 3 (isolated LOWT3, no.=682), group 4 (controls, no.=1462). RESULTS: Kaplan-Meier curves showed, after a mean follow-up of 31 months, increased total and cardiac mortality in groups 1 (30% and 20%, respectively), 2 (23%, 11%), and 3 (22%, 12%) compared to group 4 (total mortality log-rank 82.8, p<0.0001; cardiac mortality log-rank 63.1, p<0.0001). At Cox analysis, adjusted for several clinical variables, survival was reduced in groups 1 and 3 compared to group 4. Group 2 had a similar mortality to group 4, although the number of patients was too limited to accurately assess the effect of amiodarone on long-term prognosis. CONCLUSIONS: LOWT3 exerts an adverse impact on prognosis in LVSD, which is not influenced by concomitant amiodarone therapy.

Computer simulation of coronary flow waveforms during caval occlusion.

OBJECTIVES: Mathematical modeling of the cardiovascular system is a powerful tool to extract physiologically relevant information from multi-parametric experiments. The purpose of the present work was to reproduce by means of a computer simulator, systemic and coronary measurements obtained by in vivo experiments in the pig. METHODS: We monitored in anesthetized open-chest pig the phasic blood flow of the left descending coronary artery, aortic pressure, left ventricular pressure and volume. Data were acquired before, during, and after caval occlusion. Inside the software simulator (CARDIOSIM) of the cardiovascular system, coronary circulation was modeled in three parallel branching sections. Both systemic and pulmonary circulations were simulated using a lumped parameter mathematical model. Variable elastance model reproduced Starling's law of the heart. RESULTS: Different left ventricular pressure-volume loops during experimental caval occlusion and simulated cardiac loops are presented. The sequence of coronary flow-aortic pressure loops obtained in vivo during caval occlusion together with the simulated loops reproduced by the software simulator are reported. Finally experimental and simulated instantaneous coronary blood flow waveforms are shown. CONCLUSIONS: The lumped parameter model of the coronary circulation, together with the cardiovascular system model, is capable of reproducing the changes during caval occlusion, with the profound shape deformation of the flow signal observed during the in vivo experiment. In perspectives, the results of the present model could offer new tool for studying the role of the different determinants of myocardial perfusion, by using the coronary loop shape as a "sensor" of ventricular mechanics in various physiological and pathophysiological conditions.

Time course of carbon monoxide transfer factor after breath-hold diving.

Breath-hold divers may experience haemoptysis during diving. Central pooling of blood as well as compression of pulmonary gas content can damage the integrity of the blood-gas barrier, resulting in alveolar hemorrhage. The single-breath carbon monoxide test (DL,CO) was used to investigate the blood-gas barrier following diving. The study population consisted of 30 divers recruited from a training course. DL,CO levels were measured before diving and at 2, 10 and 25 min after the last of a series of four dives to depths of 10, 15, 20 and 30 m. When compared to pre-diving values, DL,CO values increased significantly at 2 min following diving in all subjects except one. Thereafter values progressively decreased toward baseline at 10 and 25 min in all subjects but one, while in four divers DL,CO values decreased below baseline. The early but transient increase in DL,CO levels shortly after diving supports the persistence of capillary pooling of red blood cells following emersion. Persistence at 25 min of high DL,CO values in one subject could be attributed by lung CT to extravasation of blood into the alveoli. Early or late DL,CO values >10% below baseline values suggest the presence of pulmonary edema. The relatively high prevalence of DL,CO alterations found suggests caution on the safety of breath-hold diving activities.

Concurrent chromothripsis events in a case of TP53 depleted acute myeloid leukemia with myelodysplasia-related changes.

Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) is a heterogeneous hematological disorder defined by morphological, genetic, and clinical features. Patients with AML-MRC often show cytogenetic changes, which are associated with poor prognosis. Straightforward criteria for AML-MRC diagnosis and a more rigorous characterization of the genetic abnormalities accompanying this disease are needed. Here we describe an informative AML-MRC case, showing two separate, but concurrent, chromothripsis events, occurred at the onset of the tumor, and originating an unbalanced t(5;7) translocation and a derivative chromosome 12 with a highly rearranged short arm. Conversely, despite chromothripsis has been often associated with genomic amplification in cancer, in this case a large marker chromosome harboring amplified sequences from chromosomes 19 and 22 arose from a stepwise mechanism. Notably, the patient also showed a TP53 mutated status, known to be associated with an increased susceptibility towards chromothripsis and a poor prognosis. Our results indicate that multiple chromothripsis events may occur early in neoplastic transformation and act in a synergistic way with progressive chromosomal alterations to determine a dramatic impact on disease outcome, as suggested by the gene expression profile analysis.

Cardiac function during breath-hold diving in humans: an echocardiographic study.

Breath-hold diving induces, in marine mammals, a reduction of cardiac output due to a decrease of both heart rate and stroke volume. Cardiovascular changes in humans during breath-hold diving are only partially known due to the technical difficulty of studying fully immersed subjects. Recently, a submersible echocardiograph has been developed, allowing a feasible assessment of cardiac anatomy and function of subjects during diving. Aim of the study was to evaluate, by Doppler-echocardiography, the cardiovascular changes inducedby breath-hold diving in humans. Ten male subjects were studied by Doppler echocardiography in dry conditions and during breath-hold diving at 3 m depth. In addition 14 male subjects were studied, using the same protocol, before and during breath-hold diving at 10 m depth. At 3 m depth significant reductions in heart rate (-17%), stroke volume (-17%), cardiac output (-29%), left atrial dimensions, and deceleration time of early diastolic transmitral flow (DTE) were observed. At 10 m depth similar but more pronounced changes occurred. In particular, increase in early transmitral flow velocity became significant (+33%), while DTE decreased by 34%. At both depths dimensions of right cardiac chambers remained unchanged. Breath-hold diving at shallow depth induced, in humans, cardiovascular changes qualitatively similar to those observed in natural divers such as seals. The reduced dimensions of left atrium associated to a left ventricular diastolic pattern resembling that of restrictive/constrictive heart disease, suggest that the hemodynamic effects of diving could be explained, at least in part, by a constriction exerted on the heart by the reduced chest volume and the increased blood content of the lungs. Finally, the absence of dimensional changes in the right chambers suggests that most of the pulmonary blood shift occurred before cardiac imaging.

Assessment of hand superficial oxygenation during ischemia/reperfusion in healthy subjects versus systemic sclerosis patients by 2D near infrared spectroscopic imaging.

BACKGROUND AND OBJECTIVE: Patients affected by systemic sclerosis (SSc) develop functional and structural microcirculatory dysfunction, which progressively evolves towards systemic tissue fibrosis (sclerosis). Disease initially affects distal extremities, which become preferential sites of diagnostic scrutiny. This pilot investigation tested the hypothesis that peripheral microcirculatory dysfunction in SSc could be non-invasively assessed by 2D Near Infrared Spectroscopic (NIRS) imaging of the hand associated with Vascular Occlusion Testing (VOT). NIRS allows measurement of hemoglobin oxygen saturation (StO2) in the blood perfusing the volume tissue under scrutiny. METHODS: In five normal volunteers and five SSc patients we applied a multispectral oximetry imaging device (Kent camera, Kent Imaging, Calgary, Canada) to acquire StO2 2D maps of the whole hand palm during baseline, ischemia and reperfusion phase. RESULTS: We found significant differences between controls and SSc patients in basal StO2 (82.80 ±â€¯2.51 vs 65.44 ±â€¯7.96%, p = 0.0016), minimum StO2 (59.35 ±â€¯4.29 vs 40.73 ±â€¯6.47%, p = 0.0007), final StO2 (83.83 ±â€¯4.09 vs 68.84 ±â€¯11.41%, p = 0.02) and time to maximum StO2 (40 ±â€¯12.25 vs 62 ±â€¯4.47 s, p = 0.005). CONCLUSIONS: This is, to our knowledge, the first application of 2D NIRS imaging of the whole hand to the investigation of microvascular dysfunction in systemic sclerosis. The image processing presented here considered the StO2 in the entire hand allowing a comprehensive view of the spatial heterogeneity of microvascular dysfunction.

Near infrared image processing to quantitate and visualize oxygen saturation during vascular occlusion.

The assessment of microcirculation spatial heterogeneity on the hand skin is the main objective of this work. Near-infrared spectroscopy based 2D imaging is a non-invasive technique for the assessment of tissue oxygenation. The haemoglobin oxygen saturation images were acquired by a dedicated camera (Kent Imaging) during baseline, ischaemia (brachial artery cuff occlusion) and reperfusion. Acquired images underwent a preliminary restoration process aimed at removing degradations occurring during signal capturing. Then, wavelet transform based multiscale analysis was applied to identify edges by detecting local maxima and minima across successive scales. Segmentation of test areas during different conditions was obtained by thresholding-based region growing approach. The method identifies the differences in microcirculatory control of blood flow in different regions of the hand skin. The obtained results demonstrate the potential use of NIRS images for the clinical evaluation of skin disease and microcirculatory dysfunction.

Paradoxical increase in microvascular resistance during tachycardia downstream from a severe stenosis in patients with coronary artery disease : reversal by angioplasty.

BACKGROUND: The pathophysiology of microvascular response to a severe coronary stenosis has not been conclusively identified. The aim of this study was to characterize the human vasomotor response to pacing-induced ischemia of both the stenotic arterial segment and the distal microcirculation. METHODS AND RESULTS: Sixteen patients with stable angina and single-vessel disease were studied. Blood flow velocity and transstenotic pressure gradient were monitored at baseline, after intracoronary adenosine (2 mg), and during ischemia induced by atrial pacing with and without adenosine. At the end of this protocol, the study was repeated after intracoronary phentolamine in 7 patients and after angioplasty in 9. Stenosis resistance was calculated as the ratio between mean pressure gradient and mean flow, and microvascular resistance as the ratio between mean distal pressure and mean flow; values were expressed as percent of baseline. Adenosine decreased (P<0.05) baseline microvascular resistance to 52+/-17%, but not stenosis resistance. Pacing increased both stenosis and microvascular resistances (244+/-96% and 164+/-60% of baseline, respectively, P<0.05). Addition of adenosine to pacing decreased both stenosis (143+/-96% of baseline, P<0.05 versus ischemia) and microvascular (51+/-17% of baseline, P<0.05 versus baseline and ischemia) resistances. Phentolamine did not affect coronary resistance at any step of the protocol. Angioplasty and stenting restored a progressive decline in microvascular resistance during pacing (51+/-19% of baseline, P<0.05 versus baseline). CONCLUSIONS: In patients with coronary artery disease, tachycardia-induced ischemia was associated with elevated resistance of both the stenotic segment and the microvasculature. Revascularization prevents this paradoxical behavior.

Myocardial contrast echo effect: the dilemma of coronary blood flow and volume.

Despite the useful information provided by myocardial contrast echocardiography, the meaning of myocardial contrast intensity remains elusive. This review is meant to define the contribution of physical and biologic factors in producing myocardial contrast and to elucidate the relative roles of coronary blood flow and intramyocardial blood volume in determining contrast effect. The main physical factors influencing the contrast echo effect include the properties of microbubbles as scattering elements (mainly their radius, compressibility, stability and concentration), electronic signal processing, instrument setting and contrast-induced signal attenuation. The effect of these factors can be limited by an appropriate experimental or clinical setup. Biologic factors are less easily controllable, and changes in coronary blood flow and alterations in myocardial blood volume appear to be the main determinants of myocardial contrast intensity. Moreover, these factors influence contrast intensity in opposite directions. Both the area under the time-intensity curve and the mean transit time of myocardial contrast are inversely related to coronary blood flow but directly related to myocardial vascularity and blood volume. Therefore, an increase in coronary flow not accompanied by an increase in myocardial vascularity and volume is accompanied by a decrease in the area under the curve and mean transit time of contrast. Conversely, an increase in coronary flow mediated by augmented myocardial vascularity and volume will produce an increase in the area under the curve and mean transit time. A better understanding of the physical and biologic determinants of contrast echo intensity will be fundamental in the clinical application of new agents and technologies.

Patterns of global and regional systolic and diastolic function in the normal right ventricle assessed by ultrafast computed tomography.

A detailed evaluation of global and regional systolic function and diastolic filling of the human right ventricle has not been previously reported. Ultrafast computed tomography enables simultaneous imaging of the right and left ventricles at an 8 mm slice thickness with a scanning rate of 17 frames/s (50 ms acquisition intervals). In 10 normal men (mean age 26 +/- 4 years) early diastolic filling data were fit to a third order polynomial curve and the peak rate of diastolic filling and time to peak filling were determined globally and regionally at three distinct ventricular levels (apex to base) within each ventricle. The right and left ventricular stroke volumes were not statistically different (89 +/- 8 ml and 90 +/- 8 ml, p = NS), neither were the peak filling rates as referenced to the stroke volume (4.9 +/- 0.9 and 5.3 +/- 0.8 stroke volumes/s, p = NS). Time to peak filling rate was not different between the two ventricles (154 +/- 33 and 161 +/- 18 ms, p = NS). However, reference of stroke volumes and absolute peak filling rates to end-diastolic volumes demonstrated lower dynamic values for the right ventricle (ejection fraction: right ventricle 57 +/- 4%; left ventricle 68 +/- 5%, p less than 0.05, and peak filling rate: right ventricle 2.7 +/- 0.4 end-diastolic volumes/s; left ventricle 3.6 +/- 0.5, p less than 0.05, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Stress echocardiography and the human factor: the importance of being expert.

The aim of this study was to evaluate how the diagnostic accuracy of a stress echocardiographic procedure, such as a dipyridamole echocardiography test, depends on the specific experience of the physician interpreting the test. Recordings of 50 consecutive dipyridamole echocardiographic tests were selected for the first part of the study. They were analyzed by 20 experienced echocardiographers with different backgrounds in stress echocardiography: 10 beginners (less than 20 stress studies interpreted with trained staff) and 10 experienced observers (greater than or equal to 100 stress studies performed). Diagnostic accuracy (true positive + true negative/total number of tests) versus the angiographic reference standard (greater than 70% coronary stenosis of at least one major coronary artery) was 62 +/- 6% for beginners and 85 +/- 3% for experienced observers (p less than 0.0001). In the second part of the study, 10 observers (5 beginners and 5 experienced observers) evaluated 2 different sets of 50 dipyridamole echocardiographic test studies before and after the training of the beginners. Before training, the accuracy of beginners was lower than that of experienced observers (61 +/- 7% versus 85 +/- 3%; p less than 0.001). After training, the accuracy gap was closed (83 +/- 3% versus 86 +/- 2%; p = NS). Therefore, interpretation of stress echocardiographic tests by an echocardiographer without specific training severely underestimates the diagnostic potential of this technique. One hundred stress echocardiographic studies are more than adequate to build the individual learning curve and reach the plateau of diagnostic accuracy that the test can yield.

High dose dipyridamole-echocardiography test in women: correlation with exercise-electrocardiography test and coronary arteriography.

The value of the exercise-electrocardiography test in detecting coronary artery disease in women is limited. Recently, the high dose dipyridamole-echocardiography test (two-dimensional echocardiographic monitoring during intravenous dipyridamole infusion, up to 0.84 mg/kg body weight over 10 min) was proposed as an alternative to exercise testing for the diagnosis of coronary artery disease. To establish the diagnostic usefulness of the exercise-electrocardiography and dipyridamole-echocardiography tests in this disease, the two tests were performed--on different days and in random order--in 83 consecutive women evaluated for a chest pain syndrome. All 83 women had taken no medications for greater than 48 h, and 15 had had a previous myocardial infarction. Positivity of the dipyridamole-echocardiography test was based on detection of a transient asynergy of contraction that was absent or of lesser degree at rest; the exercise-electrocardiography test (by upright cycloergometer) was considered positive when the ST segment was shifted greater than 0.1 mV 0.08 s after the J point. Coronary angiography showed significant coronary artery disease (greater than 70% luminal reduction of at least one major coronary vessel) in 39 women. No significant complications occurred in any patient during either test. Sensitivity and predictive value of a negative test were similar for the dipyridamole-echocardiography and the exercise-electrocardiography test (79 versus 72% and 84 versus 68%, respectively, whereas the dipyridamole-echocardiography test had greater specificity (93 versus 52%, p less than 0.001), accuracy (87 versus 62%, p less than 0.001) and a higher predictive value of a positive test (91 versus 57%, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

High dose dipyridamole echocardiography test in effort angina pectoris.

The dipyridamole echocardiography test (intravenous dipyridamole with two-dimensional echocardiographic monitoring) was performed in 93 patients with effort chest pain and in 10 control subjects. The test was considered positive when regional asynergy appeared after dipyridamole administration. When negative at the low dose (0.56 mg/kg body weight in 4 minutes), the test was repeated on a different day with a higher dose (0.84 mg/kg in 10 minutes). All 93 patients underwent coronary arteriography; 72 of them had significant (greater than 70% luminal reduction) coronary artery disease. Thirty-eight of the 93 patients had a positive low dose dipyridamole echocardiography test; 15 other patients with a negative low dose test had a positive high dose test. All 53 patients with a positive test had significant coronary artery disease; 12 of them had a negative exercise stress test. In relation to the presence of coronary artery disease, the dipyridamole echocardiography test had an overall specificity higher than that of the exercise stress test (100 versus 71%) and a similar overall sensitivity (74 versus 69%). The dipyridamole echocardiography test is feasible in all patients with a good baseline echocardiogram. It detects the site of apparent ischemia more precisely than does an exercise stress test, and can unmask electrocardiographically silent ischemia. If performed in patients with a negative low dose dipyridamole echocardiography test, the high dose test adds sensitivity (probably by achieving maximal dilation in patients in whom the low dose is only partially effective), without any loss in specificity and with no apparent increase in risk.

Coronary microcirculatory vasoconstriction during ischemia in patients with unstable angina.

OBJECTIVE: To verify the behavior of coronary microvascular tone during spontaneous ischemia in patients with unstable angina (UA). BACKGROUND: In UA, the pathogenetic role of vasoconstriction is classically confined at the stenotic coronary segment. However, microcirculatory vasoconstriction has been also suggested by previous experimental and clinical studies. METHODS: The study included 10 patients with UA (recent worsening of anginal threshold and appearance of angina at rest) and single-vessel CAD. Blood flow velocity was monitored by a Doppler catheter in the diseased artery. Transstenotic pressure gradient was monitored by aortic and distal coronary pressure monitoring. Stenosis resistance was calculated as the ratio between pressure gradient and blood flow, microvascular resistance as the ratio between distal pressure and blood flow. Measurements were obtained at baseline, following intracoronary adenosine (2 mg) and during transient ischemia. Aortic and distal coronary pressures were also measured during balloon coronary occlusion. RESULTS: Adenosine did not affect stenosis resistance, while it decreased (p < 0.05) microvascular resistance to 52 +/- 22% of baseline. Angina and ischemic ST segment shift were associated with transient angiographic coronary occlusion in 7 of 10 patients; however, in no case was ischemia associated with interruption of flow. Despite markedly different flow values, distal coronary pressure was similar during adenosine and during spontaneous ischemia (48 +/- 15 vs. 46 +/- 20 mm Hg, respectively, NS). During ischemia, a marked increase in the resistance of both coronary stenosis and coronary microcirculation was observed (to 1,233% +/- 1,298% and 671% +/- 652% of baseline, respectively, p < 0.05). Distal coronary pressure was markedly reduced during balloon coronary occlusion (14 +/- 7 mm Hg, p < 0.05 vs. both adenosine and ischemia), suggesting the absence of significant collateral circulation. CONCLUSIONS: In patients with UA, transient myocardial ischemia is associated with vasoconstriction of both stenotic arterial segment and downstream microcirculation.

Improved exercise capacity with acute aminophylline administration in patients with syndrome X.

The efficacy of the adenosine receptor blocker aminophylline on exercise capacity in patients with effort ischemia and documented coronary artery disease has been previously documented. In this study the effect of aminophylline on effort electrocardiographic (ECG) alterations and chest pain was tested in eight patients with syndrome X (anginal chest pain on effort, ischemic ECG changes during exercise, positive dipyridamole test, normal epicardial coronary arteries on angiography and absence of coronary spasm after ergonovine). After double-blind, randomized intravenous infusion of aminophylline (6 mg/kg body weight over 15 min) or placebo (20 ml of saline solution over 15 min), the eight patients with syndrome X underwent an upright bicycle exercise stress test on 2 consecutive days. After aminophylline, there was an increase in effort tolerance (aminophylline 7.7 +/- 1.2 min of exercise versus placebo 5.6 +/- 0.9, p less than 0.01) paralleled by an increase of the rate-pressure product (mm Hg x beats/min x 1/100) at 0.1 mV of ST segment depression or at peak exercise (aminophylline 278 +/- 55 versus placebo 230 +/- 24, p less than 0.05). Aminophylline provoked the abolition of ECG signs of ischemia in all eight patients. Thus, at a dosage that should effectively inhibit adenosine receptors, aminophylline infusion exerts a beneficial effect on exercise-induced chest pain and ischemia-like ECG changes in syndrome X. This effect occurs possibly through the prevention of myocardial flow maldistribution elicited by inappropriate adenosine release during effort in the presence of increased coronary resistance at the level of small intramural coronary arteries. This study, however, does not document the ischemic nature of effort-induced pain and ECG alterations in syndrome X.

Regional myocardial dysfunction in patients with angina at rest and response to isosorbide dinitrate assessed by phase analysis of radionuclide ventriculograms.

Left and right ventricular synchrony was assessed in 15 patients with angina at rest but no previous infarction by phase analysis of equilibrium radionuclide ventriculograms. Transient thallium-201 perfusion defects were noted in all during angina at rest and coronary vasospasm was documented in nine of the patients. Radionuclide ventriculograms were performed at control, during the ischemic episodes and after intravenous isosorbide dinitrate. Left and right ventricular phase histograms were quantified by the standard deviation from the mean of the peak (SD). Left ventricular ejection fraction averaged 65 +/- 11% (mean +/- standard deviation) at control, decreased in all patients during angina at rest to 49 +/- 14% (p less than 0.01) and increased in all patients after isosorbide dinitrate to 66 +/- 12%. However, ejection fraction during ischemia was abnormal in only nine patients and changed in two by less than 5% from the control value. Regional wall motion abnormalities were noted in all patients during the ischemic episodes but resolved after isosorbide dinitrate administration. Control left ventricular SD was 14.5 +/- 4 degrees, increased in all patients to 22.8 +/- 5 degrees during angina at rest (p less than 0.01) and returned to control values after isosorbide dinitrate administration (14.2 +/- 4 degrees). In contrast, right ventricular SD did not significantly change during ischemia as compared with control and isosorbide dinitrate. It is concluded that in angina at rest, a normal left ventricular ejection fraction does not exclude severe regional dysfunction; separate left and right ventricular SD is a sensitive index in detecting transient left ventricular dysfunction, and relief of ischemia is associated with rapid normalization of regional left ventricular function.