Ticlopidine-induced aplastic anemia: two new case reports,review, and meta-analysis of 55 additional cases

Ticlopidine-induced aplastic anemia (TIAA) is considered very uncommon. We present two new cases, and we review 55 additional cases from the literature. The first case concerns a 70-year-old man who developed severe aplastic anemia 7 weeks after treatment with 500 mg of ticlopidine daily. The patient sustained a severe septic episode, was treated with antibiotics and GM-CSF, and recovered the 14(th) day after ticlopidine withdrawal. The second was an 82-year-old man receiving ticlopidine for 2 years when, during a febrile episode, he was found neutropenic with marrow aplasia. Ticlopidine withdrawal and treatment with antibiotics, transfusions, and G-CSF helped him to recover. When the data of the 57 patients are evaluated, a reversible direct cytotoxic effect of ticlopidine on the pluripotent/bipotent hematopoietic progenitor stem cell is proposed. It is estimated that the real incidence if TIAA is higher, and many cases, initially presented as agranulocytosis +/- thrombocytopenia, might be true aplastic anemias, not proven by marrow aspiration or trephine biopsy. There is no effective monitoring to prevent this side effect. Recombinant growth factors appear not to help in shortening the neutropenic period.     

Sudden death in severe aortic stenosis following cardiac catheterization

Five patients with critical aortic stenosis (aortic valve area 0.6 cm² or less) died 2 days to 21 days following cardiac catheterization performed in anticipation of cardiac surgery. A sixth patient was successfully resuscitated for spontaneous ventricular fibrillation, and successful aortic valve replacement was accomplished. Two patients had prior history of syncope; one patient, of ventricular tachycardia; three patients, of pulmonary edema; and three patients, of crescendo angina. One patient had severe hypotension during maintenance hemodialysis for chronic renal failure. The mode of death was sudden but not witnessed in two patients. The terminal cardiac rhythms were slow junctional in one patient, idioventricular in one, ventricular tachycardia in one, and ventricular fibrillation in the fourth patient. We conclude that symptomatic patients with critical aortic stenosis should be monitored after cardiac catheterization, and surgery should be performed as soon as possible since sudden death is not unusual.     

The applicability of the signal averaging technique in clinical cardiology

Summary: Since 1963 the signal averaging technique has been applied to improve the signal to noise ratio in highly amplified EKG registrations. Based on the experiences from the literature and the authors own laboratory, the applications of the signal averaging technique in clinical cardiology are reviewed: extraction and analysis of the fetal EKG and P-wave variations, His bundle electro-grams from the body surface (recovery rate 33–100% of cases), ventricular delayed depolarizations within the ST segment of the surface EKG (recovery rate, 40–90% of cases, depending on patient groups investigated), preatrial activity (sinus nodal potentials) from intra-cardiac (recovery rate, 80–90% of individuals), or surface EKGs (recovery rate, 60% of patients), analysis of frequency components of surface EKG-QRS complexes in patients with previous myocardial infarctions, and detection of low amplitude diastolic signals from surface phonocardiogram (recovery rate, 80% of cases). At present, advantages and limitations of the signal averaging technique may be appraised as follows: (1) sinus nodal potentials: S-A conduction times may be more reliable than those obtained by the extra-stimulus technique, since with averaging they are recorded during undisturbed sinus rhythm; direct recordings of changing S-A blocks may be impossible due to the summation process; validation of sinus nodal potentials in man necessary, (2) A-V nodal potentials: demonstration of true A-V nodal rhythm rather than His bundle rhythm; possibly direct identification of abnormal pathways in A-V nodal tachycardias; direct recordings of single A-V nodal blocks impossible due to summation process; (3) surface His bundle potentials: follow-up or screening of patients with A-V nodal and particularly His-Pur-kinje-system blocks; monitoring of antiarrhythmic drug therapy; atrial overlap in one-third of cases; direct identification of higher degree A-V nodal blocks impossible due to summation process (future developments may overcome this problem); (4) ventricular delayed depolarizations: possible identification of patients at high risk of sudden cardiac death; follow-up of therapeutic measures like antiarrhythmic drug therapy or cardiac surgery (bypass grafting, aneurysmectomy); validation of delayed depolarizations from body surface by direct intracardiac and/or epicardial mapping necessary.     

Haemodynamic effects of frusemide and its influence on repetitive rapid volume loading in acute myocardial infarction

The haemodynamic effects of intravenous frusemide (1 mg/kg)were studied in 22 male patients with left ventricular failurefollowing acute myocardial infarction. Radiographic pulmonaryoedema was present in all patients and their average left heartfilling pressure was 20 mmHg. Bolus injection of the drug wasfollowed by immediate increases in systemic arterial pressure(P < 0.05) and heart rate (<0.05); these declined to pre-injectionvalues after 60 min. Following frusemide there were progressivereductions in left heart filling pressure (P < 0.01), thermodilutioncardiac output (P < 0.01) and stroke volume (P < 0.05)and a progressive increase in the derived systemic vascularresistance (P < 0.05). There was an average diuresis of 860ml during the 90 min following the frusemide injection. Theinfluence of frusemide on left ventricular performance was studiedby comparing the circulatory effects of passive leg raisingin the control period with those at 30, 60 and 90 min afterthe drug. In the control period this manoeuvre increased leftheart filling pressure, but not heart rate, cardiac output,stroke volume or systemic vascular resistance. Ninety minutesafter frusemide, but not before, passive leg raising resultedin a significant increase in cardiac output (P < 0.01) andstroke volume at a similar increment in filling pressure anda significant reduction in the systemic vascular resistance(P <0.05). These circulatory actions of intravenous frusemideare compatible with initial arteriolar constriction and venodilatationfollowed by depletion of blood volume with subsequent changein left ventricular pumping performance.     

Changes in DNA content,number of nuclei and cellular dimensions of young rat atrial myocytes in response to left coronary artery ligation

Studies of enzymatically isolated myocytes from atria of young male Sprague-Dawley rats at 11 days after left coronary artery ligation show that a major response of atrial myocytes to ventricular infarction is binucleation. In sham-operated animals, 23.2% of left and 15.5% of right atrial myocytes were binucleated, compared to 77.8% of left and 40.5% of right atrial myocytes of infarcted animals. Examination of 150 g and 250 g unoperated control animals indicate that this response is occurring at a time when a small but significant amount of binucleation is also occurring as a normal part of growth. Using a Feulgen-acriflavine-SO₂ method for cytofluorometry, a significant increase in ploidy was seen in left atrial myocytes of infarcted animals over those of sham or control animals. The number of left atrial myocytes in infarcted animals having a ploidy level above 3C was 10.8% above sham values. The mean length of binucleated myocytes of left atrium was significantly greater in infarcted animals (119.8 μm) than in sham-operated animals (97 μm) and the mean length of mononucleated myocytes was greater in infarcted animals (104.1 μm) than in sham-operated animals (77 μm). Thus, cardiac myocytes are capable of a substantial response to a stressful situation by increases in cell length, number of nuclei and ploidy. Study of a model system such as the rat atrium may yield an understanding of the mechanisms involved in the induction of these nuclear changes.     

Pre-Menopausal Breast Fat Density Might Predict MACE During 10 Years of Follow-Up: The BRECARD Study

ObjectivesThis study sought to determine whether the breast gland adipose tissue is associated with different rates of major adverse cardiac events (MACEs) in pre-menopausal women.BackgroundTo our knowledge, no study investigated the impact of breast adipose tissue infiltration on MACEs in pre-menopausal women.MethodsProspective multicenter cohort study conducted on pre-menopausal women >40 years of age without cardiovascular disease and breast cancer at enrollment. The study started in January 2000 and ended in January 2009, and the end of the follow-up for the evaluation of MACEs was in January 2019. Participants underwent mammography to evaluate breast density and were divided into 4 groups according to their breast density. The primary endpoint was the probability of a MACE at 10 years of follow-up in patients staged for different breast deposition/adipose tissue deposition.ResultsThe propensity score matching divided the baseline population of 16,763 pre-menopausal women, leaving 3,272 women according to the category of breast density from A to D. These women were assigned to 4 groups of the study according to baseline breast density. At 10 years of follow-up, we had 160 MACEs in group 1, 62 MACEs in group 2, 27 MACEs in group 3, and 16 MACEs in group 4. MACEs were predicted by the initial diagnosis of lowest breast density (hazard ratio: 3.483; 95% confidence interval: 1.476 to 8.257). Further randomized clinical trials are needed to translate the results of the present study into clinical practice. The loss of ex vivo breast density models to study the cellular/molecular pathways implied in MACE is another study limitation.ConclusionsAmong pre-menopausal women, a higher evidence of adipose tissue at the level of breast gland (lowest breast density, category A) versus higher breast density shows higher rates of MACEs. Therefore, the screening mammography could be proposed in overweight women to stage breast density and to predict MACEs. (Breast Density in Pre-menopausal Women Is Predictive of Cardiovascular Outcomes at 10 Years of Follow-Up [BRECARD]; NCT03779217)     

Color Flow Doppler Observations on Mitral Valve Flow in Tamponade

We studied the M-mode and two-dimensional imaging of color Doppler mitral flow in eight patients with pericardial effusion and tamponade, and in ten control subjects. Pulsed-Doppler recordings of mitral flow were also obtained in all. Marked phasic changes (presumably respiratory) were consistently recorded in all patients with tamponade with respect to brightness, hue, width (duration), and length of the M-mode Doppler color stream; in these patients, phasic changes were noted in width, length, and color of the mitral flow stream on the two-dimensionalechocardiographic recording, with reciprocal changes in tricuspid flow. In the normal subjects, only minimal fluctuations in these color Doppler characteristics were present. Phasic differences in flow velocity of mitral flow by pulsed Doppler were found between the tamponade and the control groups. Large phasic fluctuations in various characteristics of color Doppler mitral flow on M-mode and two-dimensional imaging may constitute yet another echocardiographic sign of tamponade. (ECHOCARDIOGRAPHY, Volume 8, September 1991)