Evaluation of Cardiovascular Toxicity Associated with Treatments Containing Proteasome Inhibitors in Multiple Myeloma Therapy.

INTRODUCTION: Recently new treatment options have substantially increased survival for patients with relapsed and/or refractory multiple myeloma (RRMM). Among these, proteasome inhibitors (PI), such as bortezomib and carfilzomib, offer high response rate and prolonged survival. These agents are generally well tolerated but demonstrated a significant cardiovascular toxicity, mostly for regimen containing carfilzomib. AIM: To assess the cardiovascular damage in patients treated with PI for RRMM. METHODS: 28 consecutive subjects treated with PI for RRMM were evaluated and compared with a population of 22 control (Con) subjects, matched for age, sex and mean 24 h blood pressure (24hMBP). All individuals underwent trans-thoracic echocardiography, ambulatory blood pressure monitoring and pulse wave velocity (PVW) study. RESULTS: PI patients did not have significant differences in blood pressure load and PWV compared to controls. Among echocardiographic parameters, the global longitudinal strain (GLS) was significantly decreased in PI subjects (p = 0.02). The GLS was significantly lower also considering only patients treated with carfilzomib. Moreover, among carfilzomib patients, we found increase values of left ventricle mass indexed by BSA (LVMi; p = 0.047). After correction for age, sex, BSA, 24hMBP and morphological and functional parameters of LV, treatment with PI and carfilzomib were significantly associated with GLS (p = 0.01; p = 0.036, respectively). CONCLUSIONS: PI treatment is associated with subclinical LV dysfunction in patients with RRMM compared to controls, as demonstrated by lower GLS values. These results are confirmed also considering patients treated with carfilzomib. Moreover, in this subgroup of patients, the LVMi is also increased, suggesting higher cardiotoxicity with this treatment.

Orthostatic hypotension in a cohort of hypertensive patients referring to a hypertension clinic.

The prevalence of orthostatic hypotension (OH) in hypertensive patients ranges from 3 to 26%. Drugs are a common cause of non-neurogenic OH. In the present study, we retrospectively evaluated the medical records of 9242 patients with essential hypertension referred to our Hypertension Unit. We analysed data on supine and standing blood pressure values, age, sex, severity of hypertension and therapeutic associations of drugs, commonly used in the treatment of hypertension. OH was present in 957 patients (10.4%). Drug combinations including α-blockers, centrally acting drugs, non-dihydropyridine calcium-channel blockers and diuretics were associated with OH. These pharmacological associations must be administered with caution, especially in hypertensive patients at high risk of OH (elderly or with severe and uncontrolled hypertension). Angiotensin-receptor blocker (ARB) seems to be not related with OH and may have a potential protective effect on the development of OH.

Recombinant human, active site-blocked factor VIIa reduces infarct size and no-reflow phenomenon in rabbits.

Oxygen free radicals induce de novo synthesis of tissue factor (TF), the initiator of the extrinsic pathway of coagulation, within the coronary vasculature during postischemic reperfusion. In the present study we wanted to assess whether TF expression might cause myocardial injury during postischemic reperfusion. Anesthetized rabbits underwent 30 min of coronary occlusion followed by 5.5 h of reperfusion. At reperfusion the animals received 1) saline (n = 8), 2) human recombinant, active site-blocked activated factor VII (FVIIai, 1 mg/kg, n = 8), or 3) human recombinant activated FVII (FVIIa, 1 mg/kg, n = 8). FVIIai binds to TF as native FVII, but with the active site blocked it inhibits TF procoagulant activity. The area at risk of infarction (AR), the infarct size (IS), and the no-reflow area (NR) were determined at the end of the experiment. FVIIai resulted in a significant reduction in IS and NR with respect to control animals (28.1 +/- 11.3 and 11.1 +/- 6.1% of AR vs. 59.8 +/- 12.8 and 24.4 +/- 2.7% of AR, respectively, P < 0.01), whereas FVIIa resulted in a significant increase in IS and NR to 80.1 +/- 13. 1 and 61.9 +/- 13.8% of AR, respectively (P < 0.01). In conclusion, TF-mediated activation of the extrinsic coagulation pathway makes an important contribution to myocardial injury during postischemic reperfusion.

Antithrombotic effects of recombinant human, active site-blocked factor VIIa in a rabbit model of recurrent arterial thrombosis.

The extrinsic coagulation pathway is activated when circulating factor VII (FVII) gains access to tissue factor (TF) exposed as a consequence of vascular injury. Increasing evidence indicates that this TF-dependent activation of the coagulation plays an important role in the pathophysiology of intravascular thrombus formation. In the present study, we tested the effects of recombinant human, active site-blocked activated FVII (FVIIai) in a rabbit model of carotid artery thrombosis. Cyclic flow variations (CFVs), due to recurrent thrombus formation, were obtained in stenotic rabbit carotid arteries with endothelial injury. Carotid blood flow velocity was measured by a Doppler flow probe. After 30 minutes of CFVs, the animals received FVIIai (100 microg x kg(-1) x min(-1) intracarotid infusion for 10 minutes, n=9). If CFVs were abolished, animals were followed for 30 additional minutes, after which recombinant human activated FVII (FVIIa) was infused into the carotid artery (100 microg x kg(-1) x min(-1) for 10 minutes) to determine whether FVIIai could be displaced from TF by FVIIa, thus restoring CFVs. To establish the duration of action of FVIIai, an additional group of animals received FVIIai at the same dose as above, and after CFVs were inhibited, they were followed until CFVs were restored or for up to 6 hours. To determine whether CFVs could be restored by epinephrine after their abolition with FVIIai, increasing doses of epinephrine were administered to a third group of 6 animals. FVIIai abolished CFVs in 8 of 9 rabbits (P<.01). This effect was reversible, as FVIIa administration restored CFVs in all animals. Prothrombin times and activated partial thromboplastin times did not change significantly throughout the study. One single 10-minute infusion exerted complete antithrombotic effects for at least 6 hours, despite the fact that at this time point, plasma FVIIai levels were well below threshold concentrations. Epinephrine restored CFVs in 3 of 6 animals in which CFVs were inhibited by FVIIai. FVIIai exerts potent antithrombotic effects in this model; these effects were prolonged even after FVIIai was almost completely cleared from the circulation, probably as a result of the tight binding of FVIIai to TF. Thus, FVIIai might represent an antithrombotic substance of potential interest.

[Cardiac troponin I in unstable angina]. / La troponina I cardiaca nell'angina instabile.

BACKGROUND: Unstable angina implies high risk of myocardial infarction and sudden death. Increased levels of cytoplasmatic enzymes and proteins (creatine phosphokinase, MB creatine phosphokinase troponin T, etc.) were described in unstable angina, providing information about incoming major coronary events. Cardiac troponin I (cTn-I) is a structural protein inhibiting the actinomyosine ATPase; it is only found in myocardial cells. Serum titration of cTn-I has been recently introduced into clinical practice as a sensitive and specific marker of myocardial cellular necrosis. OBJECTIVES: The aim of our prospective study was to assess the presence of cTn-I in blood samples of patients with unstable angina and no signs of myocardial necrosis. Furthermore we intended to test the possible use of cTn-I in unstable angina as a prognostic marker of major coronary events on short and middle term. METHODS: We studied 33 consecutive patients admitted to our CCU for unstable angina. According to unstable angina Braunwald's classification, 6 patients were included in the first class, 4 patients in the second class and 23 patients in the third class. We excluded patients with acute or recent myocardial infarction. Blood samples of all patients were obtained at the time of CCU admission and every eight hours in the first and second day. Serum cTn-I titration was performed with the sandwich immunoenzymometric method, recently introduced by Diagnostic Pasteur. Two months follow-up was carried out in order to survey major coronary events and revascularization procedures, either angioplasty or coronary artery bypass surgery. RESULTS: No patients with unstable angina exhibited cTn-I in their blood samples; accordingly, cTn-I was not found in the first blood sample of a patient who underwent myocardial infarction during hospitalization. During the follow-up 2 patients died of myocardial infarction, 9 patients had surgical revascularization and 5 patients angioplasty. CONCLUSIONS: CTn-I is a sensitive and specific marker of myocardial necrosis. It is not found in patients with unstable angina; therefore it has no role as a prognostic marker of major coronary events.

[Inactivated factor VII exercises a powerful antithrombotic activity in an experimental model of recurrent arterial thrombosis]. / Il fattore VII inattivato esercita una potente attività antitrombotica in un modello sperimentale di trombosi arteriosa ricorrente.

The extrinsic coagulation pathway is activated when tissue factor (TF) is exposed as a consequence of arterial damage. TF binds to factor VII (FVII) or activated FVII (FVIIa), generating a complex that activates both FX and FIX, ultimately leading to thrombin formation. To determine whether inhibition of FVII binding to TF would result in antithrombotic effects, active site-blocked FVIIa (FVIIai) was used in a rabbit model of intravascular thrombus formation. In addition, to study the interaction between extrinsic coagulation pathway activation and platelet aggregation, in the same model of intravascular thrombus formation, recombinant human FVIIa was administered in antiplatelet-treated rabbits. Cyclic flow variations (CFVs), due to recurrent thrombus formation, were initiated by placing an external constrictor around the endothelially-injured rabbit carotid arteries (Folt's model). Carotid blood flow was measured continuously by a Doppler flow probe placed proximally to the constrictor. CFVs were induced in 29 New Zealand White rabbits. After CFVs were observed for 30 min, the animals were randomly divided in four groups: 5 animals received via a small catheter (26G) placed proximally to the stenosis, an intra-arterial infusion of human recombinant FVIIai (0.1 mg/kg/min for 10 min); 9 animals received AP-1, a monoclonal antibody against rabbit TF (0.1 mg/kg i.v. bolus); 7 animals received ridogrel, a dual thromboxane A2 synthetase inhibitor and thromboxane A2 receptor antagonist (10 mg/kg i.v. bolus); finally, 8 rabbits received aurintrycarboxilic acid (ATA), an inhibitor of platelet glycoprotein Ib/von Willebrand factor interaction (10 mg/kg i.v. bolus). FVIIai abolished CFVs in 5 of 5 animals (CFV frequency minutes 0 cycles/hour; p < 0.05; carotid blood flow velocity minutes 106 +/- 9% of the baseline values; NS vs baseline). AP-1 abolished CFVs in 7 of 9 animals (CFV frequency minutes 0 cycles/hour; p < 0.05; carotid blood flow velocity minutes 58 +/- 35% of the baseline values; NS vs baseline). Finally, in all the animals receiving ridogrel or ATA CFVs were abolished (CFV frequency 0 cycles/hour; p < 0.05 in both groups; carotid blood flow velocity, respectively 62 +/- 32 and 66 +/- 40% of the baseline values; NS vs baseline in both groups). Thirty minutes following inhibition of CFVs, in the FVIIai treated rabbits, human recombinant FVIIa was infused, via the small catheter placed proximally to the stenosis, at the dose of 0.1 mg/kg/min for 10 min. In the other three groups, FVIIa, at the same dose, was infused i.v. Infusion of FVIIa restored CFVs in all FVIIai treated animals and in 6 of 7 AP-1 treated animals, thus indicating that AP-1 and FVIIai bindings to TF was competitive and was replaced by FVIIa. Infusion of FVIIa failed to restore CFVs in ridogrel e ATA treated rabbits (1 of 7 and 0 of 8 rabbits, respectively), showing that activation of extrinsic coagulation by FVIIa was overcome by inhibition of platelet function. Activated partial thromboplastin time, and ex vivo platelet aggregation in response to ADP and thrombin, were not different after FVIIai infusion, while prothrombin time was slightly but significantly prolonged as compared to baseline values. Thus, FVII-VIIa plays an important role in initiating thrombus formation in vivo. Administration of FVIIai exerts a potent antithrombotic effects in this model without affecting systemic coagulation. In addition, in this model platelets exert an important role in arterial thrombosis, since in the presence of inhibition of platelet function, activation of the extrinsic coagulation pathway failed to restore thrombus formation.

[Use of myocardial thallium-201 scintigraphy in the evaluation of infarct area]. / Utilizzo della scintigrafia miocardica con Tallio-201 nella valutazione dell'area infartuale.

In twenty-four patients admitted of the Coronary Care Unit for myocardial infarction, without signs of previous necrosis and uncomplicated course, amplitude of infarct size was estimated by 201-Thallium perfusion scintigraphy. The obtained results were compared with residual ventricular function (i.e. angiographic ejection fraction) and with other methods of fibrotic area evaluation such as electrocardiographic score and CPK and CK-MB dismission curve. Concordance was observed among: scintigraphy and ejection fraction, scintigraphy and electrocardiographic score, scintigraphy and CPK peak.

[Intravenously disopyramide phosphate administration for treatment of arrhythmias]. / La disopiramide fosfato endovenosa nella terapia acuta delle aritmie cardiache.

Disopyramide phosphate (DF) was administered intravenously to 50 patients during 55 episodes of arrhythmias. The mean dosage employed was 2 +/- 1.4 mg/kg over a period of 3 minutes to 60 minutes (mean 16 +/- 6'), followed by an infusion at a dose of 0.4 mg/kg/hr in 9 cases. Atrial premature beats were suppressed in 3 of 4 treated cases (75%). Conversion to sinus rhythm was achieved in 4 of 5 (80%) cases of paroxysmal supraventricular tachycardia, unresponsive to vagal maneuvers in 7 of 10 cases (70%) of atrial flutter of recent onset (less than 48 hours) and in 13 of 17 (76%) cases of atrial fibrillation (less than one week in duration). In 9 of 11 cases (81%) with frequent, multiform, repetitive ventricular premature beats and in 7 of 8 cases (87%) of ventricular tachycardia, DF completely suppressed the arrhythmia. The drug increased sinus rate, PR and QRS intervals, but the difference was not statistically significant: the QRS of patients with complete bundle branch block and the QTc interval were significantly prolonged. Severe hypotension was observed in 10 patients after DF i.v., in 5 of whom withdrawal of therapy was deemed to be necessary. Nine other patients had anticholinergic side effects. Our study shows that DF administered i.v. can be used successfully in 75% of supraventricular arrhythmias and in 82% of ventricular arrhythmias.