Stress-induced hyperviscosity in the pathophysiology of takotsubo cardiomyopathy.

Takotsubo cardiomyopathy (TC) is characterized by transient hypokinesis of the left ventricular apex or midventricular segments with coronary arteries without significant stenosis. It is often associated with emotional or physical stress; however, its pathophysiology is still unclear. In the present study, we analyzed the alterations in blood viscosity and markers of endothelial damage induced by sympathetic stimulation in patients with previous TC. Seventeen women (mean age 71 years) with previous TC, included and investigated in the TC Tuscany Registry, were compared to a control group of 8 age- and risk factor-matched women with chest pain and coronary arteries free of stenosis. All subjects underwent the cold pressor test (CPT). Before and after the CPT, the hemorheologic parameters (whole blood viscosity at 0.512 s(-1) and 94.5 s(-1), plasma viscosity, erythrocyte deformability index, and erythrocyte aggregation), catecholamines, plasminogen activator inhibitor-1 (PAI-1), and von Willebrand factor levels were assessed. The patients with TC had significantly greater baseline PAI-1 levels (p <0.01) and lower erythrocyte deformability index values (p <0.01). After CPT, both the patients with TC and the controls had a significant increase in several hemorheologic parameters, catecholamines, and von Willebrand factor levels and a decrease in erythrocyte deformability index. However, the PAI-1 levels were significantly increased only in the patients with TC. Compared to the controls, the patients with TC had significantly greater values of whole blood viscosity at 94.5 s(-1) (p <0.05), PAI-1 (p <0.01), von Willebrand factor (p <0.05) and lower erythrocyte deformability index values (p <0.01) after CPT. In conclusion, the results of the present study suggest that in patients with TC, the alterations in erythrocyte membranes and endothelial integrity induced by catecholaminergic storm could determine microvascular hypoperfusion, possibly favoring the occurrence of left ventricular ballooning.

Microvascular dysfunction, myocardial ischemia, and progression to heart failure in patients with hypertrophic cardiomyopathy.

Microvascular dysfunction can be demonstrated in most patients with hypertrophic cardiomyopathy (HCM), both in the hypertrophied and nonhypertrophied myocardial walls, mostly due to intimal and medial hyperplasia of the intramural coronary arteries and subsequent lumen reduction. As a consequence, regional myocardial ischemia may be triggered by exercise, increased heart rate, or arrhythmias, in areas which are unable to increase myocardial blood flow. In patients with HCM, microvascular dysfunction leading to severe myocardial hypoperfusion during maximal hyperemia represents a strong predictor of unfavorable outcome, left ventricular remodeling with progressive wall thinning, left ventricular dysfunction, and heart failure. Accurate quantitative assessment of microvascular dysfunction and myocardial ischemia is not easily feasible in clinical practice. Although signs of inducible myocardial ischemia may be detected by electrocardiogram, echocardiography, or myocardial scintigraphy, the vasodilator response to dipyridamole by positron emission tomography is considered the method of choice for the assessment of maximal regional and global flow. Cardiac magnetic resonance provides further information, by late gadolinium enhancement (LGE), which may show areas where replacement fibrosis has occurred following microvascular ischemia and focal necrosis. LGE areas colocalize with severe regional microvascular dysfunction, are associated with increased prevalence of ventricular arrhythmias, and show more extensive distribution in the late stages of the disease, when heart failure is the dominant feature. The present review aims to provide a concise overview of the available evidence of microvascular dysfunction and ischemia eventually leading to disease progression and heart failure in HCM patients.

Cytochrome P450 2C19 loss-of-function polymorphism, but not CYP3A4 IVS10 + 12G/A and P2Y12 T744C polymorphisms, is associated with response variability to dual antiplatelet treatment in high-risk vascular patients.

OBJECTIVES: The aim of this study was to evaluate the effect of polymorphisms affecting the clopidogrel metabolism (CYP3A4 IVS10+12G/A and CYP2C19*2) and the P2Y12 receptor (P2Y12 T744C) on modulating platelet function in acute coronary syndrome patients on dual antiplatelet treatment. BACKGROUND: Residual platelet reactivity (RPR) phenomenon on antiplatelet therapy requires clarification. P2Y12 T744C, CYP3A4 IVS10+12G/A and, in healthy individuals only, CYP2C19*2 polymorphisms have been investigated; however, the influence on platelet reactivity in a large population of high-risk vascular patients on dual antiplatelet treatment has not yet been elucidated. METHODS: A total of 1419 acute coronary syndrome patients on dual antiplatelet treatment were studied. Platelet function was evaluated by platelet-rich plasma aggregation. Electronic nanochips and restriction-fragment length polymorphism were used for analysis of polymorphisms. RESULTS: Only CYP2C19*2, out of the three investigated polymorphisms, is associated with higher platelet reactivity. Carriers of the *2 allele had significantly higher platelet aggregation values after arachidonic acid (AA; P=0.043), 2 micromol/l adenosine 5' diphosphate (ADP; P<0.0001) and 10 micromol/l ADP (P=0.001) stimuli. The genotype distribution of CYP2C19*2 polymorphism significantly differed between patients with and without RPR, as evaluated by 10-micromol/l ADP-induced platelet aggregation (P=0.002) and by AA-induced platelet aggregation (P=0.045). At the multivariate linear regression analysis, the CYP2C19*2 polymorphism remained a significant and independent risk factor for dual antiplatelet treatment variability. CONCLUSIONS: This study demonstrates, for the first time, that the *2 CYP2C19 allele is associated with higher platelet aggregability and RPR in high-risk vascular patients on dual antiplatelet treatment. These findings can have a significant impact on the future design of pharmacogenetic antiaggregant strategies for high-risk vascular patients on dual antiplatelet treatment.

Midventricular obstruction and clinical decision-making in obstructive hypertrophic cardiomyopathy.

The presence of intraventricular obstruction is a powerful predictor of outcome in patients with hypertrophic cardiomyopathy (HCM) and, when associated with severe, drug-refractory symptoms, should be managed aggressively. Resting left ventricular outflow obstruction is found in approximately 20% of the patients, classically occurs at the subaortic level, and is associated with mitral valve systolic anterior motion (SAM). In a minority of patients, however, the impedance to flow occurs at midventricular level, unrelated to SAM. Symptomatic midventricular obstruction represents a clinical challenge, and its treatment is not standardized. In these patients, both surgical myectomy and alcohol septal ablation (ASA) are technically feasible. A rational approach to the management of these patients depends on accurate characterization of the pathophysiology, coupled with comparison of the results of different management strategies. To illustrate these points, the details of a patient who first underwent percutaneous ASA and subsequently required redo surgical treatment are described here, with special emphasis on the implications to the management of midventricular obstruction, as well as to the more global issue of obstructive HCM.

Use of the Parodi anti-embolism system in carotid stenting: Italian trial results.

PURPOSE: To investigate the safety and efficacy of the Parodi anti-embolism system (PAES) in establishing flow reversal in the internal carotid artery (ICA) as a means of protecting against embolic phenomena during carotid stenting. METHODS: Seven centers participated in a nonrandomized, prospective trial of carotid angioplasty and stenting under PAES protection in 30 patients (22 men; mean age 72 years, range 49-88) with 15 symptomatic (>70%) and 15 asymptomatic (>80%) stenotic ICAs. Safety was defined as achieving sufficient brain oxygenation during flow reversal as determined by level of awareness and motor control. The presence of new or enhanced neurological deficits and death were endpoints. Performance was based on angiographic evidence of successful retrograde flow. RESULTS: The PAES was positioned in all 30 patients, but technical error and access-related difficulties prevented establishment of reversed flow in 2. Among the 28 (93%) patients treated under PAES protection, 1 patient developed aphasia after flow reversal, necessitating balloon deflation between subsequent stages of the procedure. Three other adverse events included 1 case of bradycardia and 2 cases of hypotension, with dysarthria and facial paresis in one and temporary loss of consciousness in the other. All events resolved with appropriate therapy, and there was no change from baseline in the neurological status or brain scans at 24 hours. There were no strokes or neurological deficits at 30 days. CONCLUSIONS: The PAES appears to be a safe and effective means of providing protection from embolic complications during carotid stenting.