The left atrial function is transiently impaired in Tako-tsubo cardiomyopathy and associated to in-hospital complications: a prospective study using two-dimensional strain.

Tako-tsubo cardiomyopathy (TTC) is characterized by the presence of transient left ventricular (LV) dysfunction. Whether left atrial (LA) function is also impaired in this setting is unclear. To assess prospectively LA peak systolic longitudinal strain (LAS) by two-dimensional strain at the acute phase of TTC and after recovery and its association with in-hospital complications. 40 patients with typical TTC (mean age 79.5 ± 10 years) underwent transthoracic-Doppler echocardiography at the acute phase and at follow-up (32 ± 18 days later), including the measurement of the LAS (mean of maximal strain from the 4-2 chamber views). A control group of 15 patients (75 ± 7 years, 13 women) without overt cardiovascular disease served as a comparative group. In-hospital complication was a composite of death, heart failure, cardiogenic shock, LV thrombus, and sustained ventricular arrhythmia. In the TTC group, LAS improved significantly between the two examinations from 15 ± 5.5% to 27 ± 8% (p < 0.01) whereas LA volume did not change (p = NS). In the control group LAS was 30 ± 4% (p < 0.01 vs. TTC acute phase, p = NS vs. TTC follow-up). In TTC, at the acute phase LAS was independently correlated to LV global longitudinal strain (LVGLS), and after recovery to E/e', and the change of LAS was independently correlated to the change of the LVGLS (all, p < 0.01). Furthermore LAS was independently correlated to in-hospital complications (p < 0.01). LA function (reservoir) is transiently impaired in TTC and associated to in-hospital complications. Furthermore, the improvement of LAS parallel the dynamic improvement of LVGLS suggests that TTC induces a transient global left heart dysfunction.

Assessment of left anterior descending artery stenosis of intermediate severity by fractional flow reserve, instantaneous wave-free ratio, and non-invasive coronary flow reserve.

To test the usefulness of non-invasive coronary flow reserve (CFR) by transthoracic Doppler echocardiography by comparison to invasive fractional flow reserve (FFR) and instantaneous wave-free ratio (IFR), a new vasodilator-free index of coronary stenosis severity, in patients with left anterior descending artery (LAD) stenosis of intermediate severity (IS) and stable coronary artery disease. 94 consecutive patients (mean age 68 ± 10 years) with angiographic LAD stenosis of IS (50-70 % diameter stenosis), were prospectively studied. IFR was calculated as a trans-lesion pressure ratio during the wave-free period in diastole; FFR as distal pressure divided by mean aortic pressure during maximal hyperemia (using 180 µg intracoronary adenosine); and CFR as hyperemic peak LAD flow velocity divided by baseline flow velocity using intravenous adenosine (140 µg/kg/min over 2 min). The mean values of IFR, FFR, and CFR were 0.88 ± 0.07, 0.81 ± 0.09, and 2.4 ± 0.6 respectively. A significant correlation was found between CFR and FFR (r = 0. 68), FFR and IFR (r = 0.6), and between CFR and IFR (r = 0.5) (all, p < 0.01). Using a ROC curve analysis, the best cut-off to detect a significant lesion based on FFR assessment (FFR ≤ 0.8, n = 31) was IFR ≤ 0.88 with a sensitivity (Se) of 74 %, specificity (Sp) of 73 %, AUC 0.81 ± 0.04, accuracy 72 %; and CFR ≤ 2 with a Se = 77 %, Sp = 89 %, AUC 0.88 ± 0.04, accuracy 85 % (all, p < 0.001). In stable patients with LAD stenosis of IS, non-invasive CFR is a useful tool to detect a significant lesion based on FFR. Furthermore, there was a better correlation between CFR and FFR than between CFR and IFR, and a trend to a better diagnostic performance for CFR versus IFR.

Assessment of left anterior descending artery stenosis of intermediate severity by fractional flow reserve, instantaneous wave-free ratio and non-invasive coronary flow reserve.

Assessment of the functional significance of left anterior descending coronary artery (LAD) stenosis of intermediate severity is challenging and often based on fractional flow reserve (FFR). The instantaneous wave-free ratio (IFR), a new vasodilator-free index of coronary stenosis severity, and non-invasive coronary flow reserve (CFR) by transthoracic Doppler echocardiography are also potentially useful. A direct comparison of FFR, IFR, and non-invasive CFR has never been performed. Our objective was to test the usefulness of non-invasive CFR by comparison to invasive FFR and IFR in patients with LAD stenosis of angiographic intermediate severity and stable coronary artery disease. METHODS: Ninety-four stable consecutive patients (mean age, 68±10years; 19 women) with angiographic proximal or mid LAD stenosis of intermediate severity (40-70% diameter stenosis on quantitative coronary angiography), were prospectively studied. They underwent IFR that was calculated as a trans-lesion pressure ratio during a specific period of baseline diastole, FFR with intracoronary bolus adenosine (180µg), and CFR using intravenous adenosine (140µg/kg/min over 2min) in the distal part of the LAD, the same day. CFR was defined as hyperemic peak diastolic LAD flow velocity divided by baseline flow velocity and FFR as distal pressure divided by mean aortic pressure during maximal hyperemia. RESULTS: The mean values of IFR, FFR, and CFR were 0.88±0.07, 0.81±0.09, and 2.4±0.6 respectively. A significant correlation was found between CFR and FFR (R=0.63, curvilinear relationship), FFR and IFR (R=0.6, linear relationship), and between CFR and IFR (R=0.5) (all, P<0.01). Using a ROC curve analysis, the best cut-off to detect a significant lesion based on FFR assessment (FFR≤0.8, N=31) was IFR≤0.88 with a sensitivity (Se) of 74%, specificity (Sp) of 73%, AUC 0.81±0.04; and CFR≤2 with a Se=77%, Sp=89%, AUC 0.88±0.04, (all, P<0.001). Based on these cut-offs, discordant results between CFR and FFR were observed in 14 cases (agreement 85%), between CFR and IFR in 26 cases (agreement 72%), and between IFR and FFR in 26 cases (agreement 72%). CONCLUSION: In stable patients with LAD stenosis of intermediate severity, non-invasive CFR is a useful tool to detect a significant lesion based on FFR. Furthermore, there was a better correlation and agreement between CFR and FFR than with IFR.

Apical rotation, a simplified index of left ventricular twist is independently linked to recovery after acute anterior myocardial infarction.

BACKGROUND: It is unclear whether apical rotation (Ar), which in normal setting represents the dominant contributions to LV twist by comparison to basal rotation (Br), predicts viability in acute anterior myocardial infarction (AMI). Our objective was to test the usefulness of Ar as a simple index to predict LV recovery after AMI. METHODS: Fourty-five consecutive patients (mean age 60±14 years, mean LVEF 44±7%) with first AMI treated successfully by primary angioplasty underwent prospectively a comprehensive transthoracic-Doppler echocardiography including analysis of Ar, Br, and LV twist by 2-dimensional speckle tracking, using a basal and apical short axis-views, within 24h after angioplasty and 3-6months later. Recovery was defined as: - the normalization of the wall motion of more than 50% of initial abnormal segments (R1) and; - absolute improvement of LVEF≥10% (R2). RESULTS: A better correlation was found between Ar and LV twist at each stage of the disease than between Br and LV twist (acute phase, R=0.77 vs. R=0.35; follow-up, R=0.9 vs. R=0.3 [all, P<0.001 for Ar, and all, P≤0.05 for Br]). Furthermore, a better correlation was found between Ar and follow-up LVEF (R=0.57), wall motion score index (R=0.44), and global longitudinal strain (R=0.54) (all, P<0.001) than between LV twist and the same parameters (R=0.39; R=0.32; R=0.32 respectively, all P<0.05). (For Br, all, P=NS). Ar as well as LV twist were significantly associated with recovery (all, P<0.01) with an area under the curve (AUC) higher for the former than for the latter (R1, N=18: AUC-Ar=0.81 and AUC-LV twist=0.69, P=0.05; R2, N=19: AUC-Ar=0.82, AUC-LV twist=0.75, P=0.1). In multivariate analysis, Ar remained an independent predictor of recovery R1 and R2 instead of LV twist (all, P≤0.01). Using a ROC curve analysis, the best cut-off of Ar to predict recovery R2 was 6.5°, with Se=77% Sp=85%, P<0.001. CONCLUSION: Apical rotation is an independent predictor of segmental and global LV recovery after anterior acute anterior myocardial infarction treated successfully by primary angioplasty.

[Coronary artery fistulas, a current problem: Clinical and therapeutic considerations]. / Les fistules coronaires, un problème d'actualité : approche clinique et considérations thérapeutiques.

The coronary fistula is a link between one or more of the coronary arteries and cardiac cavity or great vessel. The exact occurrence is unknown. The majority of these fistulas are congenital in origin. However, they may occasionally be detected after cardiac surgery. For a long time, fistulas are asymptomatic, especially if they are small; the frequency of the symptoms and especially the complications rise with age. The potential complications are: cardiac failure, endocarditis, endarteritis, atrial fibrillation, ventricular arrhythmias, rupture, and thrombosis. The main differential diagnosis is patent arterial duct, while other congenital arteriovenous shunts need to be excluded. Even though echocardiography Doppler can help to differentiate shunts, the coronary angiography remains the main diagnostic tool for the description of the anatomy. For a long time, the surgery was the only therapeutic means, up till now, percutaneous occlusion is the first line therapy of coronary fistulas and that the different devices can be tailored to meet different anatomic and functional characteristics.

Systolic anterior motion of the mitral valve in tako-tsubo cardiomyopathy: Still a matter of debate?

We present a case which developed a typical tako-tsubo-like cardiomyopathy (TTC) during dobutamine stress echocardiography (DSE). Its originality is related to several findings, which have never been described simultaneously in the same patient. This 63-year-old woman with normal coronary angiography and no evidence of coronary vasospasm had a biphasic response to DSE, a finding which usually occurs in coronary artery disease. Moreover, the symmetric extensive wall motion abnormalities (WMA) occurred simultaneously with the development of a systolic anterior motion of the mitral valve (SAM) and left ventricular obstruction, and was clinically asymptomatic. Although in TTC the stunning usually occurs for several days, WMA and SAM resolved within few minutes after cessation of dobutamine and administration of a beta-blocker. And finally, exercise echo performed at the same target heart rate few days later did not induce neither a SAM nor WMA, which suggests that left ventricular obstruction could have played a role in the pathogenesis of this case by supply-demand mismatch. Concomitant coronary microvascular dysfunction was also demonstrated by a reduction of the non-invasive coronary flow reserve in the distal part of the left anterior descending artery.

[Incidence, associated factors, and follow-up of hospital heart failure complicating acute anterior myocardial infarction successfully treated by primary angioplasty]. / Incidence, facteurs associés et devenir de l'insuffisance cardiaque hospitalière compliquant l'infarctus antérieur aigu traité avec succès par angioplastie primaire.

UNLABELLED: Heart failure (HF) complicating acute myocardial infarction (AMI) is of poor prognosis and is often associated with patient's characteristics and success of reperfusion strategies. However, few data is available regarding the high-risk subgroup of patients with anterior AMI treated successfully by primary angioplasty. The aim of the study was to assess the incidence, associated factors, and the future of HF occurring during hospitalisation, in the setting of anterior AMI treated successfully by primary angioplasty. METHODS: Eighty-five consecutive patients with anterior AMI treated successfully by primary angioplasty (final angiographic TIMI flow grade=3, without residual stenosis) were included. Clinical, biochemical, angiographic, and echocardiographic data were prospectively collected and compared between patients with (Killip 2 and 3) and without HF during hospitalisation. RESULTS: Fifteen patients had HF (18%) during hospitalisation and 70 did not. By comparison to patients without HF, patients with HF were more frequently diabetics, had troponin peak and CPK, leucocytes count, and fasting glucose higher, LVEF and wall motion score index in the left anterior descending territory (WMSi-lad) poorer, and a lower non-invasive coronary flow reserve (CFR) in the LAD 24hours after angioplasty (all, P<0.05). In multivariate analysis, fasting glucose, leucocytes count after angioplasty, CFR and WMSi-lad were independently associated with HF, even after adjusting with angiographic variables (all, P<0.05). At 6months, patients with HF had less recovery of LV function and higher frequency of adverse LV remodelling (58% versus 20%, P<0.01) by comparison to patients without HF. CONCLUSION: In conclusion, HF is not uncommon even after successful primary angioplasty for anterior AMI (nearly one patient out of 5), is associated with hyperglycaemia and inflammation, a poor microvascular reperfusion, and left ventricular systolic function, and is more frequently complicated by adverse LV remodelling and lack of LV recovery.

Multi-ethnic distribution of clinically relevant CYP2C genotypes and haplotypes.

To determine CYP2C19 and CYP2C8 allele frequencies, 28 coding and/or functional variants were genotyped in 1250 African-American, Asian, Caucasian, Hispanic and Ashkenazi Jewish (AJ) individuals. The combined CYP2C19 variant allele frequencies ranged from ∼0.30 to 0.41; however, the CYP2C8 frequencies were much lower (∼0.04-0.13). After incorporating previously reported CYP2C9 genotyping results from these populations (36 total CYP2C variants), 16 multi-ethnic CYP2C haplotypes were inferred with frequencies >0.5%. Notably, the 2C19*17-2C9*1-2C8*2 haplotype was identified among African-Americans (8%) and Hispanics (2%), indicating that CYP2C19*17 does not always tag a CYP2C haplotype that encodes efficient CYP2C-substrate metabolism. The 2C19*1-2C9*2-2C8*3 haplotype was identified in all populations except African-Americans and additional novel haplotypes were identified in selected populations (for example, 2C19*2-2C9*1-2C8*4 and 2C19*4B-2C9*1-2C8*1), together indicating that both CYP2C19*17 and *2 can be linked with other CYP2C loss-of-function alleles. These results have important implications for pharmacogenomic association studies involving the CYP2C locus and are clinically relevant when administering CYP2C-substrate medications.

Multi-ethnic cytochrome-P450 copy number profiling: novel pharmacogenetic alleles and mechanism of copy number variation formation.

To determine the role of CYP450 copy number variation (CNV) beyond CYP2D6, 11 CYP450 genes were interrogated by multiplex ligation-dependent probe amplification and quantitative PCR in 542 African-American, Asian, Caucasian, Hispanic and Ashkenazi Jewish individuals. The CYP2A6, CYP2B6 and CYP2E1 combined deletion/duplication allele frequencies ranged from 2 to 10% in these populations. High-resolution microarray-based comparative genomic hybridization (aCGH) localized CYP2A6, CYP2B6 and CYP2E1 breakpoints to directly oriented low-copy repeats. Sequencing localized the CYP2B6 breakpoint to a 529-bp intron 4 region with high homology to CYP2B7P1, resulting in the CYP2B6*29 partial deletion allele and the reciprocal, and novel, CYP2B6/2B7P1 duplicated fusion allele (CYP2B6*30). Together, these data identified novel CYP450 CNV alleles (CYP2B6*30 and CYP2E1*1Cx2) and indicate that common CYP450 CNV formation is likely mediated by non-allelic homologous recombination resulting in both full gene and gene-fusion copy number imbalances. Detection of these CNVs should be considered when interrogating these genes for pharmacogenetic drug selection and dosing.

Usefulness of capillary electrophoresis-based multiplex PCR assay for species-specific identification of Candida spp.

The study evaluated the performances of a commercial multiplex PCR assay, the Seegene Seeplex STI Master Panel 3, for Candida spp. identification. Eighty clinical strains of Candida spp. were identified with this system and a homemade multiplex PCR assay. The results were also compared with those obtained with two phenotypic methods. The study provided a preliminary evaluation of a multiplex assay from Seegene that uses capillary electrophoresis as the detection of amplified products. The Seeplex assay was found to be a rapid and useful method for identifying large numbers of yeast isolates in the clinical laboratory context.

Identification of CYP2C19*4B: pharmacogenetic implications for drug metabolism including clopidogrel responsiveness.

CYP2C19 is a principal enzyme involved in the bioactivation of the antiplatelet prodrug clopidogrel and common CYP2C19 loss-of-function alleles are associated with adverse cardiovascular events. To assess the impact of the CYP2C19*17 increased activity allele in the Ashkenazi Jewish (AJ) and Sephardi Jewish (SJ) populations and to determine the frequencies of additional variant alleles, 250 AJ and 135 SJ individuals were genotyped for CYP2C19*2-*10, *12-*17, *22 and P-glycoprotein (ABCB1) c.3435C>T. Importantly, CYP2C19*4, a loss-of-function allele, was identified in linkage disequilibrium with *17. This novel haplotype, designated CYP2C19*4B, significantly alters the interpretation of CYP2C19 genotyping when testing *17. Moreover, genotyping CYP2C19*17 changed the frequency of extensive metabolizers from ∼70 to ∼40%, reclassifying ∼30% as ultrarapid metabolizers. Combining CYP2C19 and ABCB1 identified ∼1 in 3 AJ and ∼1 in 2 SJ individuals at increased risk for adverse responses to clopidogrel. These data underscore the importance of including *4B and *17 when clinically genotyping CYP2C19.

The Italian experience of a Pap test and speculoscopy based screening programme.

OBJECTIVES: The main objective of the study was to evaluate if speculoscopy, a magnified chemiluminescent examination, combined with a Pap smear, could improve the detection of early cervical lesions compared with the Pap smear alone. SETTING: Pap tests and speculoscopies were performed in two family planning centres located in the surrounding areas of Modena. Colposcopic investigations and biopsies of the uterine cervix were performed in a second level centre (Gynaecological Prevention Centre of Modena Policlinico). Histological specimens were analysed at the Section of Pathological Anatomy of Modena Policlinico. SUBJECTS: The study population comprised 1000 women aged 25-64 years, invited to undergo a Pap smear every three years in accordance with the screening programme for cervical cancer started in Modena in 1997. METHODS: Midwives performed the Pap smear and speculoscopy in succession. Women with a positive Pap test and/or positive speculoscopy underwent colposcopy and, if colposcopic findings were positive, targeted punch biopsies were performed. RESULTS: A total of 1000 patients were subjected to cytology and speculoscopy examinations. Among these women, 10 had abnormal Pap smear findings whereas 144 had an abnormal speculoscopic pattern. Only three of 59 patients with a histological diagnosis of cervical intraepithelial neoplasia grade I (CIN I)/human papillomavirus and only three of seven patients with CIN II/CIN III had a positive Pap test. CONCLUSIONS: Speculoscopy combined with a Pap test can significantly increase the detection of cervical lesions when included in a screening programme.