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Pathogenic germline exonuclease domain (ED) variants of POLE and POLD1 cause the Mendelian dominant condition polymerase proof-reading associated polyposis (PPAP). We aimed to describe the clinical features of all PPAP patients with probably pathogenic variants. We identified patients with a variants mapping to the EDs of POLE or POLD1 from cancer genetics clinics, a colorectal cancer (CRC) clinical trial, and systematic review of the literature. We used multiple evidence sources to separate ED variants into those with strong evidence of pathogenicity and those of uncertain importance. We performed quantitative analysis of the risk of CRC, colorectal adenomas, endometrial cancer or any cancer in the former group. 132 individuals carried a probably pathogenic ED variant (105 POLE, 27 POLD1). The earliest malignancy was colorectal cancer at 14. The most common tumour types were colorectal, followed by endometrial in POLD1 heterozygotes and duodenal in POLE heterozygotes. POLD1-mutant cases were at a significantly higher risk of endometrial cancer than POLE heterozygotes. Five individuals with a POLE pathogenic variant, but none with a POLD1 pathogenic variant, developed ovarian cancer. Nine patients with POLE pathogenic variants and one with a POLD1 pathogenic variant developed brain tumours. Our data provide important evidence for PPAP management. Colonoscopic surveillance is recommended from age 14 and upper-gastrointestinal surveillance from age 25. The management of other tumour risks remains uncertain, but surveillance should be considered. In the absence of strong genotype–phenotype associations, these recommendations should apply to all PPAP patients.

Purpose: Precise mechanism-based gene expression signatures (GES) have been developed in appropriate in vitro and in vivo model systems, to identify important cancer-related signaling processes. However, some GESs originally developed to represent specific disease processes, primarily with an epithelial cell focus, are being applied to heterogeneous tumor samples where the expression of the genes in the signature may no longer be epithelial-specific. Therefore, unknowingly, even small changes in tumor stroma percentage can directly influence GESs, undermining the intended mechanistic signaling. Experimental Design: Using colorectal cancer as an exemplar, we deployed numerous orthogonal profiling methodologies, including laser capture microdissection, flow cytometry, bulk and multiregional biopsy clinical samples, single-cell RNA sequencing and finally spatial transcriptomics, to perform a comprehensive assessment of the potential for the most widely used GESs to be influenced, or confounded, by stromal content in tumor tissue. To complement this work, we generated a freely-available resource, ConfoundR; https://confoundr.qub.ac.uk/, that enables users to test the extent of stromal influence on an unlimited number of the genes/signatures simultaneously across colorectal, breast, pancreatic, ovarian and prostate cancer datasets. Results: Findings presented here demonstrate the clear potential for misinterpretation of the meaning of GESs, due to widespread stromal influences, which in-turn can undermine faithful alignment between clinical samples and preclinical data/models, particularly cell lines and organoids, or tumor models not fully recapitulating the stromal and immune microenvironment. Conclusions: Efforts to faithfully align preclinical models of disease using phenotypically-designed GESs must ensure that the signatures themselves remain representative of the same biology when applied to clinical samples.

Outcomes inPatients with newly diagnosed mCRC were registered into FOCUS4 and tested forFOCUS4-C was conducted between April 2017 and Mar 2020 during which time 718 patients were registered; 247 (34%) wereIn this phase II randomized trial, adavosertib improved PFS compared with AM and demonstrates potential as a well-tolerated therapy for

Aims: After local excision of early rectal cancer, definitive lymph node status is not available. An alternative means for accurate assessment of recurrence risk is required to determine the most appropriate subsequent management. Currently used measures are suboptimal. We assess three measures of tumour stromal content to determine their predictive value after local excision in a well-characterised cohort of rectal cancer patients without prior radiotherapy. Methods and results: A total of 143 patients were included. Haematoxylin and eosin (H&E) sections were scanned for (i) deep neural network (DNN, a machine-learning algorithm) tumour segmentation into compartments including desmoplastic stroma and inflamed stroma; and (ii) digital assessment of tumour stromal fraction (TSR) and optical DNA ploidy analysis. 3′ mRNA sequencing was performed to obtain gene expression data from which stromal and immune scores were calculated using the ESTIMATE method. Full results were available for 139 samples and compared with disease-free survival. All three methods were prognostic. Most strongly predictive was a DNN-determined ratio of desmoplastic to inflamed stroma >5.41 (P < 0.0001). A ratio of ESTIMATE stromal to immune score 36.5% (P = 0.037). Conclusions: The DNN-determined ratio of desmoplastic to inflamed ratio is a novel and powerful predictor of disease recurrence in locally excised early rectal cancer. It can be assessed on a single H&E section, so could be applied in routine clinical practice to improve the prognostic information available to patients and clinicians to inform the decision concerning further management.

Insights into oncogenesis derived from cancer susceptibility loci (SNP) hold the potential to facilitate better cancer management and treatment through precision oncology. However, therapeutic insights have thus far been limited by our current lack of understanding regarding both interactions of these loci with somatic cancer driver mutations and their influence on tumorigenesis. For example, although both germline and somatic genetic variation to the p53 tumor suppressor pathway are known to promote tumorigenesis, little is known about the extent to which such variants cooperate to alter pathway activity. Here we hypothesize that cancer risk-associated germline variants interact with somatic TP53 mutational status to modify cancer risk, progression, and response to therapy. Focusing on a cancer risk SNP (rs78378222) with a well-documented ability to directly influence p53 activity as well as integration of germline datasets relating to cancer susceptibility with tumor data capturing somatically-acquired genetic variation provided supportive evidence for this hypothesis. Integration of germline and somatic genetic data enabled identification of a novel entry point for therapeutic manipulation of p53 activities. A cluster of cancer risk SNPs resulted in increased expression of prosurvival p53 target gene KITLG and attenuation of p53-mediated responses to genotoxic therapies, which were reversed by pharmacologic inhibition of the prosurvival c-KIT signal. Together, our results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and identify novel combinatorial therapies. Significance: These results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and present novel therapeutic targets.

Background Improved markers of prognosis are needed to stratify patients with early-stage colorectal cancer to refine selection of adjuvant therapy. The aim of the present study was to develop a biomarker of patient outcome after primary colorectal cancer resection by directly analysing scanned conventional haematoxylin and eosin stained sections using deep learning. Methods More than 12 000 000 image tiles from patients with a distinctly good or poor disease outcome from four cohorts were used to train a total of ten convolutional neural networks, purpose-built for classifying supersized heterogeneous images. A prognostic biomarker integrating the ten networks was determined using patients with a non-distinct outcome. The marker was tested on 920 patients with slides prepared in the UK, and then independently validated according to a predefined protocol in 1122 patients treated with single-agent capecitabine using slides prepared in Norway. All cohorts included only patients with resectable tumours, and a formalin-fixed, paraffin-embedded tumour tissue block available for analysis. The primary outcome was cancer-specific survival. Findings 828 patients from four cohorts had a distinct outcome and were used as a training cohort to obtain clear ground truth. 1645 patients had a non-distinct outcome and were used for tuning. The biomarker provided a hazard ratio for poor versus good prognosis of 3·84 (95% CI 2·72–5·43; p

Background Immunohistochemical quantification of the immune response is prognostic for colorectal cancer (CRC). Here, we evaluate the suitability of alternative immune classifiers on prognosis and assess whether they relate to biological features amenable to targeted therapy. Methods Overall survival by immune (CD3, CD4, CD8, CD20 and FOXP3) and immune-checkpoint (ICOS, IDO-1 and PD-L1) biomarkers in independent CRC cohorts was evaluated. Matched mutational and transcriptomic data were interrogated to identify associated biology. Results Determination of immune-cold tumours by combined low-density cell counts of CD3, CD4 and CD8 immunohistochemistry constituted the best prognosticator across stage II–IV CRC, particularly in patients with stage IV disease (HR 1.98 [95% CI: 1.47–2.67]). These immune-cold CRCs were associated with tumour hypoxia, confirmed using CAIX immunohistochemistry (P = 0.0009), which may mediate disease progression through common biology (KRAS mutations, CRIS-B subtype and SPP1 mRNA overexpression). Conclusions Given the significantly poorer survival of immune-cold CRC patients, these data illustrate that assessment of CD4-expressing cells complements low CD3 and CD8 immunohistochemical quantification in the tumour bulk, potentially facilitating immunophenotyping of patient biopsies to predict prognosis. In addition, we found immune-cold CRCs to associate with a difficult-to-treat, poor prognosis hypoxia signature, indicating that these patients may benefit from hypoxia-targeting clinical trials.

Purpose:The cytokine IL22 promotes tumor progression in murine models of colorectal cancer. However, the clinical significance of IL22 in human colorectal cancer remains unclear. We sought to determine whether the IL22 pathway is associated with prognosis in human colorectal cancer, and to identify mechanisms by which IL22 can influence disease progression.Experimental Design:Transcriptomic data from stage II/III colon cancers in independent discovery (GSE39582 population-based cohort, N = 566) and verification (PETACC3 clinical trial, N = 752) datasets were used to investigate the association between IL22 receptor expression (encoded by the genes IL22RA1 and IL10RB), tumor mutation status, and clinical outcome using Cox proportional hazard models. Functional interactions between IL22 and mutant KRAS were elucidated using human colorectal cancer cell lines and primary tumor organoids.Results:Transcriptomic analysis revealed a poor-prognosis subset of tumors characterized by high expression of IL22RA1, the alpha subunit of the heterodimeric IL22 receptor, and KRAS mutation [relapse-free survival (RFS): HR = 2.93, P = 0.0006; overall survival (OS): HR = 2.45, P = 0.0023]. KRAS mutations showed a similar interaction with IL10RB and conferred the worst prognosis in tumors with high expression of both IL22RA1 and IL10RB (RFS: HR = 3.81, P = 0.0036; OS: HR = 3.90, P = 0.0050). Analysis of human colorectal cancer cell lines and primary tumor organoids, including an isogenic cell line pair that differed only in KRAS mutation status, showed that IL22 and mutant KRAS cooperatively enhance cancer cell proliferation, in part through augmentation of the Myc pathway.Conclusions:Interactions between KRAS and IL22 signaling may underlie a previously unrecognized subset of clinically aggressive colorectal cancer that could benefit from therapeutic modulation of the IL22 pathway.

BACKGROUND: Precision cancer medicine depends on defining distinct tumour subgroups using biomarkers that may occur at very modest frequencies. One such subgroup comprises patients with exceptionally mutated (ultramutated) cancers caused by mutations that impair DNA polymerase epsilon (POLE) proofreading.METHODS: We examined the association of POLE proofreading domain mutation with clinicopathological variables and immune response in colorectal cancers from clinical trials (VICTOR, QUASAR2, and PETACC-3) and colorectal cancer cohorts (Leiden University Medical Centre 1 and 2, Oslo 1 and 2, Bern, AMC-AJCC-II, and Epicolon-1). We subsequently investigated its association with prognosis in stage II/III colorectal cancer by Cox regression of pooled individual patient data from more than 4500 cases from these studies.FINDINGS: Pathogenic somatic POLE mutations were detected in 66 (1·0%) of 6517 colorectal cancers, and were mutually exclusive with mismatch repair deficiency (MMR-D) in the 6277 cases for whom both markers were determined (none of 66 vs 833 [13·4%] of 6211; pINTERPRETATION: POLE proofreading domain mutations identify a subset of immunogenic colorectal cancers with excellent prognosis. This association underscores the importance of rare biomarkers in precision cancer medicine, but also raises important questions about how to identify and implement them in practice.FUNDING: Cancer Research UK, Academy of Medical Sciences, Health Foundation, EU, ERC, NIHR, Wellcome Trust, Dutch Cancer Society, Dutch Digestive Foundation.

Background We report here the prognostic value of ploidy and digital tumour-stromal morphometric analyses using material from 2624 patients with early stage colorectal cancer (CRC). Patients and methods DNA content (ploidy) and stroma-tumour fraction were estimated using automated digital imaging systems and DNA was extracted from sections of formalin-fixed paraffin-embedded (FFPE) tissue for analysis of microsatellite instability. Samples were available from 1092 patients recruited to the QUASAR 2 trial and two large observational series (Gloucester, n = 954; Oslo University Hospital, n = 578). Resultant biomarkers were analysed for prognostic impact using 5-year cancer-specific survival (CSS) as the clinical end point. Results Ploidy and stroma-tumour fraction were significantly prognostic in a multivariate model adjusted for age, adjuvant treatment, and pathological T-stage in stage II patients, and the combination of ploidy and stroma-tumour fraction was found to stratify these patients into three clinically useful groups; 5-year CSS 90% versus 83% versus 73% [hazard ratio (HR) = 1.77 (95% confidence interval (95% CI): 1.13–2.77) and HR = 2.95 (95% CI: 1.73–5.03), P Conclusion A novel biomarker, combining estimates of ploidy and stroma-tumour fraction, sampled from FFPE tissue, identifies stage II CRC patients with low, intermediate or high risk of CRC disease specific death, and can reliably stratify clinically relevant patient sub-populations with differential risks of tumour recurrence and may support choice of adjuvant therapy for these individuals.

It is unclear why among patients with first acute myocardial infarction and an occluded culprit artery only some present ST segment elevation. In fact, there is no study that compares the angiographic area at risk and the collateral circulation in first NSTEMI vs STEMI patients.205 patients admitted for myocardial infarction with occluded culprit artery were included, 132 STEMI and 73 NSTEMI. Demographic data, the area at risk determined by the BARI score and collateral supply by the Rentrop score from the 2 groups were compared. NSTEMI patients showed lower peak Tn I than STEMI in the overall group but also in the 3 subsets with different culprit arteries (p .001). They also presented a higher rate of left circumflex coronary artery (CFX) as culprit artery (52% vs 14%, p .001), smaller BARI score area of the culprit artery (5.4 vs 7.6, p .001), and higher frequency of well-developed collaterals (Rentrop score ≥ 2, 1.82 vs 0.41, p .001). The latter was also higher in each of the 3 different culprit arteries (p = .002-0.001) Among 38 NSTEMI patients with CFX occlusion, 20 with ≥1 mm ST depression in V2 to V4 (possible posterior infarction) showed a similar Rentrop score than the 18 with other ECG changes but lower Tn I peak (p = .012).In first acute myocardial infarction with an occluded culprit artery NSTEMI patients - including those with possible posterior infarction - present smaller infarct size and higher collateral blood supply than STEMI patients in each of the 3 main culprit arteries.

Intratumoural T-cell infiltrate intensity cortes wrelaith clinical outcome in stage II/III colorectal cancer (CRC). We aimed to determine whether this association varies across this heterogeneous group.We performed a pooled analysis of 1804 CRCs from the QUASAR2 and VICTOR trials. Intratumoural CD8In QUASAR2, intratumoural CD8The prognostic value of intratumoural CD8

We read with great interest the recent article by Sharma et al. [1] on the evaluation of right ventricular (RV) reserve in pulmonary arterial hypertension (PAH) by the dobutamine stress test. Their work highlights the potential clinical value of the RV systolic reserve into the evaluation of PAH patients beyond resting measurements. Sharma et al. [1] reported that RV contractile reserve (tricuspid annular plane systolic excursion (TAPSE) and tricuspid annulus systolic myocardial velocity ( S ′)) is markedly attenuated in PAH patients and correlates with exercise capacity. Although the merit of the work is in assessing RV contractile reserve by direct functional parameters, there are some topics that deserve discussion. Patients with PAH exhibit markedly diminished RV contractile reserve and pulmonary arterial vascular reserve

Objectives The spectrum of patients with 'angina and normal coronary arteries' ranges from severe vasospasm to atypical chest pain. Among those with typical angina, however, little is known about similarities in the clinical profile and circadian presentation between typical nonvasospastic angina and normal coronary arteries (tANCA) and vasospastic angina (VA). Materials and methods Clinical, ECG, and angiographic features as well as the circadian characteristics of angina were compared between 384 tANCA and 273 VA patients. Follow-up events were also analyzed. Results tANCA patients had greater female predominance (61 vs. 18%), higher incidence of dyspnea to moderate exertion (49 vs. 12%), lower incidence of tobacco smoking (25 vs. 67%), but a similar low rate of diabetes (8.9 vs. 4.4%). In both groups, however, dyspnea and smoking were associated with female and male sex, respectively. tANCA patients showed lower but non-negligible frequency of early morning (25 vs. 67%) and evening angina (37 vs. 54%), similar rate of nocturnal angina (47 vs. 50%), and higher rate of emotional angina (49 vs. 31%). Moreover, a high proportion of patients gained pain relief with nitroglycerin (97% in VA, 246/253, and 76% in tANCA, 231/306). At 140 months, frequent angina (>10 episodes/year) was rare (VA: 7.1% vs. tANCA: 6.3%) as was the rate of cardiac death/myocardial infarction (7.3 vs. 6.0%, P=0.524). Conclusion Despite differences in the clinical profile between VA and tANCA patients, there is notable sharing of circadian presentation of rest angina, response to nitroglycerin, and long-term presence and frequency of angina that suggests more similarities in underlying mechanisms than heretofore suspected.

Background Antiangiogenic agents have established efficacy in the treatment of metastatic colorectal cancer. We investigated whether bevacizumab could improve disease-free survival in the adjuvant setting after resection of the primary tumour. Methods For the open-label, randomised, controlled QUASAR 2 trial, which was done at 170 hospitals in seven countries, we recruited patients aged 18 years or older with WHO performance status scores of 0 or 1 who had undergone potentially curative surgery for histologically proven stage III or high-risk stage II colorectal cancer. Patients were randomly assigned (1:1) to receive eight 3-week cycles of oral capecitabine alone (1250 mg/m2 twice daily for 14 days followed by a break for 7 days) or the same regimen of oral capecitabine plus 16 cycles of 7·5 mg/kg bevacizumab by intravenous infusion over 90 min on day 1 of each cycle. Randomisation was done by a computer-generated schedule with use of minimisation with a random element stratified by age, disease stage, tumour site, and country. The study was open label and no-one was masked to treatment assignment. The primary endpoint was 3-year disease-free survival, assessed in the intention-to-treat population. Toxic effects were assessed in patients who received at least one dose of randomised treatment. This trial is registered with the ISRCTN registry, number ISRCTN45133151. Findings Between April 25, 2005, and Oct 12, 2010, 1952 eligible patients were enrolled, of whom 1941 had assessable data (968 in the capecitabine alone group and 973 in the capecitabine and bevacizumab group). Median follow-up was 4·92 years (IQR 4·00–5·16). Disease-free survival at 3 years did not differ between the groups (75·4%, 95% CI 72·5–78·0 in the capecitabine and bevacizumab group vs 78·4%, 75·7–80·9 in the capecitabine alone group; hazard ratio 1·06, 95% CI 0·89–1·25, p=0·54). The most common grade 3–4 adverse events were hand–foot syndrome (201 [21%] of 963 in the capecitabine alone group vs 257 [27%] of 959 in the capecitabine and bevacizumab group) and diarrhoea (102 [11%] vs 104 [11%]), and, with the addition of bevacizumab, expected increases were recorded in all-grade hypertension (320 [33%] vs 75 [8%]), proteinuria (197 [21%] vs 49 [5%]), and wound healing problems (30 [3%] vs 17 [2%]). 571 serious adverse events were reported (221 with capecitabine alone and 350 with capecitabine and bevacizumab). Most of these were gastrointestinal (n=245) or cardiovascular (n=169). 23 deaths within 6 months of randomisation were classified as being related to treatment, eight in the capecitabine alone group and 15 in the capecitabine and bevacizumab group. Interpretation The addition of bevacizumab to capecitabine in the adjuvant setting for colorectal cancer yielded no benefit in the treatment of an unselected population and should not be used.

Molecular classification of colorectal cancer (CRC) is currently based on microsatellite instability (MSI), KRAS or BRAF mutation and, occasionally, chromosomal instability (CIN). Whilst useful, these categories may not fully represent the underlying molecular subgroups. We screened 906 stage II/III CRCs from the VICTOR clinical trial for somatic mutations. Multivariate analyses (logistic regression, clustering, Bayesian networks) identified the primary molecular associations. Positive associations occurred between: CIN and TP53 mutation; MSI and BRAF mutation; and KRAS and PIK3CA mutations. Negative associations occurred between: MSI and CIN; MSI and NRAS mutation; and KRAS mutation, and each of NRAS, TP53 and BRAF mutations. Some complex relationships were elucidated: KRAS and TP53 mutations had both a direct negative association and a weaker, confounding, positive association via TP53–CIN–MSI–BRAF–KRAS. Our results suggested a new molecular classification of CRCs: (1) MSI+ and/or BRAF-mutant; (2) CIN+ and/or TP53– mutant, with wild-type KRAS and PIK3CA; (3) KRAS- and/or PIK3CA-mutant, CIN+, TP53-wild-type; (4) KRAS– and/or PIK3CA-mutant, CIN–, TP53-wild-type; (5) NRAS-mutant; (6) no mutations; (7) others. As expected, group 1 cancers were mostly proximal and poorly differentiated, usually occurring in women. Unexpectedly, two different types of CIN+ CRC were found: group 2 cancers were usually distal and occurred in men, whereas group 3 showed neither of these associations but were of higher stage. CIN+ cancers have conventionally been associated with all three of these variables, because they have been tested en masse. Our classification also showed potentially improved prognostic capabilities, with group 3, and possibly group 1, independently predicting disease-free survival. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Background The cause of coronary vasoconstriction in patients with angina at rest, nonsignificant coronary stenosis, and endothelial dysfunction remains unknown. Our objective was to investigate the association between enhanced coronary vasoconstriction and increased circulating levels of vasoconstrictor agents. Methods Plasma levels of big endothelin-1, serotonin, and superoxide produced by polymorphonuclear leukocytes were measured in 38 patients with stable angina at rest without significant coronary artery stenosis—23 with nonvasospastic angina and 15 with vasospastic angina—and were compared with 10 patients with stable coronary disease and 20 age-matched controls. Results Patients with angina at rest showed higher big endothelin-1 (1.28 vs 0.72 fmol/mL, P 0.001), serotonin (18.0 vs 9.1 ng/mL, P = 0.002), and superoxide produced by polymorphonuclear leukocytes (177 vs 67 nmol/10 × E8 × minutes, P = 0.001) than did controls. Serotonin and superoxide produced by polymorphonuclear leukocytes were also higher than in coronary disease patients (5.4 ng/mL, P = 0.001, and 97 nmol/10 x E8 x minutes, P = 0.005), and big endothelin-1 levels tended to be higher (0.99 fmol/mL, P = 0.073). Moreover, there were no significant differences in these 3 parameters between patients with vasospastic and nonvasospastic angina, and among the latter, between patients with a positive and those with a negative exercise stress test. Conclusion Systemic plasma levels of agents with the potential to produce coronary vasoconstriction are increased in patients with stable vasospastic or nonvasospastic angina and, hence, may contribute to their angina, increased coronary tone, and impaired vasodilatory capacity. Furthermore, they may establish a mechanistic link between the 2 conditions.

AIMS To evaluate the feasibility and safety of the Nile Croco® coronary bifurcation stent system (Minvasys, Gennevilliers, France). METHODS AND RESULTS The primary endpoint was to assess the acute device success and angiographic success with the use of the Nile Croco® stent system. Secondary endpoints included in-hospital and six month major cardiac events (MACE).There were 151 consecutive patients enrolled in the Nile Croco Study at Vall Hebron Hospital. The Nile Croco® stent was successfully implanted in 144 patients (95.4%) and final angiographic success was obtained in 100% of the patients. 138 out of the 151 (91%) patients included have accomplished the six month follow-up. There was one in-hospital MACE in the 151 recruited patients. The MACE rate at six months in the 138 patients with follow-up was 14% and the ischaemia-driven TLR rate was 7.2 %. CONCLUSIONS The results of our Nile Croco® Study are the first to demonstrate the safety and high performance of this dedicated stent system for the treatment of bifurcation lesions. The device can be successfully implanted in more than 95% of all cases, with a high procedural success rate and low in-hospital and six month MACE rates.

A 64-year-old diabetic and dyslipidemic woman was admitted to our hospital with a history of 3 episodes of acute pulmonary edema in the past 4 months, without evidence of organic heart disease. She was affected by a hypopituitarism and was treated with levothyroxine and desmopressin. She had atypical chest pain 1 year before, but 2 exercise stress tests were negative. In the past 4 months, she had been admitted 3 times for severe dyspnea at rest of sudden onset without chest pain, requiring endotracheal intubation because of severe acute pulmonary edema. Basal physical examination was normal. ECGs and serial troponin levels were normal. Clinical treatment was successful with early extubation. Echocardiography (echo) at rest was completely normal with normal left ventricular systolic and diastolic function and no valvular regurgitations. Coronary angiography revealed normal coronary arteries and normal global and regional left ventricular systolic motion. Thoracoabdominal computerized tomography was normal; and pulmonary thromboembolism, aortic disease, and suprarenal tumor were ruled out. Pulmonary biopsy also was normal. Laboratory tests including hemoglobin, electrolytes, autoantibodies, catecholamine, and thyroid hormones were also normal. Holter and telemetry did not reveal arrhythmias. Gated single-photon emission computed tomography and stress echo were negative for ischemia. Most of …

The common single-nucleotide polymorphism (SNP) rs3802842 at 11q23.1 has recently been reported to be associated with risk of colorectal cancer (CRC). To examine this association in detail we genotyped rs3802842 in eight independent case-control series comprising a total of 10 638 cases and 10 457 healthy individuals. A significant association between the C allele of rs3802842 and CRC risk was found (per allele OR = 1.17; 95% confidence interval [CI]: 1.12-1.22; P = 1.08 x 10(-12)) with the risk allele more frequent in rectal than colonic disease (P = 0.02). In combination with 8q21, 8q24, 10p14, 11q, 15q13.3 and 18q21 variants, the risk of CRC increases with an increasing numbers of variant alleles for the six loci (OR(per allele) = 1.19; 95% CI: 1.15-1.23; P(trend) = 7.4 x 10(-24)). Using the data from our genome-wide association study of CRC, LD mapping and imputation, we were able to refine the location of the causal locus to a 60 kb region and screened for coding changes. The absence of exonic mutations in any of the transcripts (FLJ45803, LOC120376, C11orf53 and POU2AF1) mapping to this region makes the association likely to be a consequence of non-coding effects on gene expression.

To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P < 10(-4) in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping (10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 (P = 2.5 x 10(-13) overall; P = 6.9 x 10(-12) replication), and rs16892766, at 8q23.3 (P = 3.3 x 10(-18) overall; P = 9.6 x 10(-17) replication), which tags a plausible causative gene, EIF3H. These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition.

Several studies have demonstrated a correlation between myocardial ischemia and severity of coronary lesions as determined by intravascular ultrasound (IVUS) and fractional flow reserve (FFR) measurements. However, their value for the assessment of mild coronary stenoses that are associated with myocardial perfusion abnormalities has not been well studied. The objective of this study was to prospectively compare the results of myocardial perfusion as determined by exercise/dipyridamole myocardial single-photon emission computed tomography with IVUS and FFR measurements in patients who had angiographically mild coronary stenosis (50% diameter stenosis by quantitative coronary angiography). Forty-eight patients who had stable coronary disease (61 +/- 11 years of age; 6 women) were included. All had mild coronary stenosis in the proximal/middle segment ofor = 1 coronary artery and had undergone maximal exercise myocardial technetium-99m tetrofosmin single-photon emission computed tomography within 48 hours before coronary angiography. IVUS measurements included lesion lumen area, external elastic membrane area, lesion plaque burden (calculated as external elastic membrane minus lumen area, divided by external elastic membrane, and multiplied by 100), and lumen area stenosis (calculated as reference lumen area minus lesion lumen area, divided by reference lumen area, multiplied by 100). Fifty-three coronary lesions were studied, with a mean percent diameter stenosis of 34.9 +/- 7.9% on angiography. Myocardial perfusion defects were demonstrated by single-photon emission computed tomography in 11 patients (12 myocardial regions) with no differences in lesion percent diameter stenosis compared with those without perfusion defects. The presence of reversible perfusion defects was associated with a higher lesion plaque burden as evaluated by IVUS (67.4 +/- 8.1% vs 60.2 +/- 9.3%, p = 0.01). FFR values did not differ in the presence or absence of perfusion defects (0.90 +/- 0.06 vs 0.92 +/- 0.07, respectively; p = NS). In conclusion, plaque burden as determined by IVUS may partly explain the presence of myocardial perfusion defects in cases of angiographically nonsignificant coronary lesions. However, the high FFR values associated with these lesions suggest that other mechanisms, such as endothelial/microvascular dysfunction, might also account for perfusion abnormalities in these patients.

Objective: To assess the structural and functional characteristics of pulmonary arteries by intravascular ultrasound (IVUS) in the setting of primary pulmonary hypertension, and to correlate the ultrasound findings with haemodynamic variables and mortality at follow up. Design: Prospective observational study. Setting: University hospital (tertiary referral centre). Patients: 20 consecutive patients with primary pulmonary hypertension (16 female; mean (SD) age, 39 (14) years). Methods: Cardiac catheterisation and simultaneous IVUS of pulmonary artery branches at baseline and after infusion of epoprostenol. Results: 33 pulmonary arteries with a mean diameter of 3.91 (0.80) mm were imaged, and wall thickening was observed in all cases, 64% being eccentric. Mean wall thickness was 0.37 (0.13) mm, percentage wall area 31.0 (9.3)%, pulsatility 14.6 (4.8)%, and pulmonary/elastic strain index 449 (174) mm Hg. No correlation was observed between IVUS findings and haemodynamic variables. Epoprostenol infusion increased pulsatility by 53% and decreased the pulmonary/elastic strain index by 41% (p = 0.0001), irrespective of haemodynamic changes. At 18 (12) months follow up, nine patients had died. A reduced pulsatility and an increased pulmonary/elastic strain index were associated with increased mortality at follow up (12.0 (4.4)% v 16.4 (4.4)%, p = 0.03; 369 (67) v 546 (216) mm Hg, p = 0.02). Conclusions: IVUS demonstrated pulmonary artery wall abnormalities in all patients with primary pulmonary hypertension, mostly eccentric. The severity of the changes did not correlate with haemodynamic variables, and epoprostenol improved pulmonary vessel stiffness. There was an association between impaired pulmonary artery functional state as determined by IVUS and mortality at follow up.

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) protect against colorectal cancer (CRC) and are associated with reduced disease recurrence and improved outcome after primary treatment. However, toxicities of NSAIDs have limited their use as antineoplastic therapy. Recent data have suggested that the benefit of aspirin after CRC diagnosis is limited to patients with PIK3CA-mutant cancers. We sought to determine the predictive utility of PIK3CA mutation for benefit from both cyclooxygenase-2 inhibition and aspirin.We performed molecular analysis of tumors from 896 participants in the Vioxx in Colorectal Cancer Therapy: Definition of Optimal Regime (VICTOR) trial, a large randomized trial comparing rofecoxib with placebo after primary CRC resection. We compared relapse-free survival and overall survival between rofecoxib therapy and placebo and between the use and nonuse of low-dose aspirin, according to tumor PIK3CA mutation status.We found no evidence of a greater benefit from rofecoxib treatment compared with placebo in patients whose tumors had PIK3CA mutations (multivariate adjusted hazard ratio [HR], 1.2; 95% CI, 0.53 to 2.72; P = .66; (P)INTERACTION = .47) compared with patients with PIK3CA wild-type cancers (HR, 0.87; 95% CI, 0.64 to 1.16; P = .34). In contrast, regular aspirin use after CRC diagnosis was associated with a reduced rate of CRC recurrence in patients with PIK3CA-mutant cancers (HR, 0.11; 95% CI, 0.001 to 0.832; P = .027; (P)INTERACTION = .024) but not in patients lacking tumor PIK3CA mutation (HR, 0.92; 95% CI, 0.60 to 1.42; P = .71).Although tumor PIK3CA mutation does not predict benefit from rofecoxib treatment, it merits further evaluation as a predictive biomarker for aspirin therapy. Our findings are concordant with recent data and support the prospective investigation of adjuvant aspirin in PIK3CA-mutant CRC.

Objectives: To determine whether inflammation (C-reactive protein, CRP), oxidative stress (malondialdehyde, MDA) or haemodialysis (HD) affect associations between asymmetric (ADMA), symmetric (SDMA) dimethylarginine, NG-monomethyl-L-arginine (L-NMMA) and nitrite/nitrate (NOx) in end-stage renal disease (ESRD).Method: Metabolites were measured pre-HD, after 1 hour and end-HD in 40 ESRD patients (age 63 ± 14 years).Results: Positive associations between NOx and ADMA (p = 0.04), SDMA (p

The incidence of cardiac events in patients with variant angina pectoris without significant coronary stenosis and ST-segment elevation was analyzed during a 12-year follow-up period in 273 consecutive patients (82% men) admitted from 1986 through 2010. Among the 252 patients who underwent electrocardiography during pain, 205 had ST-segment elevation (82%) and 45 had ST-segment depression (18%). During index hospitalization, angina occurred in 179 patients (66%), ventricular tachycardia or fibrillation in 28 (10%), and complete atrioventricular block in 3 (1%), but there were no deaths or myocardial infarctions (MIs). At 140 months, angina was still present in 129 patients (47%), but frequent angina (>10 episodes/year) occurred in only 6%. Total mortality, cardiac mortality, and MI rates were 24%, 7.0%, and 6%, respectively. Cardiac death or MI occurred in 28 patients (10%), associated with tobacco smoking (p = 0.004), antecedent "first-wind" angina (p = 0.020), and angina during hospitalization (p = 0.044) and with continued smoking (p = 0.056) and recurrent angina during follow-up (p

Purpose: Oncogene mutations contribute to colorectal cancer development. We searched for differences in oncogene mutation profiles between colorectal cancer metastases from different sites and evaluated these as markers for site of relapse. Experimental Design: One hundred colorectal cancer metastases were screened for mutations in 19 oncogenes, and further 61 metastases and 87 matched primary cancers were analyzed for genes with identified mutations. Mutation prevalence was compared between (a) metastases from liver (n = 65), lung (n = 50), and brain (n = 46), (b) metastases and matched primary cancers, and (c) metastases and an independent cohort of primary cancers (n = 604). Mutations differing between metastasis sites were evaluated as markers for site of relapse in 859 patients from the VICTOR trial. Results: In colorectal cancer metastases, mutations were detected in 4 of 19 oncogenes: BRAF (3.1%), KRAS (48.4%), NRAS (6.2%), and PIK3CA (16.1%). KRAS mutation prevalence was significantly higher in lung (62.0%) and brain (56.5%) than in liver metastases (32.3%; P = 0.003). Mutation status was highly concordant between primary cancer and metastasis from the same individual. Compared with independent primary cancers, KRAS mutations were more common in lung and brain metastases (P < 0.005), but similar in liver metastases. Correspondingly, KRAS mutation was associated with lung relapse (HR = 2.1; 95% CI, 1.2 to 3.5, P = 0.007) but not liver relapse in patients from the VICTOR trial. Conclusions: KRAS mutation seems to be associated with metastasis in specific sites, lung and brain, in colorectal cancer patients. Our data highlight the potential of somatic mutations for informing surveillance strategies. Clin Cancer Res; 17(5); 1122–30. ©2011 AACR.

article i nfo Background: Acute vasoreactivity testing (VT) is considered mandatory in the diagnostic work-up of patients with pulmonary arterial hypertension (PAH). We studied the relation between the acute absolute arterial vasodilatation and the severity of vascular remodeling estimated by intravascular ultrasound (IVUS) in patients with idiopathic PAH. Methods: Simultaneous right heart catheterization and IVUS of the pulmonary artery (PA) were performed both in basal conditions and during short-term intravenous epoprostenol infusion in nineteen idiopathic PAH patients. Pulmonary vascular resistance (PVRi) and capacitance indexes (stroke volume/pulse pressure, Cp), were calculated. Local pulsatility was estimated by IVUS (IVUSp) (systolic-diastolic lumen area/diastolic lumen area×100; sA-dA/dA) and PA stiffness was assessed by the elastic modulus (E: pulse pressure/IVUSp). Results: Epoprostenol infusion (11±2 ng/kg/min) determined a real vasodilatation (increment of dAN10%) in six patients. This vasodilation group presented on average significantly higher cardiac index, stroke volume index and Cp, and lower PVRi and IVUSp (Pb0.05), with a lower E (P=0.08). Three patients were responders according to the actual criteria, but only one showed a real vasodilator response. Baseline E below the median value (≤190 mm Hg) was able to differentiate patients with an acute vasodilator response (sensibility 83%, specificity 73%, area under ROC 0.81; Pb0.05). Neither E nor vasodilator response is correlated with delta mean PA pressure and PVRi. Conclusions: Patients with higher IVUSp and lesser E displayed an absolute PA vasodilation during VT with epoprostenol. The patients with a positive VT according to actual criteria do not necessarily have a real vasodilatation on intravascular ultrasound.

Most patients with ST-elevation myocardial infarction fulfilling ST-segment elevation (STE) lytic criteria present an occluded culprit artery but the occlusion rate in those with minimal STE (minSTE) not fulfilling lytic criteria is unknown.In 63 patients with minSTE (mean STE:1.2 +/- 0.6 mm) and 149 with lytic STE criteria (lyticSTE, 4.8 +/- 3.1 mm), an emergency coronary angiography was performed, serial creatine kinase-MB was determined, and ejection fraction was measured by 2-dimensional echocardiography.The 2 groups showed similar time from pain onset to electrocardiogram (minSTE 196 +/- 199 vs lyticSTE, 176 +/- 172 min, P = .444), and although time to catheterization was longer in patients with minSTE (426 +/- 314 vs 253 +/- 239 min, P.001), the rate of TIMI flow 0 to I (88% vs 81%, P = .21) was similar and percutaneous coronary intervention was performed in80% of patients from the 2 groups. Moreover, patients with minSTE had higher rate of collateral circulation (27% vs 13%, P = .013), lower rate of Q waves (44% vs 60%, P = .041), lower creatine kinase-MB (202 +/- 150 vs 335 +/- 280, microg/L, P.001), higher ejection fraction (54% +/- 9% vs 49% +/- 12%, P = .004), and lower mortality (0% vs 7.4%, P = .036).ST-elevation myocardial infarction patients with minSTE present a high prevalence of TIMI flow 0 to I similar to those meeting lyticSTE suggesting an identical underlying mechanism and the potential to benefit from primary angioplasty.

To evaluate the prognostic role of combined cardiac studies (submaximal exercise test, thallium-201 scintigraphy, radionuclide exercise ventriculography, two-dimensional echocardiography, Holter monitoring and cardiac catheterization) in patients with a first acute myocardial infarction without complications during hospital admission, 115 consecutive patients aged less than 65 years were prospectively evaluated. The studies were carried out before hospital discharge and the patients were then clinically followed up for 12 months. During the follow-up period, 69 patients (60%) developed complications, which were severe in 23 (20%). Half of all complications and 70% of severe complications developed during the 1st follow-up month. Logistic regression analysis disclosed that the combination of studies with the highest predictive power for complications (probability of complications 99%) and severe complications (probability of severe complications 95%) was the association of exercise test + thallium-201 + echocardiogram. Four decision models (exercise test + echocardiography, exercise test + radionuclide ventriculography, thallium-201 scintigraphy + echocardiography, thallium-201 scintigraphy + radionuclide ventriculography) allowed the stratification of all patients in a particular risk category (high, intermediate or low). The best decision model was the association of thallium-201 scintigraphy + radionuclide ventriculography (probability of complications if both tests were positive 84%; probability of absence of severe complications if both tests were negative 88%), but there were no significant differences with the other models. Any association of a test detecting residual ischemia or functional capacity, or both (exercise test or thallium-201) and a test assessing ventricular function (echocardiography or radionuclide ventriculography) results in significant prognostic information in patients with an uncomplicated first acute myocardial infarction. Additional cardiac catheterization does not improve the predictive power of noninvasive studies, which should ideally be performed before hospital discharge because most complications develop during the 1st follow-up month.

Objective Treatment with bosentan improves exercise capacity in patients with pulmonary hypertension. Few studies have assessed treatment with this drug over long periods. The aim was therefore to assess long-term treatment with bosentan. Patients and methods A group of 22 functional class III patients—18 women and 4 men, mean age, 45.5 years (range, 19-77 years)—with pulmonary hypertension were treated with bosentan between April 2002 and June 2005. Pulmonary hypertension was idiopathic in 10 patients. In the remaining patients, etiologies were associated with compensated heart failure (n=4), scleroderma (n=4), peripheral embolism (n=3), and portal hypertension (n=1). Clinical and hemodynamic variables and their changes between baseline and the end of study were analyzed. Results The mean duration of follow-up of the patients was 15.7 months (range, 12.6-31.8 months). Functional class improved or stabilized after 3 months of treatment in 21 (95%) and after 1 year in 14 (64%). At 3 months, the distance covered in the 6-minute walk test increased by a mean of 64.5 m, an improvement that was maintained at 6, 12, and 18 months. Treatment was interrupted in 4 patients (18%). Reasons for discontinuation were death in 2 patients, deterioration in 1 patient, and intolerance of the medication in 1 patient. Treatment was ineffective for 4 patients (18%). No patient experienced notable liver toxicity. Conclusions The results of this study suggest that treatment with bosentan is associated with long-term improvement in clinical variables and exercise capacity in approximately two thirds of the patients with pulmonary hypertension.

Microsatellite instability (MSI) characterizes tumors arising in patients with hereditary non-polyposis colorectal cancer (HNPCC) syndrome. HNPCC is a hereditary autosomal dominant disease caused by germline mutations in genes from the DNA (MMR) mismatch repair system. In these tumors, the loss of MMR compromises the genome integrity, allowing the progressive accumulation of mutations and the establishment of a mutator phenotype in a recessive manner. It is not clear, however, whether MSI can be detected in HNPCC carriers before tumor diagnosis. The aim of this study was to evaluate the presence of genetic instability in MMR gene carriers in peripheral blood lymphocytes of carriers and non-carriers members of two HNPCC families harboring a germline MLH1 and MSH2 mutation, respectively. An extensive analysis of the allelic distribution of single molecules of the polyA tract bat26 was performed using a highly sensitive PCR-cloning approach. In non-carriers, the allelic distribution of single bat26 molecules followed a gaussian distribution with no bat26 alleles shorter than (A)21. All mutation carriers showed unstable alleles [(A)20 or shorter] with an overall frequency of 5.6% (102/1814). We therefore suggest that low levels of genomic instability characterize MMR mutation carriers. These observations suggest that somatic mutations accumulate well before tumor diagnosis. Even though it is not clear whether this is due to the presence of a small percentage of cells with lost MMR or due to MMR haploinsufficiency, detection of these short unstable alleles might help in the identification of asymptomatic carriers belonging to families with no detectable MMR gene mutations.

Patients with variant angina pectoris showed greater serotonin plasma levels than did control subjects and patients with healed myocardial infarction. The levels also tended to be greater in those with >1 episode/month than in those with fewer episodes. Moreover, patients with variant angina pectoris also had greater levels of nitrite and nitrate plasma levels than did control subjects or patients with healed myocardial infarction, partly, perhaps, as a compensatory mechanism.

BRAF, a serine/threonine kinase of the RAF family, is a downstream transducer of the RAS-regulated MAPK pathway and signals upstream of MEK1/2 kinases. Recently, activating mutations within BRAF have been reported in a high percentage of melanomas and colorectal carcinomas and shown to have oncogenic capabilities. Further, their association to mismatch-repair-deficient tumors has suggested the involvement of the RAS/RAF pathway in the tumorigenesis of microsatellite-unstable colon cancers, and that RAS and RAF mutations are alternative genetic events. We determined whether colorectal mismatch-repair-deficient tumors with BRAF mutations show a specific genotype when compared with tumors with wild-type BRAF, and whether they can be associated with a particular clinicopathological feature. Here, we report a striking association of BRAF, but not of APC, KRAS2, AXIN2, and TP53 mutations, with proximal mismatch-repair-deficient colon tumors and MLH1 hypermethylation. Our results support the hypothesis that proximal and distal colorectal tumors with mismatch repair deficiency harbor different genetic alterations, and we suggest that the involvement of the RAS/RAF pathway in colorectal tumorigenesis is differentially modulated according to tumor location and MLH1 inactivation.

Aims To analyse the relationship between the in-hospital course of ST segment elevation (STE) and negative T wave (NTW) with ejection fraction, regional contractility and left ventricular end-diastolic volume at pre-discharge and at 1 year in patients with a first anterior STE acute myocardial infarction (AMI). Methods and results ECG changes were measured during hospitalization and at 1 year whereas ejection fraction, regional contractility score and end-diastolic volume index were measured by isotopic ventriculography at pre-discharge and at 1 year. At 72h but not earlier patients with ΣSTE >0.6mV (group A, n : 35) had a lower ejection fraction ( P

Clinical and ECG prognostic markers, ischemic threshold (IT) and extent of coronary disease were analyzed in 383 patients with unstable angina (UA) and correlated with long-term events. Patients74 years or those with severe heart failure or previous revascularization procedures were excluded. There were 369 events in 245 patients: 87 deaths, 96 myocardial infarction (MI), 111 coronary artery bypass grafting (CABG), and 75 angioplasty procedures (PTCA). Follow-up was obtained in 367 hospital survivors (99%, 114 (44) months) and ST depression on admission ECG, a modest enzyme rise, refractory angina (2 episodes), two to three vessel coronary disease and a reduced IT (==130 beats/min) were each associated with cardiac events. A multivariate analysis, however, showed refractory angina (p0.001) and multivessel disease (p0.001) as most significant predictors. After their exclusion, IT was most relevant predictor (p0.001). However, the predictive value of these markers was essentially centered on first-year events (249, 67%). Moreover, refractory angina, minor enzyme rise and admission ST depression were each highly correlated with a reduced IT (p0.006) and with multivessel disease (p0.0001). Therefore, these findings underscore that the prognostic value of conventional clinical markers in patients with UA is limited to first-year events and that their remarkable correlation with extensive coronary disease and reduced coronary reserve reveal the anatomical substrate of this prognostic significance.

Through the nitric oxide (NO) production in the vascular system, the endothelial nitric oxide synthase (eNOS or NOS3) is a key enzyme in blood pressure regulation and atherosclerosis control. Several previous studies have suggested an important role of eNOS as a genetic risk factor for cardiovascular diseases. In this context, a genetic association study was carried out between two eNOS polymorphisms (the ecNOS4a/b VNTR and the G894T substitution) in a sample of 101 nuclear families having one affected offspring of ischemic heart disease (IHD). Transmission disequilibrium test (TDT) revealed partial associations between the VNTR marker and IHD in patients with a type A behavior pattern (TABP) (P = 0.0325, RR = 3.67) and for the haplotype formed by variant b of the VNTR and the T mutation of the G894T substitution in the IHD-affected subgroup having body mass index (BMI) lower than 25 (P = 0.0348, RR = 0.22). However, once multiple testing correction was applied, the associations became nonsignificant. A significant effect of the haplotype b-G increasing high-density lipoprotein cholesterol (HDL-C) plasma levels was detected (P = 0.021 after Bonferroni correction). From a population point of view, frequencies found for G894T substitution in Spain were significantly different from other populations.

Background Exercise capacity is impaired in pulmonary arterial hypertension (PAH). We hypothesized that cardiovascular reserve abnormalities would be associated with impaired hemodynamic response to pharmacological stress and worse outcome in PAH. Methods Eighteen PAH patients (p) group 1 NYHA class II/III and ten controls underwent simultaneous right cardiac catheterization and intravascular ultrasound at rest and during low dose-dobutamine (10 mcg/kg/min) with trendelenburg (DST). We estimated cardiac output (CO), pulmonary vascular resistance (PVR) and capacitance (PC), and PA elastic modulus (EM). We concomitantly measured tricuspid annular plane systolic excursion (TAPSE), RV myocardial peak systolic velocity (Sm) and isovolumic myocardial acceleration (IVA) in PAH patients. Based on the rounded mean + 2 SD of the increase in mPAP in our healthy control group during DST (2.8 + 1.8 mm Hg), PAH p were divided into two groups according to mean PA pressure (mPAP) response during DST, 1: ΔmPAP > 5 mm Hg and 2: ΔmPAP ≤ 5 mm Hg. Cardiovascular reserve was estimated as the change (delta, Δ) during DST compared with rest, including ΔmPAP with respect to ΔCO (ΔmPAP/ΔCO). All patients were prospectively followed up for 2 years. Results PAH p showed significant lower heart rate and CO increase than controls during DST, with a significant mPAP and pulse PAP increase and higher ΔmPAP/ΔCO (p 0.05). Conclusions Pulmonary vascular reserve and RV systolic reserve are significantly impaired in patients with PAH. The lower recruitable cardiovascular reserve is significantly related to a worse hemodynamic response to DST and it could be associated with a poor clinical outcome.

The magnitude of the benefit of percutaneous transluminal coronary angioplasty (PTCA) in terms of quality of life depending on baseline and outcome clinical variables is not sufficiently understood because of the restrictive inclusion criteria of randomized clinical trials. The present study was designed to assess perceived health outcome at 3 years and its association with clinical variables after successful elective PTCA in a tertiary hospital throughout a prospective cohort study. Questionnaires were administered on the day before the procedure and 1 month and 3.4 years later (as mean follow-up) to 106 patients recruited during a 15-month period. Mean perceived health scores improved significantly for the population as a whole 1 month after PTCA, and improvement was maintained at the end of follow-up. The magnitude of the effect was different depending on clinical subgroups: (a) It was greatest in patients free from angina, myocardial infarction, or new revascularization procedures at the end of follow-up; (b) It was moderately reduced in patients with comorbidity; (c) Patients who reported to have dyspnea or angina at rest after the latest revascularization procedure did not improve, with poor final perceived health scores. Elective PTCA is associated with a significant improvement in perceived health, which varies depending on the clinical outcome. Comorbidity and initial perceived health influence outcome but do not preclude improvement.

Variant angina identifies angina at rest with transient ST elevation (ASTE) caused by coronary vasospasm in patients with non-significant coronary stenosis ( 6 years.2 Thus, we analysed the long-term prognostic markers in patients with ASTE with emphasis on potential sex differences. Consecutive patients with ASTE (n = 364) from January 1984 to December 1999 were included. ASTE diagnosis was based on ⩾1 episodes of ASTE (⩾1 mm) without enzyme increase. Exclusion criteria were age >70 years, left bundle branch block, associated cardiac disease, previous myocardial infarction or coronary revascularisation. Severe coronary vasospasm was documented when ergonovine or intracoronary acetylcholine was given intravenously in patients with

Postprandial angina develops within minutes after a meal in patients with unstable angina, but the clinical characteristics of these patients and why it develops in only some of those with advanced coronary artery disease remain largely unknown. A severely reduced coronary reserve associated with postprandial increases in heart rate could be a contributory mechanism.The clinical and angiographic characteristics of 277 patients with unstable angina with (23) or without (254) postprandial angina were analyzed. The coronary reserve was also analyzed by measuring the ischemic threshold by atrial pacing in a fasting state in all patients and 15 minutes after a 900-calorie meal in 54.Patients with postprandial angina were older, more likely to be women, and had a higher incidence of hypertension and three-vessel disease than those without (p0.005) and had a lower fasting ischemic threshold (131.8 [SD 13.0] vs 147.5 [SD 23.4] beats/min, p0.0001). However, 67 of the 79 patients with the lowest fasting thresholds (or =130 beats/min) (84.8%) had no postprandial angina. Moreover, among patients with and without postprandial angina who were matched for age, sex, and extent of coronary disease, the ischemic threshold was also lower in those with postprandial angina (p0.005) and there were no differences in left ventricular end-diastolic pressure or volume. Postprandial pacing was positive in 37 patients but postprandial ischemic threshold was comparable to fasting threshold (132 [SD 14] vs 132 [SD 16] beats/min). Moreover, in the 10 patients who experienced in-hospital postprandial angina, heart rate during postprandial angina was similar to nonpostprandial angina (93.1 [SD 14.7] vs 90.3 [SD 17.6]) and lower than the fasting ischemic threshold (132.0 [SD 10.8] beats/min, p0.0001).Thus postprandial angina tends to occur among elderly and hypertensive patients with advanced coronary disease and severely reduced ischemic threshold. The fact that the postprandial ischemic threshold was clearly higher than the heart rate attained during postprandial angina suggest that factors others than increases in heart rate account for postprandial angina. Furthermore, the lack of a decline in the postprandial ischemic threshold suggests that, in the absence of postprandial angina, there is not a consistent postprandial change in coronary tone or that the increases in myocardial oxygen demands due to increased myocardial contractility-wall tension do not seem to play a major role in postprandial ischemia.

To determine whether transtracheal catheter and reservoir nasal cannula contribute to maintaining adequate oxygen saturation during sleep, and to calculate the oxygen saving they allow compared to nasal prongs.A prospective study in which patients were randomly assigned to either nasal prongs or oxymizer device prior to transtracheal oxygen delivery. Arterial oxygen saturation was then monitored by a finger pulse oximeter during 8 h of sleep.Pulmonary ward of 'The Hospital Universitari Germans Trias i Pujol, Badalona (Barcelona/Spain)'.Fourteen stable hypoxemic (PaO2 50 +/- 6.9 mm Hg; PaCO2 51.5 +/- 9.3 mm Hg) COPD patients (FVC 44 +/- 19%; FEV1 26.5 +/- 11.5%; FEV1/FVC 44.9 +/- 9.7%) already receiving oxygen therapy at home.Pulmonary function test was performed. The lowest flow required to obtain an SaO2 at or above 88% for over 95% of the sleep time was determined for each type of oxygen delivery. Patients were not switched to the next type of oxygen delivery device until 3 reliable pulse oximetries had been obtained. The percentage of oxygen savings was calculated. Awake PaO2 was measured in patients using nasal prongs and transtracheal catheter while continuing to inspire oxygen at the same flow rate as when asleep.As expected, no differences were found in SaO2 measurements for the three types of oxygen delivery. Oxygen savings were 48.65% for the oxymizer device and 52.87% for the transtracheal catheter. Awake PaO2 was significantly higher (p0.04) in patients with nasal prongs than in those with transtracheal catheter at the flow rate required when asleep.The oxymizer device and transtracheal oxygen delivery benefit hypoxemic COPD patients reducing oxygen use during sleep by around 50%. Higher PaO2 levels were necessary to prevent nocturnal SaO2 decreases in patients with nasal prongs than in patients with transtracheal oxygen delivery. Oxygen-conserving devices are reliable and advisable methods for nocturnal oxygenation.

A 69-year-old woman was referred for asthenia and dizziness when walking in the last two months. No clinical abnormalities were found, and sinus rhythm was present when lying down. On orthostatism and walking, advanced AV block developed. Atropine and isoproterenol ameliorated the AV conduction abnormality, suggesting a nodal block. The patient remained asymptomatic after pacemaker implantation.

We prospectively studied 60 ischemic patients with 5F catheters (Pigtail and Amplatz) using the percutaneous right brachial artery approach (group I), in order to compare this technique with two groups of 100 patients each randomly studied by the femoral route with either 5F (group II) or 8F (group III) catheters (Pigtail and Judkins). The following parameters were analyzed: need to change the initially elected catheter diameter or/and artery approach; technical difficulty for obtaining LV, LCA, and RCA angiograms; total time of X-ray exposure; quality image of LV, LCA, and RCA angiograms; incidence of arterial puncture related hematomas or total arterial occlusion; and duration of local compression after sheath removal. There were no differences between 5F brachial and femoral approaches except for the arterial compression time (p less than 0.01) and the X-ray exposure time (p = 0.03) which were longer with the brachial approach. Whatever the route used, 5F showed a mild increase difficulty (brachial p = 0.001; femoral p = 0.01) and a mild decreased quality image for LCA (branchial p = 0.006; femoral p less than 0.05). Mild hematomas were more frequent with 8F catheters (p less than 0.05). The procedure could be completed by the elected first artery and type of catheter (5F or 8F) in 57/60 patients in group I, in 95/100 in group II, and in 96/100 in group III (nonsignificant differences). Thus, the percutaneous right brachial artery approach using 5F catheters is similar to the femoral artery approach with the same catheters. Although both of them showed a mild increased technical difficulty and a mild decreased quality image compared to 8F, mainly for LCA angiograms, they allowed complete and reliable angiograms reading and analysis.

In order to compare 5 French versus 8 French catheters for assessing ischemic heart disease, we prospectively studied 2 groups of 100 patients each, one with 5 French (group I) and the other with 8 French (group II) catheters by the Judkins technique. Significant differences were found in the greater easiness to catheterize LV (p less than 0.05) and LCA (p = 0.01) in group II and in better quality image for LCA in group II (p less than 0.05), although all patients in both groups had acceptable image quality. Pressure curves quality was better in group II (p less than 0.01); X-ray exposure time was longer in group I (p less than 0.001) and arterial compression time in group II (p less than 0.0001). Group I showed 3 and group II 10 mild hematomas (p less than 0.05). The procedure could be completed by the elected first artery and type of catheter in 95 patients in group I and in 96 in group II. Thus, the Judkins technique with 5 French catheters is as valid as with 8 French for assessing ischemic patients, reducing arterial morbidity, although mildly increasing technical difficulty and mildly decreasing quality image.

We prospectively studied 110 patients with a first acute myocardial infarction with cross–sectional echocardiography, between 7–10 days post–infarction, to assess the value of semiquantitative segmental con–tractility score for the first year post–AM I risk stratification. 87 patients had acceptable recordings (40 anterior and 47 inferior infarction). Twelve patients had severe complications (severe angina or heart failure, reinfarction or death) and 40 had nonsevere complications. The total segmental score was higher in complicated than in non–complicated patients. The score also differentiated angina from heart failure. The score of necrotic area was more discriminating than that of non-necrotic area. Discriminating power was higher in anterior than in inferior acute myocardial infarction. Thus we conclude that the semiquantitative assessment of segmental contractility by cross–sectional echocardiography is useful for risk stratification following acute infarction identifying severe complications, particularly heart failure, with better discrimination in anterior acute myocapdial infarction.

Digital angiography has been reported to be a valid technique for anatomical studies of the peripheral cardiovascular system and for dynamic studies of ventricular function. The purpose of the present study was to assess the usefulness and accuracy of venous digital angiography (2 images per second) for imaging coronary bypass grafts after coronary artery bypass surgery, comparing its results with those of selective angiography. Fifty-two patients with 108 grafts (101 venous grafts and 7 internal mammary artery grafts) were studied by venous digital angiography and selective angiography. Venous digital angiography correctly diagnosed 95 out of 97 patent grafts and the 11 occluded grafts visualized by selective angiography. These results are better than those obtained in the very few studies so far reported in the literature. We were not able to adequately visualize distal anastomoses in most patients although we could identify the distal portion of 7 out of 8 patent sequential bypass grafts. Thus, these results suggest that venous digital angiography is a useful and accurate technique for assessing coronary bypass graft patency.

Objectives.Our aim was to use noninvasive studies early after infarction to assess medium-term prognosis in patients with a first uncomplicated myocardial infarction.Background.Although the use of early postinfarction assessment to gauge short-term prognosis in myocardial infarction is well established, there have been few comprehensive evaluations of noninvasive methods for assessing medium- and long-term prognosis.Methods.We prospectively studied 115 consecutive patients

Mitral area is the parameter used for quantitating mitral stenosis (MS) severity. When mitral gradient (MG) is low and reduction of mitral valve area (MVA) might be critical, interventions presumably increasing mitral valve flow (MVF), such as stress or atrial pacing, have been carried out. The purpose of this study was to analyze in 28 patients the combined effect of left ventriculography (LVG) and intravenous atropine (ATR) in the hemodynamic evaluation of MS. The rationale for combining these two interventions is to add up the ATR-positive chronotropic effect to the LVG potentiation of cardiac output. The LVG plus ATR markedly accelerated heart rate (from 80 +/- 14 to 104 +/- 18 bts/min, P less than 0.001), mildly increased cardiac index (from 2.6 +/- 0.6 to 2.9 +/- 0.6 1/min/m2, P less than 0.05), and importantly increased MVF (from 136 +/- 30 to 172 +/- 46 ml/bt, P less than 0.001). Pulmonary wedge pressure increased (from 14 +/- 5 to 21 +/- 5 mmHg, P less than 0.001) because of an important increment of MG (from 12 +/- 6 to 18 +/- 7 mmHg, P less than 0.001). None of six cases with mild MS (MVA greater than 1.5 cm2) and nine of ten cases with severe MS (MVA less than or equal to 1.0 cm2) had MG after LVG plus ATR greater than 12 mmHg. The remaining case with severe MS and the two cases (out of 12) with moderate MS having MG after LVG plus ATR less than or equal to 12 mmHg had, at surgical evaluation, noncritically reduced MVA. This study shows that LVG plus ATR is a valid and easy intervention for increasing MVF during cardiac catheterization. It also allows the reclassification of patients with low baseline MG and reduced MVA into two subgroups: Cases with critically reduced MVA at surgery achieve a postintervention MG greater than 12 mmHg and those cases with noncritically reduced MVA achieve a postintervention MG less than or equal to 12 mmHg.

The dynamic behavior of fixed LV outflow tract stenosis partly resembles that of OCM. To analyze their differences we studied basal and postextrasystolic (post-PVC) peak-to-peak LV aortic gradients, aortic systolic pressure, and pulse pressure in 14 OCM and in 36 pure VAS without two-dimensional echocardiographic findings of OCM. Fifteen mild VAS had basal gradients similar to those of OCM (39 +/- 17 mm Hg vs 24 +/- 16 mm Hg). Patients with OCM show a post-PVC gradient (109 +/- 41 mm Hg) similar to that of VAS (110 +/- 50 mm Hg). However, the latter were departing from much higher gradients (VAS 72 +/- 30 mm Hg vs OCM 24 +/- 16 mm Hg). Decrement of post-PVC aortic systolic pressure and pulse pressure were frequent in both groups, but decrement of pulse pressure greater than 5 mm Hg were more frequent in OCM. We concluded that (1) post-PVC increased aortic gradients and decreased aortic systolic pressure occurred in both VAS and OCM; (2) post-PVC decreased aortic pulse pressure might occur in VAS; and (3) association of post-PVC gradient increment greater than 75 percent and pulse pressure decrement greater than 5 mm Hg are strongly suggestive of OCM.