Thrombotic Occlusion of All Left Coronary Branches in a Young Woman with Severe Ulcerative Colitis

Background. The thrombosis risk is increased in active ulcerative colitis. The limited number of reported complications have predominantly been cerebrovascular but other vessel territories may also be affected. Patient. During a severe attack of ulcerative colitis a 37-year-old woman suffered occlusion of all left coronary artery branches. Serial angiographies showed progressive recanalisation of the coronary arteries during anticoagulation, but no atherosclerotic stenosis. The cause of infarction was thus considered to be an extensive coronary thrombosis. However, a large battery of blood tests failed to identify any procoagulant abnormality. Conclusion. Evidence is now accumulating that the increased thrombosis risk also may involve the coronary arteries, even in young patients. To the best of our knowledge this is the third reported case of myocardial infarction despite angiographically normal coronary arteries in a patient with active ulcerative colitis. The extent of affected myocardium was in this case exceptionally large

Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis

Alkaline sphingomyelinase (alk-SMase) is expressed in the intestine and human liver. It may inhibit colonic tumorigenesis, and loss of function mutations have been identified in human colon cancer. The present study investigates its expression in human liver cancer. In HepG2 liver cancer cells, RT–PCR identified three transcripts with 1.4, 1.2 and 0.4 kb, respectively. The 1.4 kb form is the wild-type cDNA with five translated exons, the 1.2 kb product lacks exon 4 and the 0.4 kb form is a combination of exons 1 and 5. Genomic sequence showed that these aberrant transcripts were products of alternative splicing. Transient expression of the 1.2 kb form showed no alk-SMase activity. In HepG2 cells, the alk-SMase activity is low in monolayer condition and increased with cell polarisation. Coexistence of 1.4 and 1.2 kb forms was also identified in one hepatoma biopsy. GenBank search identified a cDNA clone from human liver tumour, which codes a protein containing full length of alk-SMase plus a 73-amino-acid tag at the N terminus. The aberrant form was translated by an alternative starting codon upstream of the wild-type mRNA. Expression study showed that linking the tag markedly reduced the enzyme activity. We also analysed human liver biopsy samples and found relatively low alk-SMase activity in diseases with increased risk of liver tumorigenesis. In conclusion, expression of alk-SMase is changed in hepatic tumorigenesis, resulting in loss or marked reduction of the enzyme function

Familial adenomatous polyposis is associated with a marked decrease in alkaline sphingomyelinase activity: a key factor to the unrestrained cell proliferation?

The hydrolysis of sphingomyelin generates key molecules regulating cell growth and inducing apoptosis. Data from animal cancer models support an inhibitory role for this pathway in the malignant transformation of the colonic mucosa. In the intestinal tract, a sphingomyelinase with an optimum alkaline pH has been identified. We recently found that the activity of alkaline sphingomyelinase is significantly decreased in colorectal adenocarcinomas, indicating a potential anticarcinogenic role of this enzyme. To further examine whether the reduction of sphingomyelinase is present already in the premalignant state of neoplastic transformation, we measured sphingomyelinase activities in patients with familial adenomatous polyposis (FAP) and in sporadic colorectal tubulovillous adenomas. Tissue samples were taken from adenomas and surrounding macroscopically normal mucosa from 11 FAP patients operated with ileorectal anastomosis, from three FAP patients with intact colon, from 13 patients with sporadic colorectal adenomas and from 12 controls. Activities of acid, neutral and alkaline sphingomyelinase were measured together with alkaline phosphatase. In FAP adenoma tissue, alkaline sphingomyelinase activity was reduced by 90% compared to controls (P < 0.0001), acid sphingomyelinase by 66% (P < 0.01) and neutral sphingomyelinase by 54% (P < 0.05). Similar reductions were found in the surrounding mucosa. In sporadic adenoma tissue, only alkaline sphingomyelinase was reduced significantly, by 57% (P < 0.05). Alkaline phosphatase was not changed in FAP adenomas, but decreased in the sporadic adenomas. We conclude that the markedly reduced levels of alkaline sphingomyelinase activities in FAP adenomas and in the surrounding mucosa may be a pathogenic factor that can lead to unrestrained cell proliferation and neoplastic transformation. © 1999 Cancer Research Campaig

Non-invasive evaluation of ventricular refractoriness and its dispersion during ventricular fibrillation in patients with implantable cardioverter defibrillator

BACKGROUND: Local ventricular refractoriness and its dispersion during ventricular fibrillation (VF) have not been well evaluated, due to methodological difficulties. METHODS: In this study, a non-invasive method was used in evaluation of local ventricular refractoriness and its dispersion during induced VF in 11 patients with VF and/or polymorphic ventricular tachycardia (VT) who have implanted an implantable cardioverter defibrillator (ICD). Bipolar electrograms were simultaneously recorded from the lower oesophagus behind the posterior left ventricle (LV) via an oesophageal electrode and from the right ventricular (RV) apex via telemetry from the implanted ICD. VF intervals were used as an estimate of the ventricular effective refractory period (VERP). In 6 patients, VERP was also measured during sinus rhythm at the RV apex and outflow tract (RVOT) using conventional extra stimulus technique. RESULTS: Electrograms recorded from the RV apex and the lower esophagus behind the posterior LV manifested distinct differences of the local ventricular activities. The estimated VERPs during induced VF in the RV apex were significantly shorter than that measured during sinus rhythm using extra stimulus technique. The maximal dispersion of the estimated VERPs during induced VF between the RV apex and posterior LV was that of 10 percentile VF interval (40 ± 27 ms), that is markedly greater than the previously reported dispersion of ventricular repolarization without malignant ventricular arrhythmias (30–36 ms). CONCLUSIONS: This study verified the feasibility of recording local ventricular activities via oesophageal electrode and via telemetry from an implanted ICD and the usefulness of VF intervals obtained using this non-invasive technique in evaluation of the dispersion of refractoriness in patients with ICD implantation

Withdrawal of infliximab or concomitant immunosuppressant therapy in patients with Crohn's disease on combination therapy (SPARE): a multicentre, open-label, randomised controlled trial.

BACKGROUND: The combination of infliximab and immunosuppressant therapy is a standard management strategy for patients with Crohn's disease. Concerns regarding the implications of long-term combination therapy provided the rationale for a formal clinical trial of treatment de-escalation. Our aim was to compare the relapse rate and the time spent in remission over 2 years between patients continuing combination therapy and those stopping infliximab or immunosuppressant therapy. METHODS: This multicentre, open-label, randomised controlled trial was performed in 64 hospitals in seven countries in Europe and Australia. Adult patients with Crohn's disease in steroid-free clinical remission for more than 6 months, on combination therapy of infliximab and immunosuppressant therapy for at least 8 months were randomly assigned (1:1:1) to either continue combination therapy (combination group), discontinue infliximab (infliximab withdrawal group), or discontinue immunosuppressant therapy (immunosuppressant withdrawal group). Randomisation was stratified according to disease duration before start of first anti-TNF treatment (≤2 or >2 years), failure of immunosuppressant therapy before start of infliximab, and presence of ulcers at baseline endoscopy. The patient number and group of each stratum were assigned by a central online randomisation website. Treatment was optimised or resumed in case of relapse in all groups. Participants, those assessing outcomes, and those analysing the data were not masked to group assignment. The coprimary endpoints were the relapse rate (superiority analysis) and time in remission over 2 years (non-inferiority analysis, non-inferiority margin 35 days). Analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT02177071, and with EU Clinical Trials Register, EUDRACT 2014-002311-41. The trial was completed in April, 2021. FINDINGS: Between Nov 2, 2015, and April 24, 2019, 254 patients were screened. Of these, 211 were randomised and 207 were included in the final analysis (n=67 in the combination group, n=71 in the infliximab withdrawal group, and n=69 in the immunosuppressant withdrawal group). 39 patients had a relapse (eight [12%] of 67 in the combination group, 25 [35%] of 71 in the infliximab withdrawal group, six [9%] of 69 in the immunosuppressant withdrawal group). 2-year relapse rates were 14% (95% CI 4-23) in the combination group, 36% (24-47) in the infliximab withdrawal group, and 10% (2-18) in the immunosuppressant withdrawal group (hazard ratio [HR] 3·45 [95% CI 1·56-7·69], p=0·003, for infliximab withdrawal vs combination, and 4·76 [1·92-11·11], p=0·0004, for infliximab withdrawal vs immunosuppressant withdrawal). Of 28 patients who had a relapse and were retreated or optimised according to protocol, remission was achieved in 25 patients (one of two in the combination group, 22 of 23 in the infliximab withdrawal group, and two of three in the immunosuppressant withdrawal group). The mean time spent in remission over 2 years was 698 days (95% CI 668-727) in the combination group, 684 days (651-717) in the infliximab withdrawal group, and 706 days (682-730) in the immunosuppressant withdrawal group. The difference in restricted mean survival time in remission was -14 days (95% CI -56 to 27) between the infliximab withdrawal group and the combination group and -22 days (-62 to 16) between the infliximab withdrawal group and the immunosuppressant withdrawal group. The 95% CIs contained the non-inferiority threshold (-35 days). We recorded 31 serious adverse events, in 20 patients, with no difference in frequency between groups. The most frequent serious adverse events were infections (four in the combination group, two in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group) and Crohn's disease exacerbation (three in the combination group, four in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group). No death nor malignancy was recorded. INTERPRETATION: In patients with Crohn's disease in sustained steroid-free remission under combination therapy with infliximab and immunosuppressant therapy, withdrawal of infliximab should only be considered after careful assessment of risks and benefits for each patient, whereas withdrawal of immunosuppressant therapy could generally represent a preferable strategy when considering treatment de-escalation. FUNDING: European Union's Horizon 2020

Conduction Disturbances in Patients with Atrial Fibrillation

Background: The electrophysiological mechanisms underlying atrial fibrillation (AF) are incompletely understood. Experimental studies have shown that remodelling of the atrial myocardium is linked to the occurrence and perpetuation of AF. Interatrial conduction disturbances and also delayed conduction at the posteroparaseptal region have also been reported as potential arrhythmogenic substrates. However, there is insufficient clinical evidence. Pulmonary vein (PV) potentials are invariably recordable at the PV ostia in patients with AF, and delayed conduction around the PV ostia may play a role in the initiation and maintenance of AF. Objectives: 1) To find clinical evidence for the atrial remodelling in patients with chronic and paroxysmal AF; 2) to delineate the electrophysiological properties of transseptal conduction from the left to the right atrium in patients with paroxysmal AF; 3) to analyze the conduction velocities across the coronary sinus (CS) ostium (cross-CS ostium) and within the coronary sinus (intra-CS) in patients with and without paroxysmal AF; and 4) to investigate the presence and extent of PV potentials in patients without AF. Methods: Study I: To estimate the refractoriness of the atrium during AF, monophasic action potentials (MAPs) were recorded during AF from 1?3 sites in the right atrium in 7 patients with chronic AF (CAF) and in 11 patients with paroxysmal AF (PAF). The fibrillatory (FF) interval between two consecutive upstrokes of the MAP was measured. The mean, median, 15th, 10th, and 5th percentile and the shortest FF intervals were calculated in each patient and used as estimates of the local atrial effective refractory period (AERP) during AF. In 9 patients, AERP was also tested using the extra stimulus technique during sinus rhythm. Study II: To evaluate the left-to-right transseptal conduction, right atrial mapping using the CARTO electroanatomic mapping system was performed at 111 ? 16 sites during pacing from the distal CS in 16 patients with paroxysmal AF. Activation maps of the right atrium were obtained from all patients and the earliest breakthrough site was identified. The conduction times from the pacing site 1) to the earliest activation site of the septum, 2) to CS ostium, 3) to the presumed insertion of Bachmann's bundle, 4) the total septal activation time, and 5) the total right atrial activation time. Study III: To study the conduction delay across the CS ostium, the activation times and spatial distances of cross-CS ostium and intra-CS were measured between 5?11 paired sites, from which the activation velocities of cross-CS ostium and intra-CS were obtained in 13 patients with paroxysmal AF and 10 control patients with AV nodal re-entry tachycardia or ectopic atrial tachycardia, using the CARTO electroanatomic mapping system. Study IV: Circumferential catheter recordings at the PV ostia were obtained from 10 patients with paroxysmal AF and 9 with concealed WPW syndrome without any history of AF. Typical PV potential was defined as either rapid deflections that were separate from local atrial deflection with a time delay in between, or continuous, fractionated potentials that were not separate from the atrial deflection. The existence of PV potentials was verified during sinus rhythm and during atrial pacing at the distal CS for the left PVs or at the right atrial appendage for the right PVs. To quantify the extent to which the PV potentials were recordable, the number of PVs with typical PV potentials for each PV and for each patient was counted. The time interval from the onset to the end of the electrograms recordable at the PV ostium (A-PV interval) was measured, and the maximum and mean of these intervals were obtained. Results: Study I: Thirty-eight MAP recordings were obtained. The shortest FF interval during AF was significantly shorter in patients with chronic AF than in patients with paroxysmal AF (50±13 vs. 72±31 ms, p 0.05) during sinus rhythm and distal CS pacing. Study IV: Typical PV potentials were recorded in 31 of 34 PVs (91%) in patients with AF, but in 4 of 36 PVs (11.1%) in patients with concealed WPW syndrome. A simple, narrow potential was recorded in 3/34 PVs (9%) in patients with AF, but in 29/36 (81%) PVs in patients with concealed WPW syndrome. The maximal and mean A-PV intervals were significantly longer in patients with AF (71±24 and 49±13 ms, respectively) than in patients with concealed WPW syndrome (33±14 and 25±6 ms). Conclusions: Electrical remodelling of the atrial myocardium is more marked in patients with chronic AF than in patients with paroxysmal AF. The AERP was significantly shortened during AF as compared to that during sinus rhythm, and the AERP shortening was more marked in patients with chronic AF than in patients with paroxysmal AF. These clinical findings support the connection between the electrical remodelling and the occurrence and/or perpetuation of the AF. The preferential site of transseptal conduction during distal CS pacing is near the CS ostium in patients with paroxysmal AF. This has clinical implications when surgical dissection or catheter ablation is considered to eliminate interatrial connection in patients with AF. Interatrial conduction at the postero-paraseptal region across the CS ostium was significantly slower in patients with paroxysmal AF than in control patients, further supporting the link between interatrial conduction deterioration and paroxysmal AF. In patients with AF, typical PV potentials with marked conduction time delay were almost invariably recordable at the PV ostium; but in patients without any history of AF, merely simple, narrow potentials were found. These findings support the involvement of conduction delay and re-entrant activities around the PV ostia in the genesis and/or perpetuation of AF

The cost-effectiveness of biological therapy cycles in the management of Crohn’s disease

Objectives: to examine the cost-effectiveness of continued treatment for patients with moderate-severe Crohn’s disease in clinical remission, with a combination of anti-TNFα (infliximab) and immunosuppressant therapy compared to two different withdrawal strategies (1) withdrawal of the anti-TNFα therapy, and (2) withdrawal of the immunosuppressant therapy, respectively. Material and methods: A decision-tree model (Markov type) was constructed mimicking three treatment arms: (1) continued combination therapy with infliximab and antimetabolites, (2) withdrawal of infliximab, or (3) withdrawal of the immunosuppressant. Relapses in each arm are managed with treatment intensification. State dependent relapse risks, remission probabilities and quality of life weights were collected from previous published studies. Results: Combination therapy was less costly and more efficient than the withdrawal of the immunosuppressant, and more costly and more efficient than withdrawal of infliximab. The incremental cost-effectiveness ratio for the combination therapy compared with withdrawal of infliximab was estimated at SEK 755 449 per additional QALY. This is well above the informal willingness-to-pay threshold in Sweden (500 000 SEK/QALY). The estimated cost-effectiveness of the combination therapy was found highly sensitive to the unit cost of infliximab; at a 36% lower unit cost of infliximab, the combination treatment would become cost-effective. The qualitative content of these results were quite robust to changes in the clinical effectiveness and the quality-of-life figures adopted in the calculations. The qualitative content of these results were quite robust to changes in the clinical effectiveness and quality-of-life values. Conclusions: Combination therapy using a combination of anti-TNFα (infliximab) and immunosuppressant is cost effective in the treatment of Crohn’s disease compared to treatment cycles in which the immunosuppressant is withdrawn. Combination treatment is not cost effective compared to treatment cycles in which infliximab is withdrawn, at current pharmaceutical prices.I