Early onset and progression of left ventricular remodeling after alcohol septal ablation in hypertrophic obstructive cardiomyopathy

Background - Alcohol septal ablation (ASA) reduces left ventricular outflow tract (LVOT) pressure gradient in patients with hypertrophic obstructive cardiomyopathy (HOCM), which leads to left ventricular remodeling. We sought to describe the early to midterm changes and modulating factors of the remodeling process using cardiac MRI (CMR). Methods and Results - CMR was performed at baseline and 1 and 6 months after ASA in 29 patients with HOCM (age 52±16 years). Contrast-enhanced CMR showed no infarct-related hyperenhancement outside the target septal area. Septal mass decreased from 75±23 g at baseline to 68±22 and 58±19 g (P<0.001) at 1- and 6-month follow-up, respectively. Remote, nonseptal mass decreased from 141±41 to 132±40 and 111±27 g (P<0.001), respectively. Analysis of temporal trends revealed that septal mass reduction was positively associated with contrast-enhanced infarct size and transmural or left-sided septal infarct location at both 1 and 6 months. Remote mass reduction was associated with infarct location at 6 months but not with contrast-enhanced infarct size. By linear regression analysis, percentage remote mass reduction correlated significantly with LVOT gradient reduction at 6-month follow-up (P=0.03). Conclusions - Left ventricular remodeling after ASA occurs early and progresses on midterm follow-up, modulated by CMR infarct size and location. Remote mass reduction is associated with infarct location and correlates with reduction of the LVOT pressure gradient. Thus, myocardial hypertrophy in HOCM is, at least in part, afterload dependent and reversible and is not exclusively caused by the genetic disorder

A family history of breast cancer will not predict female early onset breast cancer in a population-based setting

ABSTRACT: BACKGROUND: An increased risk of breast cancer for relatives of breast cancer patients has been demonstrated in many studies, and having a relative diagnosed with breast cancer at an early age is an indication for breast cancer screening. This indication has been derived from estimates based on data from cancer-prone families or from BRCA1/2 mutation families, and might be biased because BRCA1/2 mutations explain only a small proportion of the familial clustering of breast cancer. The aim of the current study was to determine the predictive value of a family history of cancer with regard to early onset of female breast cancer in a population based setting. METHODS: An unselected sample of 1,987 women with and without breast cancer was studied with regard to the age of diagnosis of breast cancer. RESULTS: The risk of early-onset breast cancer was increased when there were: (1) at least 2 cases of female breast cancer in first-degree relatives (yes/no; HR at age 30: 3.09; 95% CI: 128-7.44), (2) at least 2 cases of female breast cancer in first or second-degree relatives under the age of 50 (yes/no; HR at age 30: 3.36; 95% CI: 1.12-10.08), (3) at least 1 case of female breast cancer under the age of 40 in a first- or second-degree relative (yes/no; HR at age 30: 2.06; 95% CI: 0.83-5.12) and (4) any case of bilateral breast cancer (yes/no; HR at age 30: 3.47; 95%: 1.33-9.05). The positive predictive value of having 2 or more of these characteristics was 13% for breast cancer before the age of 70, 11% for breast cancer before the age of 50, and 1% for breast cancer before the age of 30. CONCLUSION: Applying family history related criteria in an unselected population could result in the screening of many women who will not develop breast cancer at an early age

Reduced Vitamin K Status as a Potentially Modifiable Risk Factor of Severe Coronavirus Disease 2019

BACKGROUND: Respiratory failure and thromboembolism are frequent in SARS-CoV-2-infected patients. Vitamin K activates both hepatic coagulation factors and extrahepatic endothelial anticoagulant protein S, required for thrombosis prevention. In times of vitamin K insufficiency, hepatic procoagulant factors are preferentially activated over extrahepatic proteins. Vitamin K also activates matrix Gla protein (MGP), which protects against pulmonary and vascular elastic fiber damage. We hypothesized that vitamin K may be implicated in coronavirus disease 2019 (COVID-19), linking pulmonary and thromboembolic disease. METHODS: 135 hospitalized COVID-19 patients were compared with 184 historical controls. Poor outcome was defined as invasive ventilation and/or death. Inactive vitamin K-dependent MGP (dp-ucMGP) and prothrombin (PIVKA-II) were measured, inversely related to extrahepatic and hepatic vitamin K status, respectively. Desmosine was measured to quantify the rate of elastic fiber degradation. Arterial calcification severity was assessed by computed tomography. RESULTS: Dp-ucMGP was elevated in COVID-19 patients compared to controls (p<0.001), with even higher dp-ucMGP in patients with poor outcomes (p<0.001). PIVKA-II was normal in 82.1% of patients. Dp-ucMGP was correlated with desmosine (p<0.001), and coronary artery (p=0.002) and thoracic aortic (p<0.001) calcification scores. CONCLUSIONS: Dp-ucMGP was severely increased in COVID-19 patients, indicating extrahepatic vitamin K insufficiency, which was related to poor outcome while hepatic procoagulant factor II remained unaffected. These data suggest a mechanism of pneumonia-induced extrahepatic vitamin K depletion leading to accelerated elastic fiber damage and thrombosis in severe COVID-19 due to impaired activation of MGP and endothelial protein S, respectively. A clinical trial could assess whether vitamin K administration improves COVID-19 outcomes

pharmacist; F.W. Snel, MSc, resident in rheumatology

ABSTRACT. Objective. To determine whether a double dose of intraarticular triamcinolone acetonide is more effective for knee arthritis than a 40-mg dose. Methods. In this 12-week randomized controlled clinical trial, 40 mg and 80 mg of intraarticular triamcinolone acetonide were compared in patients with knee arthritis. Evaluated variables included a Likert burden scale, visual analog scale pain scale, degree of arthritis activity, presence of swelling, and presence of functional limitation. Results. Ninety-seven patients were randomized. No significant differences were observed between the groups regarding any outcomes. Conclusion. An 80-mg dose of triamcinolone acetonide had no additional benefit compared with 40 mg as treatment for knee arthritis. Popma, MSc, clinical pharmacist; F.W. Snel, MSc, resident in rheumatology; C.J. Haagsma, PhD, rheumatologist; P. BrummelhuisVisser, MSc, clinical pharmacist; H.G. Oldenhof, MSc, clinical pharmacist, Ziekenhuisgroep Twente; J. van der Palen, PhD, clinical epidemiologist, M.A. van de Laar, PhD, rheumatologist, Medisch Spectrum Twente. Address correspondence to F.W. Snel, Zwolsedijk 3, 8061 RE, Hasselt, the Netherlands. E-mail: [email protected] Accepted for publication June 3, 2015. Intraarticular corticosteroid injections are a widely used and recommended therapy for either rheumatoid arthritis (RA) or osteoarthritis (OA) 1,2 . Side effects are mainly related to discomfort from the procedure, localized pain post injection, and flushing 3 . The knee injection is the best studied intraarticular injection Because side effects are not an important issue of corticosteroid injections, the main problem is degree and duration of response. We hypothesized that a higher amount of corticosteroid in the target compartment could be related to a greater relief of symptoms and a prolonged local effect. The main objective of our study was to investigate whether a higher dose of intraarticular corticosteroid was related to greater symptomatic relief than a conventional dose as treatment for knee arthritis. MATERIALS AND METHODS We conducted a double-blind, randomized, controlled clinical trial in which a usual dose of 40 mg intraarticular triamcinolone acetonide was compared with a double dose of 80 mg as treatment for knee arthritis. Patients. Adult patients with symptomatic synovitis of 1 knee and having an indication for intraarticular corticosteroid injection, at the discretion of the attending rheumatologist, were consecutively enrolled. Symptomatic was defined as a score of at least 3 on a 5-point Likert patient scale for burden of arthritis symptoms. An additional inclusion criterion was the use of stable antirheumatic medication. Exclusion criteria were the diagnosis of gout, contraindications for intraarticular corticosteroid injection, and use of more than 10 mg prednisone daily. Study design. This was a 12-week multicenter, double-blind, randomized, controlled clinical trial at 2 investigational centers. Patients were randomly assigned to either the low-dose group (40 mg triamcinolone acetonide) or the high-dose group (80 mg). Randomization was achieved by means of a randomization list stratified by hospital, based on a random number generator. The injections were prepared by an independent research nurse in a separate room. No anesthetics were added. All syringes had a volume of 2 ml and the content of all syringes was visually concealed, thereby ensuring complete blinding for patient and rheumatologist. At baseline the following variables were recorded: type of underlying rheumatic condition [RA, psoriatic arthritis (PsA), other (including OA), unknown], duration of the knee arthritis, a 5-point Likert patient scale for burden of arthritis symptoms (none, little, moderate, much, very much), a patient 100-mm visual analog scale (VAS) for pain, a 5-point scale for arthritis activity (none, mild, moderate, active, very active) by the attending rheumatologist, as well as presence of swelling and functional limitation (defined as an inability to extend 0°). During the procedure of injection, the volume of aspirated knee joint fluid was measured. After assessment of baseline variables, the rheumatologist performed the injection. Once weekly, up to Week 12, patients completed a questionnaire with the Likert scale and the VAS, as described. At Week 12, during the second visit to the clinic, the following variables were recorded by the rheumatologist: a 5-point scale for arthritis activity, presence of swelling, and presence of functional limitation. Our 5-point Likert patient scale is analogous to the target joint pain score (pain of a 5-point Likert patient scale), which proved to be a reliable single-joint outcome measure for determining response in inflammatory arthritis 9 . The primary endpoint was the percentage of patients with good response, which was defined as a positive change ≥ 2 points on the 5-point Likert scale for burden from baseline at weeks 11 and 12. The main secondary outcomes were the courses over time of Likert burden scores and VAS pain scores. Other secondary outcomes were, at Week 12, the percentages of patients with no arthritis activity on the 5-point scale, loss of swelling, and normalization of functional limitation. Patient data were excluded for the primary endpoint and other 12-week outcomes when, during the study, patients received an additional intraarticular injection, antirheumatic medication was altered, or knee surgery was performed. Data until the moment of exclusion were used for analysis. Statistical analysis. Analyses were performed using SPSS Version 22.0. A p &lt; 0.05 was considered statistically significant. We postulated that a 30% difference on the primary endpoint would be clinically significant. Assuming that the proportion of good responders would be 30% in the control group of 40 mg, using a 5% significance level and 80% power, 42 patients were needed in each treatment group. The independent samples t test and Wilcoxon rank-sum test were used for, respectively, normally and non-normally distributed continuous variables. The chi-square test (or Fisher&apos;s exact test) was used for dichotomous variables. Repeated measurements analyses were performed for comparison of Likert burden scores and VAS pain scores over time. The McNemar test was performed for analysis of improvement of both swelling and functional limitation. Our study was approved by the Medical Ethical Committee Twente in Enschede, the Netherlands. All patients provided written informed consent. RESULTS Study population. Ninety-seven patients (mean age 58 yrs, 41% male) were included and randomized. Baseline characteristics are presented in Outcomes. There was no difference between the groups on the primary endpoint, with 49% good responders in the 40-mg group and 55% in the 80-mg group (p = 0.586). Both groups showed rapid response to the injection, with good response at Week 1 in more than half of patients in both groups (data not shown). The courses of Likert burden scores and VAS pain scores over time are displayed in No significant differences were observed concerning good response at Week 12 regarding arthritis activity, presence of swelling, and presence of functional limitation DISCUSSION Our study demonstrated no difference in efficacy between 40-mg and 80-mg doses of intraarticular triamcinolone acetonide for knee arthritis during a 12-week followup. This suggests that both doses are in the plateau phase of the dose-response relationship of intraarticular triamcinolone acetonide. Combining our results with preceding studies suggests that the dose-response relationship is linear up to 40 mg of corticosteroid, followed by a plateau phase with higher dosages 10,11 . Our study is the first, to our knowledge, to compare 40 mg and 80 mg of the same corticosteroid for knee arthritis. It is in line with the study by Robinson, et al, comparing 40 mg and 80 mg of methylprednisolone for hip OA, but we also studied arthritis due to rheumatic conditions other than OA 8 . The 5-point Likert patient scale for burden of arthritis symptoms was chosen as primary outcome because the primary goal of intraarticular corticosteroid treatment is symptom reduction, and this is best reflected by a patient score. The classification of a beneficial change ≥ 2 points a

Early and long-term outcome of elective stenting of the infarct-related artery in patients with viability in the infarct-area: Rationale and design of the Viability-guided Angioplasty after acute Myocardial Infarction-trial (The VIAMI-trial)

BACKGROUND: Although percutaneous coronary intervention (PCI) is becoming the standard therapy in ST-segment elevation myocardial infarction (STEMI), to date most patients, even in developed countries, are reperfused with intravenous thrombolysis or do not receive a reperfusion therapy at all. In the post-lysis period these patients are at high risk for recurrent ischemic events. Early identification of these patients is mandatory as this subgroup could possibly benefit from an angioplasty of the infarct-related artery. Since viability seems to be related to ischemic adverse events, we initiated a clinical trial to investigate the benefits of PCI with stenting of the infarct-related artery in patients with viability detected early after acute myocardial infarction. METHODS: The VIAMI-study is designed as a prospective, multicenter, randomized, controlled clinical trial. Patients who are hospitalized with an acute myocardial infarction and who did not have primary or rescue PCI, undergo viability testing by low-dose dobutamine echocardiography (LDDE) within 3 days of admission. Consequently, patients with demonstrated viability are randomized to an invasive or conservative strategy. In the invasive strategy patients undergo coronary angiography with the intention to perform PCI with stenting of the infarct-related coronary artery and concomitant use of abciximab. In the conservative group an ischemia-guided approach is adopted (standard optimal care). The primary end point is the composite of death from any cause, reinfarction and unstable angina during a follow-up period of three years. CONCLUSION: The primary objective of the VIAMI-trial is to demonstrate that angioplasty of the infarct-related coronary artery with stenting and concomitant use of abciximab results in a clinically important risk reduction of future cardiac events in patients with viability in the infarct-area, detected early after myocardial infarction

Modulation of Serotonin Transporter Function during Fetal Development Causes Dilated Heart Cardiomyopathy and Lifelong Behavioral Abnormalities

BACKGROUND: Women are at great risk for mood and anxiety disorders during their childbearing years and may become pregnant while taking antidepressant drugs. In the treatment of depression and anxiety disorders, selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed drugs, while it is largely unknown whether this medication affects the development of the central nervous system of the fetus. The possible effects are the product of placental transfer efficiency, time of administration and dose of the respective SSRI. METHODOLOGY/PRINCIPAL FINDINGS: In order to attain this information we have setup a study in which these parameters were measured and the consequences in terms of physiology and behavior are mapped. The placental transfer of fluoxetine and fluvoxamine, two commonly used SSRIs, was similar between mouse and human, indicating that the fetal exposure of these SSRIs in mice is comparable with the human situation. Fluvoxamine displayed a relatively low placental transfer, while fluoxetine showed a relatively high placental transfer. Using clinical doses of fluoxetine the mortality of the offspring increased dramatically, whereas the mortality was unaffected after fluvoxamine exposure. The majority of the fluoxetine-exposed offspring died postnatally of severe heart failure caused by dilated cardiomyopathy. Molecular analysis of fluoxetine-exposed offspring showed long-term alterations in serotonin transporter levels in the raphe nucleus. Furthermore, prenatal fluoxetine exposure resulted in depressive- and anxiety-related behavior in adult mice. In contrast, fluvoxamine-exposed mice did not show alterations in behavior and serotonin transporter levels. Decreasing the dose of fluoxetine resulted in higher survival rates and less dramatic effects on the long-term behavior in the offspring. CONCLUSIONS: These results indicate that prenatal fluoxetine exposure affects fetal development, resulting in cardiomyopathy and a higher vulnerability to affective disorders in a dose-dependent manner

Treatment outcome of intravenous artesunate in patients with severe malaria in the Netherlands and Belgium

<p>Abstract</p> <p>Background</p> <p>Intravenous (IV) artesunate is the treatment of choice for severe malaria. In Europe, however, no GMP-manufactured product is available and treatment data in European travellers are scarce. Fortunately, artesunate became available in the Netherlands and Belgium through a named patient programme. This is the largest case series of artesunate treated patients with severe malaria in Europe.</p> <p>Methods</p> <p>Hospitalized patients treated with IV artesunate between November 2007 and December 2010 in the Netherlands and Belgium were retrospectively evaluated. Patient characteristics, treatment and clinical outcome were recorded on a standardized form and mortality, parasite clearance times and the occurrence of adverse events were evaluated.</p> <p>Results</p> <p>Of the 68 treated patients, including 55 with severe malaria, two patients died (2/55 = 3.6%). The mean time to 50% parasite clearance (PCT50), 90% and 99% were 4.4 hours (3.9 - 5.2), 14.8 hours (13.0 - 17.2), and 29.5 hours (25.9 - 34.4) respectively. Artesunate was well tolerated. However, an unusual form of haemolytic anaemia was observed in seven patients. The relationship with artesunate remains uncertain.</p> <p>Conclusions</p> <p>Data from the named patient programme demonstrate that IV artesunate is effective and well-tolerated in European travellers lacking immunity. However, increased attention needs to be paid to the possible development of haemolytic anaemia 2-3 weeks after start of treatment.</p> <p>Treatment of IV artesunate should be limited to the period that IV treatment is required and should be followed by a full oral course of an appropriate anti-malarial drug.</p

Radiofrequency Ablation vs Endoscopic Surveillance for Patients With Barrett Esophagus and Low-Grade Dysplasia: A Randomized Clinical Trial

Importance Barrett esophagus containing low-grade dysplasia is associated with an increased risk of developing esophageal adenocarcinoma, a cancer with a rapidly increasing incidence in the western world.Objective To investigate whether endoscopic radiofrequency ablation could decrease the rate of neoplastic progression.Design, Setting, and Participants Multicenter randomized clinical trial that enrolled 136 patients with a confirmed diagnosis of Barrett esophagus containing low-grade dysplasia at 9 European sites between June 2007 and June 2011. Patient follow-up ended May 2013.Interventions Eligible patients were randomly assigned in a 1:1 ratio to either endoscopic treatment with radiofrequency ablation (ablation) or endoscopic surveillance (control). Ablation was performed with the balloon device for circumferential ablation of the esophagus or the focal device for targeted ablation, with a maximum of 5 sessions allowed.Main Outcomes and Measures The primary outcome was neoplastic progression to high-grade dysplasia or adenocarcinoma during a 3-year follow-up since randomization. Secondary outcomes were complete eradication of dysplasia and intestinal metaplasia and adverse events.Results Sixty-eight patients were randomized to receive ablation and 68 to receive control. Ablation reduced the risk of progression to high-grade dysplasia or adenocarcinoma by 25.0% (1.5% for ablation vs 26.5% for control; 95% CI, 14.1%-35.9%; P