Outcome of transcatheter atrial septal defect closure in a nationwide cohort.

BACKGROUND: Transcatheter (TC) atrial septal defect (ASD) closure has been the mainstay of therapy for secundum-type ASDs for over 20 years. AIMS: This nationwide cohort evaluated the long-term outcome of transcatheter-closed ASDs. METHODS: The study enrolled every transcatheter ASD closure performed in Finland from 1999 to 2019. Five age, sex, and municipality-matched controls per ASD patient were gathered from the general population. The median follow-up period was 5.9 years (range 0-20.8). We used the hospital discharge register to gather all hospital visits and diagnoses. Closure complications and echocardiographic changes were collected from the electronic health records. RESULTS: Transcatheter ASD closure was performed in 1000 patients (68.5% females) during the study period. The median (range) age at the time of the procedure was 37.9 (1.8-87.5) years. ASD patients had an increased risk for new-onset atrial fibrillation (RR 2.45, 95% CI: 1.84-3.25), migraine (RR 3.61, 95% CI: 2.54-5.14), ischemic heart disease (RR 1.73, 95% CI: 1.23-2.45), ventricular fibrillation/tachycardia (RR 3.54 (95% CI: 1.48-8.43) and AV conduction disorder (RR 3.60, 95% CI: 1.94-6.70) compared to the control cohort. Stroke risk was not increased (RR 1.36, 95% CI: 0.91-2.03). Adverse events occurred in 6.3% (n = 63) of the patients, including four erosions and ten device embolizations. CONCLUSION: After TC closure of ASD, patients had a higher risk of new-onset atrial fibrillation and migraine than controls without ASD. As novel findings, we found an increased risk for ischemic heart disease, AV conduction disorders, and ventricular fibrillation/tachycardia.Key messagesEven though patients have an excellent overall prognosis after percutaneous ASD closure, the increased incidence of major comorbidities like atrial fibrillation and heart failure prompts more thorough lifelong follow-up.This study's novel findings revealed the increased risk for ischemic heart disease, AV conduction disorders, or ventricular tachycardia/fibrillation during the follow-up.Major complications after the closure are rare; erosion is seen in 0.4% of the patients and embolization in 1.0% of the patients.

Comparative transcriptome analysis of matched primary and distant metastatic ovarian carcinoma.

BACKGROUND: High grade serous ovarian carcinoma (HGSOC) is the most common subtype of epithelial ovarian cancers (EOC) with poor prognosis. In most cases EOC is widely disseminated at the time of diagnosis. Despite the optimal cytoreductive surgery and chemotherapy most patients develop chemoresistance, and the 5-year overall survival being only 25-35%. METHODS: Here we analyzed the gene expression profiles of 10 primary HGSOC tumors and 10 related omental metastases using RNA sequencing and identified 100 differentially expressed genes. RESULTS: The differentially expressed genes were associated with decreased embryogenesis and vasculogenesis and increased cellular proliferation and organismal death. Top upstream regulators responsible for this gene signature were NR5A1, GATA4, FOXL2, TP53 and BMP7. A subset of these genes were highly expressed in the ovarian cancer among the cancer transcriptomes of The Cancer Genome Atlas. Importantly, the metastatic gene signature was suggestive of poor survival in TCGA data based on gene enrichment analysis. CONCLUSION: By comparing the gene expression profiles of primary HGSOC tumors and their matched metastasis, we provide evidence that a signature of 100 genes is able to separate these two sample types and potentially predict patient survival. Our study identifies functional categories of genes and transcription factors that could play important roles in promoting metastases and serve as markers for cancer prognosis.

Wrist band photoplethysmography in detection of individual pulses in atrial fibrillation and algorithm-based detection of atrial fibrillation.

AIMS: Atrial fibrillation (AF) is the most common tachyarrhythmia and a significant cause of cardioembolic strokes. Atrial fibrillation is often intermittent and asymptomatic making detection a major clinical challenge. We evaluated a photoplethysmography (PPG) wrist band in individual pulse detection in patients with AF and tested the reliability of two commonly used algorithms for AF detection. METHODS AND RESULTS: A 5-min PPG was recorded from patients with AF or sinus rhythm (SR) with a wrist band and analysed with two AF detection algorithms; AFEvidence and COSEn. Simultaneously registered electrocardiogram served as the golden standard for rhythm analysis and was interpreted by two cardiologists. The study population consisted of 213 (106 AF, 107 SR) patients. The wrist band PPG achieved individual pulse detection with a sensitivity of 91.7 ± 11.2% and a positive predictive value (PPV) of 97.5 ± 4.6% for AF, with a sensitivity of 99.4 ± 1.5% [7.7% (95% confidence interval, 95% CI 5.5% to 9.9%); P < 0.001] and PPV of 98.1 ± 4.1% [0.6% (95% CI -0.6% to 1.7%); P = 0.350] for SR. The pulse detection sensitivity was lower 86.7 ± 13.9% with recent-onset AF (AF duration <48 h, n = 43, 40.6%) as compared to late AF (≥48 h, n = 63, 59.4%) with 95.1 ± 7.2% [-8.3% (95% CI -12.9% to -3.7%); P = 0.001]. For the detection of AF from the wrist band PPG, the sensitivities were 96.2%/95.3% and specificity 98.1% with two algorithms. CONCLUSION: The wrist band PPG enabled accurate algorithm-based detection of AF with two AF detection algorithms and high individual pulse detection. Algorithms allowed accurate detection of AF from the PPG. A PPG wrist band provides an easy solution for AF screening.

Stroke recurrence in patients with atrial fibrillation: concomitant carotid artery stenosis doubles the risk.

BACKGROUND AND PURPOSE: Atrial fibrillation (AF) and significant carotid artery stenosis (CAS) often coexist in patients with acute stroke but whether CAS affects the stroke recurrence rate in anticoagulated AF patients is largely unknown. The effect of concomitant CAS on both short- and long-term prognosis after stroke in patients with AF was evaluated. METHODS: The multicentre, retrospective FibStroke registry included AF patients with an ischaemic stroke or transient ischaemic attack (TIA) during 2003-2012. In this sub-study, 165 AF patients with ischaemic stroke or TIA with significant (>50%) CAS (CAS group) and 734 AF patients without CAS (non-CAS group) were identified. The median follow-up time after an index event was 3.5 (interquartile range 3.9) years. Long-term stroke recurrence rate, 30-day mortality, CHA2 DS2 -VASc score, other risk factors and the use and intensity of anticoagulation were assessed. RESULTS: The recurrence rate of ischaemic stroke (21.2% vs. 12.7%, P = 0.005, 8.1 vs. 3.6 events per100 follow-up years) was significantly higher in CAS patients compared to the non-CAS group despite similar anticoagulation/antithrombotic therapy. CAS patients had higher mean CHA2 DS2 -VASc scores than non-CAS patients (4.3 vs. 3.3, P < 0.001). However, in a multivariate analysis CAS was shown to be an independent risk factor for stroke recurrence (hazard ratio 2.02, 95% confidence interval 1.37-3.01, P = 0.001). The 30-day all-cause mortality was significantly higher in CAS patients (7.9% vs. 1.9%, P < 0.001) and CAS was an independent risk factor also for 30-day mortality (odds ratio 3.34, 95% confidence interval 1.51-7.38, P = 0.003). CONCLUSIONS: In patients with AF, concomitant CAS was an independent risk factor for both long-term stroke recurrence and 30-day mortality.

Underuse of anticoagulation in stroke patients with atrial fibrillation--the FibStroke Study.

BACKGROUND AND PURPOSE: Current guidelines recommend oral anticoagulation (OAC) for patients with atrial fibrillation (AF) and increased risk of thromboembolic events. The reasons for not using OAC in AF patients suffering stroke or transient ischaemic attack (TIA) were assessed. METHODS: This retrospective registry included 3404 patients with previously diagnosed AF who suffered a total of 2955 ischaemic strokes and 895 TIAs during 2003-2012. RESULTS: A CHA2DS2-VASc score ≥2 and a CHADS2 score ≥2 was observed in 3590 (93.2%) and in 2784 (72.3%) of the events, respectively. Of the high-risk patients (CHADS2 ≥2) only 55.1% were on OAC before the onset of stroke or TIA. The most frequently documented reasons for withholding OAC were infrequent paroxysms of AF (14%), previous bleeding episodes (13%) and the patient's decline/independent discontinuation of treatment (9%). Moreover, patients with paroxysmal AF (40% using OAC), previous bleeding (26% using OAC) and alcohol abuse (30% using OAC) were using OAC significantly less often than patients without these characteristics. A significant increase in the proportion of high-risk patients using OAC from 49% in 2003 to 65% in 2012 was seen. CONCLUSIONS: Underuse of anticoagulation is a common contributor to ischaemic strokes and TIA episodes in patients with AF. Infrequent AF episodes, previous bleeds, patient preference and alcohol abuse were the most common reasons for not using OAC.

Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation: results on health-related quality of life and symptom burden. The MANTRA-PAF trial.

AIMS: The Medical ANtiarrhythmic Treatment or Radiofrequency Ablation in Paroxysmal Atrial Fibrillation (MANTRA-PAF) trial assessed the long-term efficacy of an initial strategy of radiofrequency ablation (RFA) vs. antiarrhythmic drug therapy (AAD) as first-line treatment for patients with PAF. In this substudy, we evaluated the effect of these treatment modalities on the Health-Related Quality of Life (HRQoL) and symptom burden of patients at 12 and 24 months. METHODS AND RESULTS: During the study period, 294 patients were enrolled in the MANTRA-PAF trial and randomized to receive AAD (N = 148) or RFA (N = 146). Two generic questionnaires were used to assess the HRQoL [Short Form-36 (SF-36) and EuroQol-five dimensions (EQ-5D)], and the Arrhythmia-Specific questionnaire in Tachycardia and Arrhythmia (ASTA) was used to evaluate the symptoms appearing during the trial. All comparisons were made on an intention-to-treat basis. Both randomization groups showed significant improvements in assessments with both SF-36 and EQ-5D, at 24 months. Patients randomized to RFA showed significantly greater improvement in four physically related scales of the SF-36. The three most frequently reported symptoms were breathlessness during activity, pronounced tiredness, and worry/anxiety. In both groups, there was a significant reduction in ASTA symptom index and in the severity of seven of the eight symptoms over time. CONCLUSION: Both AAD and RFA as first-line treatment resulted in substantial improvement of HRQoL and symptom burden in patients with PAF. Patients randomized to RFA showed greater improvement in physical scales (SF-36) and the EQ-visual analogue scale. CLINICAL TRIAL REGISTRATION: URL http://www.clinicaltrials.gov. Unique identifier: NCT00133211.

Finnish Fanconi anemia mutations and hereditary predisposition to breast and prostate cancer.

Mutations in downstream Fanconi anemia (FA) pathway genes, BRCA2, PALB2, BRIP1 and RAD51C, explain part of the hereditary breast cancer susceptibility, but the contribution of other FA genes has remained questionable. Due to FA's rarity, the finding of recurrent deleterious FA mutations among breast cancer families is challenging. The use of founder populations, such as the Finns, could provide some advantage in this. Here, we have resolved complementation groups and causative mutations of five FA patients, representing the first mutation confirmed FA cases in Finland. These patients belonged to complementation groups FA-A (n = 3), FA-G (n = 1) and FA-I (n = 1). The prevalence of the six FA causing mutations was then studied in breast (n = 1840) and prostate (n = 565) cancer cohorts, and in matched controls (n = 1176 females, n = 469 males). All mutations were recurrent, but no significant association with cancer susceptibility was observed for any: the prevalence of FANCI c.2957_2969del and c.3041G>A mutations was even highest in healthy males (1.7%). This strengthens the exclusive role of downstream genes in cancer predisposition. From a clinical point of view, current results provide fundamental information of the mutations to be tested first in all suspected FA cases in Finland.

Assessment of myocardial perfusion with MRI using a modified dual bolus method.

Quantification of regional myocardial blood flow (rMBF) with first-pass magnetic resonance imaging (FP-MRI) requires two contrast agent injections (dual bolus technique), inducing error in the determined rMBF if the injections differ. We hypothesize that using input and residue curves of the same injection would be more reliable. We aim to introduce and evaluate a novel method to correct the high concentration arterial input function (AIF) for determination of rMBF. Sixteen patients with non-Hodgkin's lymphoma were examined before and after chemotherapy. The input function was solved by correcting initial high concentration AIF using the ratio of low and high contrast AIF areas, normalized by corresponding heart rates (modified dual bolus method). For comparison, the scaled low contrast AIF was used as an input function (dual bolus method). Unidirectional transfer coefficient K(trans) was calculated using both methods. K(trans)-values determined with the dual bolus (0.81 ± 0.32 ml g(-1) min(-1)) and modified dual bolus (0.77 ± 0.42 ml g(-1) min(-1)) methods were in agreement (p = 0.21). Mean K(trans)-values increased from 0.76 ± 0.43 to 0.89 ± 0.55 ml g(-1) min(-1) after chemotherapy (p = 0.17). The modified dual bolus technique agrees with the dual bolus technique (R2 = 0.899) when the low and high contrast injections are similar. However, when this is not the case, the modified dual bolus technique may be more reliable.

Preventive strategies for atrial fibrillation after cardiac surgery in Nordic countries.

BACKGROUND AND AIMS: Atrial fibrillation is a common arrhythmia after cardiac surgery. It increases morbidity, length of hospital stay, and costs of operative treatment. Beta-blockers, sotalol, amiodarone, corticosteroids, and biatrial pacing have been shown to be efficient in the prevention of postoperative atrial fibrillation. The aim of this study was to find out how widely different prophylactic strategies for postoperative atrial fibrillation are used in Scandinavian countries. MATERIAL AND METHODS: An online link for a questionnaire was emailed to (214) cardiac surgeons in Finland, Sweden, Norway, Denmark, and Estonia to assess the use of prophylactic methods for postoperative atrial fibrillation. RESULTS: A total of 97 surgeons responded to the survey. Oral beta-blockers were routinely used for atrial fibrillation prophylaxis by 62% of responders. The main reasons for nonuse of beta-blockers were that responders were unconvinced of the evidence of benefit or they preferred some alternative prophylaxis. Intravenous beta-blockers were used frequently by 6% of responders. Amiodarone was used for prophylaxis by 18% of responders. Nonusers were unconvinced of its efficacy, were afraid of its complications, or found its use too cumbersome. Other prophylactic atrial fibrillation strategies that were used are as follows: sotalol by 2%, magnesium by 17%, corticosteroids by 1%, and atrial pacing by 11% of respondents. CONCLUSIONS: There is still widely varying implementation of strategies for atrial fibrillation prophylaxis among Scandinavian cardiac surgeons. Lack of confidence in the efficacy of these approaches is the main rationale for nonimplementation.

Intravenous metoprolol versus biatrial pacing in the prevention of atrial fibrillation after coronary artery bypass surgery: a prospective randomized open trial.

BACKGROUND AND AIMS: Atrial fibrillation (AF) is the most common arrhythmia after coronary artery bypass surgery (CABG). Intravenous metoprolol and biatrial pacing have been reported to be effective in AF prophylaxis after cardiac surgery. The purpose of this trial was to compare the efficacy of intravenous metoprolol versus biatrial pacing combined with oral metoprolol in the prevention of AF after CABG. METHODS: A single-centre prospective randomized open trial of 165 consecutive patients undergoing their first CABG. Patients were randomized to receive either intravenous metoprolol infusion 1-3 mg per hour or biatrial overdrive pacing and oral metoprolol (50-150 mg) daily for 72 hours after CABG starting immediately after the surgery. AAI pacing with a pacing rate of 10 beats/minute above the baseline heart rate was used. Patients had continuous ECG-monitoring. The primary end point was the first episode of AF. RESULTS: The incidence of postoperative AF in the intravenous metoprolol and biatrial pacing groups did not differ from each other (14% vs. 18% respectively, p=0.66). There was no difference in the time of AF onset between the groups (28.2 ± 16.2 h vs. 30.1 ± 21.2 h respectively, p = 0.8). Intravenous metoprolol infusion had to be temporarily interrupted for one hour in eleven patients because of hypotension or bradycardia. One case of bleeding from the left atria related to the pacemaker electrode wire was found. CONCLUSION: We found no difference in the incidence of AF between patients treated with intravenous metoprolol or the combination of biatrial pacing and oral metoprolol.

Pooled week 96 results of the phase III DUET-1 and DUET-2 trials of etravirine: further analysis of adverse events and laboratory abnormalities of special interest.

OBJECTIVES: The aim of the study was to investigate the frequency and severity of adverse events (AEs) and laboratory abnormalities of interest over 96 weeks of treatment with etravirine or placebo in the pooled TMC125 DUET (Demonstrate Undetectable viral load in patients Experienced with ARV Therapy) trials. METHODS: Treatment-experienced, HIV-1-infected patients randomly received etravirine 200 mg twice a day (bid) or placebo, plus a background regimen. The frequency and severity of neuropsychiatric, rash, hepatic and lipid AEs were analysed; frequencies were also adjusted for total patient-years of exposure (PYE). RESULTS: A total of 599 and 604 patients received etravirine and placebo, respectively (median treatment duration 96.0 and 69.6 weeks, respectively). There was no significant difference between the treatment groups in the frequency of neuropsychiatric AEs. However, a significant difference in the frequency of rash was observed (20.5% vs. 11.8%, respectively; P < 0.0001); rash was generally mild to moderate in severity; the rate of discontinuation because of rash was low (2.2% vs. 0% in the etravirine and placebo groups, respectively). The frequency of hepatic AEs was low and similar between the treatment groups (8.7% vs. 7.1%, respectively; P = 0.3370); hepatic enzyme levels did not increase over time. Lipid-related laboratory abnormalities and changes over time in lipid levels were generally comparable between treatment groups. Adjusting for treatment exposure, the frequency of AEs remained similar between treatment groups, with the exception of rash [13.7 vs. 9.3 per 100 PYE; relative risk (95% confidence interval) 1.48 (1.02-1.95)]. CONCLUSIONS: The frequency of AEs of interest was generally similar between the treatment groups, both overall and when adjusted for treatment exposure, with the exception of rash which was more frequent in the etravirine group.

Progress and prospects: hurdles to cardiovascular gene therapy clinical trials.

Several gene therapy approaches have been designed for the treatment of cardiovascular diseases. A positive finding is that the safety of cardiovascular gene therapy has been excellent even in long-term follow-up. However, several hurdles to this field are still present. A major disappointing feature of the trials is that while preclinical and uncontrolled phase-I gene therapy trials have been positive, none of the randomized controlled phase-II/III cardiovascular gene therapy trials have shown clinically relevant positive effects. Low gene transfer efficiency seems to be associated with several trials. A sophisticated efficient delivery method for cardiovascular applications is still lacking and only low concentrations of the gene product are produced in the target tissues. Only a few gene therapy vectors can be produced in large scale. In addition, inflammatory reactions against vectors and inability to regulate gene expression are still present. Furthermore, a strong placebo effect is affecting the results in gene therapy trials, and long-term trials have become more difficult to conduct because of the multiplicity of therapies applied simultaneously on the patients. This review summarizes advances and obstacles of current cardiovascular clinical gene therapy trials.

Eight-year safety follow-up of coronary artery disease patients after local intracoronary VEGF gene transfer.

Vascular endothelial growth factor (VEGF) has been shown to stimulate angiogenesis and myocardial perfusion. The short-term safety of VEGF gene therapy is excellent. However, there are only limited results regarding the long-term effects. The Kuopio Angiogenesis Trial (KAT) studied the efficiency and short-term safety of the local VEGF-A(165) gene transfer in 103 patients with coronary artery disease. Three patient groups received either VEGF as an adenoviral (n=37), or as a plasmid/liposome vector (n=28), or as a placebo (n=38), during coronary angioplasty and stenting (percutaneous coronary intervention, PCI)AQ1. The aim of this study was to examine the long-term effects and safety of VEGF gene therapy. Patients were interviewed by telephone or with a questionnaire on their current status of health, coronary and other cardiovascular events and symptoms, working ability, exercise tolerance, other diseases, such as cancer and diabetes, as well as their personal experience of the treatment. Causes of death were clarified from hospital records. The total follow-up time was 8.1 years (range 6.9-9.7 years). Overall 82% of the patients were reached across the study. Eight (7.5%) of the patients died during the follow-up, but there was no significant difference in mortality between the groups (3/32 vs 2/26 vs 3/31 VEGF-adenovirus vs VEGF-plasmid/liposome vs placebo, respectively; P=0.88). The incidence of major adverse cardiovascular events (MACEs) (10 vs 11 vs 15; P=0.85), cancer (1 vs 4 vs 2; P=0.38) or diabetes (2 vs 2 vs 2; P=0.97) did not differ between the groups. Local intracoronary VEGF gene transfer is safe and does not increase the risk of MACE, arrhythmias, cancer, diabetes or other diseases.

Cardiac autonomic regulation during gastroscopy.

BACKGROUND: Gastroscopy is sometimes associated with adverse cardiovascular events. AIMS: We evaluated the effects of sedation and pharyngeal anaesthesia on cardiac autonomic regulation during gastroscopy. PATIENTS: Two hundred thirteen outpatients undergoing gastroscopy. METHODS: The patients were assigned to 4 groups: (1) sedation with intravenous midazolam and placebo throat spray (midazolam group), (2) placebo sedation and pharyngeal anaesthesia with lidocaine (lidocaine group), (3) placebo sedation and placebo throat spray (placebo group), and (4) no intravenous cannula nor throat spray (control group). Continuous electrocardiogram was recorded. Heart rate variability was assessed; the powers of low frequency (0.04-0.15 Hz) and high frequency (0.15-0.40 Hz) components as well as total power (0.0-0.4 Hz) were calculated. RESULTS: Gastroscopy was associated with a decrease in high frequency normalized units, increases in low frequency normalized units and low frequency/high frequency ratio indicating activation of sympathetic and withdrawal of vagal modulation. Sympathetic activation resulted in a decrease in total power and all components of heart rate variability. The decrease was most prominent in the midazolam treated patients (p<0.001 vs the lidocaine group and p<0.01 vs placebo and control groups during the postendoscopy phase). CONCLUSION: Gastroscopy induces a shift towards dominance of the sympathetic modulation of the heart. Premedication with midazolam potentiates this shift.

Screening for BRCA1 and BRCA2 mutations in Eastern Finnish breast/ovarian cancer families.

Familial aggregation is thought to account for 5-10% of all breast cancer cases, and high penetrance breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 explain < or =20% of these. Hundreds of mutations among breast/ovarian cancer families have been found in these two genes. The mutation spectrum and prevalence, however, varies widely among populations. Thirty-six breast/ovarian cancer families were identified from a population sample of breast and ovarian cancer cases among a relatively isolated population in Eastern Finland, and the frequency of BRCA1/BRCA2 germline mutations were screened using heteroduplex analysis, protein truncation test and sequencing. Five different mutations were detected in seven families (19.4%). Two mutations were found in BRCA1 and three in BRCA2. One of the mutations (BRCA2 4088insA) has not been detected elsewhere in Finland while the other four, 4216-2nt A-->G and 5370 C-->T in BRCA1 and 999del5 and 6503delTT in BRCA2, are recurrent Finnish founder mutations. These results add to the evidence of the geographical differences in distribution of Finnish BRCA1/BRCA2 mutations. This screen also provides further evidence for the presumption that the majority of Finnish BRCA1/BRCA2 founder mutations have been found and that the proportion of BRCA1/BRCA2 mutations in Finnish breast/ovarian cancer families is around 20%.

Cardiac effects within 3 months of BEAC high-dose therapy in non-Hodgkin's lymphoma patients undergoing autologous stem cell transplantation.

OBJECTIVES: Limited data are available on the cardiac effects of high-dose cyclophosphamide (CY) in patients with non-Hodgkin's lymphoma (NHL). We prospectively assessed the cardiac effects of high-dose CY in 30 adult NHL patients receiving CY 6 g/m(2) as part of BEAC high-dose therapy (HDT). METHODS: Radionuclide ventriculography (RVG) and plasma natriuretic peptide (NT-proANP, NT-proBNP) measurements were performed simultaneously prior to BEAC at baseline (d - 7), 12 days (d + 12) and 3 months (m + 3) after stem cell infusion (D0). In addition to these time points, natriuretic peptides were measured 2 days before (d - 2) and 1 week (d + 7) after stem cell infusion. RESULTS: Left ventricular ejection fraction (LVEF) decreased from d - 7 (53% +/- 2%) to d + 12 (49% +/- 2%, P = 0.009). However, no significant change in cardiac diastolic function was observed. The LVEF returned towards baseline by m + 3. Plasma NT-proANP and NT-proBNP increased significantly from baseline (445 +/- 65 pmol/L and 129 +/- 33 pmol/L) to d - 2 (1,127 +/- 142 pmol/L, P < 0.001 and 624 +/- 148 pmol/L, P < 0.001, respectively). Thereafter, they started to decrease, but on d + 7 NT-proANP (404 +/- 157 pmol/L, P = 0.048) and NT-proBNP (648 +/- 125 pmol/L, P = 0.015) were still significantly higher than at baseline. On d + 12 and m + 3 they no longer differed from baseline. CONCLUSIONS: Our findings suggest that high-dose CY results in acute, subclinical systolic dysfunction in NHL patients previously treated with anthracyclines. Natriuretic peptides seem to be more sensitive than LVEF to reflect this transient cardiac effect. Serial measurements of natriuretic peptides might be a useful tool to assess cardiac effects of high-dose CY.

Very acute cardiac toxicity during BEAC chemotherapy in non-Hodgkin's lymphoma patients undergoing autologous stem cell transplantation.

Cardiotoxicity is potentially the most threatening nonhaematological side effect of high-dose CY. We prospectively evaluated the very acute cardiac effects of high-dose CY in 17 adult non-Hodgkin's lymphoma (NHL) patients receiving CY 1500 mg/m2/day as a part of BEAC high-dose therapy (HDT). Magnetic resonance imaging (MRI) and plasma natriuretic peptide (NT-proBNP, NT-proANP) measurements were performed prior to HDT (d-7) and just after completing HDT (d-2). After the high-dose CY left atrial end-systolic area increased from 15.2+/-1.2 to 18.5+/-1.4 cm2 (P=0.001), left ventricular end-diastolic volume from 136.1+/-12.3 to 156.6+/-11.1 cm3 (P=0.04) and left ventricular end-systolic volume from 67.4+/-7.8 to 75.3+/-7.1 cm3 (P=0.018). However, no significant change in left ventricular ejection fraction (LVEF) was observed. At the same time, plasma levels of NT-proBNP increased from 134.9+/-53.3 to 547.1+/-168.4 pmol/l (P=0.003) and NT-proANP from 481.1+/-105.5 to 1056.6+/-193.1 pmol/l (P=0.001), respectively. To conclude, high-dose CY results in very acute cardiac toxicity characterised by enlargement of the heart chambers in NHL patients previously treated with anthracyclines. This toxicity can be detected with increased concentrations of circulating natriuretic peptides but not with LVEF measurement.

Inducibility of life-threatening ventricular arrhythmias is related to maximum left ventricular thickness and clinical markers of sudden cardiac death in patients with hypertrophic cardiomyopathy attributable to the Asp175Asn mutation in the alpha-tropomyosin gene.

We investigated inducibility of life-threatening arrhythmias with programmed ventricular stimulation (PVS) in relation to clinical markers of sudden cardiac death (SCD) in subjects with hypertrophic cardiomyopathy (HCM) attributable to the Asp175Asn mutation in the alpha-tropomyosin gene (TPM1-Asp175Asn). PVS was performed with up to three extrastimuli and distribution of markers of SCD was evaluated in 21 adult subjects with the TPM1-Asp175Asn. Sustained polymorphic ventricular tachycardia (VT) or ventricular fibrillation (VF) was induced in seven of 21 subjects (33%). Inducible subjects had more severe left ventricular hypertrophy (LVH) and an increased number of markers of SCD (family history of SCD, syncope or presyncope, fall in systolic blood pressure (BP) during exercise, documented non-sustained VT (NSVT), and marked LVH) compared to non-inducible subjects (IVS 2.4 +/- 0.3 cm vs. 1.6 +/- 0.5 cm, P < 0.001; and two to three vs. one to two markers of SCD, P = 0.007, respectively). In conclusion, in HCM attributable to the Asp175Asn mutation in the alpha-tropomyosin gene, life-threatening arrhythmias were induced in one third of the patients. Inducibility was associated with the maximum left ventricular (LV) thickness and the number of markers of SCD, suggesting that in HCM patients with an identical causative mutation, susceptibility to ventricular arrhythmias is related to the cardiomyopathic phenotype.

The effect of carbon dioxide, respiratory rate and tidal volume on human heart rate variability.

BACKGROUND: Heart rate variability (HRV) has been used for assessment of depth of anesthesia. Alterations in respiratory rate and tidal volume modulate the sympatovagal neural drive to the heart. The changes in PaCO2 that accompany changes in breathing pattern may, through chemoreceptors in the brainstem, independently influence the autonomic control of the heart and modulate HRV. METHODS: We measured the effects of PaCO2, tidal volume and respiratory rate on HRV during spontaneous and mechanical ventilation in 22 healthy volunteers and in 25 mechanically ventilated anesthetized patients. RESULTS: Adding CO2 to the inspiratory gas increased high frequency (HF) and low frequency (LF) components of HRV in awake volunteers both during spontaneous and mechanical ventilation, while this effect of CO2 was abolished in patients during anesthesia. Increase of tidal volume increased HF component of HRV only in volunteers during spontaneous ventilation. On the other hand, when respiratory rate was reduced, the balance of HF and LF power moved toward LF power in all study groups. Breathing frequency altered HRV independent on PaCO2, tidal volume and the level of consciousness. In contrast, the effect of PaCO2 appeared to be related to normal level of consciousness, suggesting that a cortical modulation of the autonomic nervous activity contributes to the effects of PaCO2 on HRV. CONCLUSIONS: PaCO2, tidal volume and respiratory rate should be controlled when HRV power spectrum is measured in conscious patients or volunteers, while in anesthetized patients small changes in end-tidal CO2 or tidal volume do not modulate HRV if respiratory rate remains unchanged.

Myocardial function and haemodynamics in extensive burn trauma: evaluation by clinical signs, invasive monitoring, echocardiography and cytokine concentrations. A prospective clinical study.

BACKGROUND: The objectives of this study were to (1). describe the haemodynamic profile of patients with extensive burns during the early fluid resuscitation phase, (2). evaluate myocardial performance by invasive monitoring and echocardiography and (3). analyze the relations between serum cytokine (IL-6, IL-8, TNF) and natriuretic peptide (ANP, BNP) concentrations and myocardial function in these patients. METHODS: Prospective, clinical study in a tertiary care burn centre. Invasive haemodynamic measurements including a pulmonary artery catheter, echocardiography, blood samples for cytokine and atriopeptide analyses. The follow-up time was up to 72 h postinjury. RESULTS: According to echocardiography, patients were hypovolaemic despite aggressive (median 7,9 ml kg(-1) h(-1), range 3.3-11.7) fluid resuscitation and adequate urine output (median 0.9 ml kg(-1) h(-1), range 0.46-1.35) during the first day postinjury. There were no consistent findings of hyperlactatemia, metabolic acidosis or low mixed venous oxygen saturations. Daily highest and lowest values of cardiac index and stroke volume index increased and the lowest and highest values of systemic vascular resistance decreased. Cardiac performance (stroke volume index) improved during the study period even though there were no initial signs of myocardial depression in echocardiography. Three patients received a dobutamine infusion based on clinical judgement. There was no consistent association between haemodynamic changes and plasma cytokine concentrations. CONCLUSION: Persisting hypovolaemia is evident in the resuscitation phase of extensive burns despite aggressive fluid therapy and the lack of classic signs of hypoperfusion. Cardiac performance improves during the first days after extensive burn injury without association with plasma cytokine profile.