Search

Acute coronary syndrome is a precipitant of acute heart failure in a substantial proportion of cases, and the presence of both conditions is associated with a higher risk of short-term mortality compared to acute coronary syndrome alone. The diagnosis of acute coronary syndrome in the setting of acute heart failure can be challenging. Patients may present with atypical or absent chest pain, electrocardiograms can be confounded by pre-existing abnormalities, and cardiac biomarkers are frequently elevated in patients with chronic or acute heart failure, independently of acute coronary syndrome. It is important to distinguish transient or limited myocardial injury from primary myocardial infarction due to vascular events in patients presenting with acute heart failure. This paper outlines various clinical scenarios to help differentiate between these conditions and aims to provide clinicians with tools to aid in the recognition of acute coronary syndrome as a cause of acute heart failure. Interpretation of electrocardiogram and biomarker findings, and imaging techniques that may be helpful in the diagnostic work-up are described. Guidelines recommend an immediate invasive strategy for patients with acute heart failure and acute coronary syndrome, regardless of electrocardiographic or biomarker findings. Pharmacological management of patients with acute coronary syndrome and acute heart failure should follow guidelines for each of these syndromes, with priority given to time-sensitive therapies for both. Studies conducted specifically in patients with the combination of acute coronary syndrome and acute heart failure are needed to better define the management of these patients. The authors acknowledge the Heart Failure Association of the European Society of Cardiology for organizing the meeting during which this topic was discussed. The authors acknowledge T.J. for her expert review of the manuscript, and W.G. S., PharmD (Campbell University College of Pharmacy and Health Sciences), supported by the Heart Failure Association of the European Society of Cardiology for contributions to content development, writing, and editing the manuscript. J.M., C.M. and F.P. performed their expert review of the paper on behalf of Acute Cardiovascular Care Association of the European Society of Cardiology. J.B. and T.T. were supported by the Deutsche Forschungsgemeinschaft, Clinical Research Group 311 (KFO 311) '(Pre-)terminal heart and lung failure: unloading and repair' (DFG; TP1 and TP11). Harjola, VP (corresponding author), Helsinki Univ Hosp, Dept Emergency Med & Serv, Div Emergency Med, PL 340, Helsinki 00029, Finland. veli-pekka.harjola@hus.fi

Background We have earlier reported that amiodarone, a potent and commonly used antiarrhythmic drug increases serum desmosterol, the last precursor of cholesterol, in 20 cardiac patients by an unknown mechanism. Objective Here, we extended our study to a large number of cardiac patients of heterogeneous diagnoses, evaluated the effects of combining amiodarone and statins (inhibitors of cholesterol synthesis at the rate-limiting step of hydroxy-methyl-glutaryl CoA reductase) on desmosterol levels and investigated the mechanism(s) by which amiodarone interferes with the metabolism of desmosterol using in vitro studies. Methods and Results We report in a clinical case-control setting of 236 cardiac patients (126 with and 110 without amiodarone treatment) that amiodarone medication is accompanied by a robust increase in serum desmosterol levels independently of gender, age, body mass index, cardiac and other diseases, and the use of statins. Lipid analyses in patient samples taken before and after initiation of amiodarone therapy showed a systematic increase of desmosterol upon drug administration, strongly arguing for a direct causal link between amiodarone and desmosterol accumulation. Mechanistically, we found that amiodarone resulted in desmosterol accumulation in cultured human cells and that the compound directly inhibited the 24-dehydrocholesterol reductase (DHCR24) enzyme activity. Conclusion These novel findings demonstrate that amiodarone blocks the cholesterol synthesis pathway by inhibiting DHCR24, causing a robust accumulation of cellular desmosterol in cells and in the sera of amiodarone-treated patients. It is conceivable that the antiarrhythmic potential and side effects of amiodarone may in part result from inhibition of the cholesterol synthesis pathway.

BACKGROUND There were gaps between guidelines and practice when surgery was the only treatment for aortic stenosis (AS). OBJECTIVES This study analyzed the decision to intervene in patients with severe AS in the EORP VHD (EURObservational Research Programme Valvular Heart Disease) II survey. METHODS Among 2,152 patients with severe AS, 1,271 patients with high-gradient AS who were symptomatic fulfilled a Class I recommendation for intervention according to the 2012 European Society of Cardiology guidelines; the primary end point was the decision for intervention. RESULTS A decision not to intervene was taken in 262 patients (20.6%). In multivariate analysis, the decision not to intervene was associated with older age (odds ratio [OR]: 1.34 per 10-year increase; 95% CI: 1.11 to 1.61; P = 0.002), New York Heart Association functional classes I and II versus III (OR: 1.63; 95% CI: 1.16 to 2.30; P = 0.005), higher age adjusted Charlson comorbidity index (OR: 1.09 per 1-point increase; 95% CI: 1.01 to 1.17; P = 0.03), and a lower transaortic mean gradient (OR: 0.81 per 10-mm Hg decrease; 95% CI: 0.71 to 0.92; P < 0.001). During the study period, 346 patients (40.2%, median age 84 years, median EuroSCORE II [European System for Cardiac Operative Risk Evaluation II] 3.1%) underwent transcatheter intervention and 515 (59.8%, median age 69 years, median EuroSCORE II 1.5%) underwent surgery. A decision not to intervene versus intervention was associated with lower 6-month survival (87.4%; 95% CI: 82.0 to 91.3 vs 94.6%; 95% CI: 92.8 to 95.9; P < 0.001). CONCLUSIONS A decision not to intervene was taken in 1 in 5 patients with severe symptomatic AS despite a Class I recommendation for intervention and the decision was particularly associated with older age and combined comorbidities. Transcatheter intervention was extensively used in octogenarians. (J Am Coll Cardiol 2021;78:2131-2143) (c) 2021 by the American College of Cardiology Foundation.

Aims To assess the prognosis of patients with coronary heart disease (CHD) after first myocardial revascularisation procedure in real-world practice and to compare the differences in outcomes of coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) among diabetic and non-diabetic patients. Methods and results A database was compiled from the national hospital discharge register to collect data on all cardiac revascularisations performed in Finland in 2000–2015. The outcomes (all-cause deaths, cardiovascular (CV) deaths, major CV events and need for repeat revascularisation) after the first revascularisation were identified from the national registers at 28 day, 1 year, and 3 year time points. A total of 139 242 first-time revascularisations (89 493 PCI and 49 749 CABG) were performed during the study period. Of all the revascularised patients, 24% had diabetes, and 76% were non-diabetic patients. At day 28, the risk of fatal outcomes was lower after PCI than after CABG among non-diabetic patients, whereas no difference was seen among diabetic patients. In long-term follow-up the situation was reversed with PCI showing higher risk compared with CABG for most of the outcomes. In particular, at 3 year follow-up the risk of all-cause deaths was elevated among diabetic patients [HR 1.30 (95% CI 1.22–1.38) comparing PCI with CABG] more than among non-diabetic patients [HR 1.09 (1.04–1.15)]. The same was true for CV deaths [HR 1.29 (1.20–1.38) among diabetic patients, and HR 1.03 (0.98–1.08) among non-diabetic patients]. Conclusion Although PCI was associated with better 28 day prognosis, CABG seemed to produce better long-term prognosis especially among diabetic patients.

BackgroundAortic valve stenosis (AS) is the most prevalent valvular disease in the developed countries. Four-dimensional (4D) flow cardiovascular magnetic resonance (CMR) is an emerging imaging technique, which has been suggested to improve the evaluation of AS severity compared to two-dimensional (2D) flow and transthoracic echocardiography (TTE). We investigated the reliability of CMR 2D flow and 4D flow techniques in measuring aortic transvalvular peak systolic flow in patients with severe AS.MethodsWe prospectively recruited 90 patients referred for aortic valve replacement due to severe AS (73.3 ± 11.3 years, aortic valve area 0.7 ± 0.1 cm2, and 54/36 tricuspid/bicuspid), and 10 non-valvular disease controls. All the patients underwent echocardiography and 2D flow and 4D flow CMR. Peak flow velocity measurements were compared using Wilcoxon signed rank sum test and Bland–Altman analysis.Results4D flow underestimated peak flow velocity in the AS group when compared with TTE (bias − 1.1 m/s, limits of agreement ± 1.4 m/s) and 2D flow (bias − 1.2 m/s, limits of agreement ± 1.6 m/s). The differences between values obtained by TTE (median 4.3 m/s, range 2.7–6.1 m/s) and 2D flow (median 4.5 m/s, range 2.9–6.5 m/s) compared to 4D flow (median 3.1 m/s, range 1.7–5.1 m/s) were significant (p ConclusionsCMR 4D flow significantly underestimates systolic peak flow velocity in patients with severe AS. 2D flow, in turn, estimated the AS velocity accurately, with measured peak flow velocities comparable to TTE.

Background: Ischemia-reperfusion injury may compromise the short-term and long-term prognosis after heart transplantation. Experimental studies show that simvastatin administered to the organ donor is vasculoprotective and inhibits cardiac allograft ischemia-reperfusion injury. Methods: Eighty-four multiorgan donors were randomly assigned to receive 80 mg of simvastatin (42 donors) via nasogastric tube after declaration of brain death and upon acceptance as a cardiac donor, or to receive no simvastatin (42 donors). The primary efficacy end point was postoperative plasma troponin T and I levels during the first 24 hours after heart transplantation. Secondary end points included postoperative hemodynamics, inflammation, allograft function, rejections and rejection treatments, and mortality. Results: Organ donor simvastatin treatment significantly reduced the heart recipient plasma levels of troponin T by 34% (14 900 ± 12 100 ng/L to 9800 ± 7900 ng/L, P =0.047), and troponin I by 40% (171 000 ± 151 000 ng/L to 103 000 ± 109 000 ng/L, P =0.023) at 6 hours after reperfusion, the levels of NT-proBNP (N-terminal pro-B-type natriuretic peptide) by 36% (32 800 ± 24 300 ng/L to 20 900 ± 15 900 ng/L; P =0.011) at 1 week, and the number of rejection treatments with hemodynamic compromise by 53% within the first 30 days ( P =0.046). Donor simvastatin treatment did not affect donor lipid levels but was associated with a specific transplant myocardial biopsy gene expression profile, and a decrease in recipient postoperative plasma levels of CXCL10 (C-X-C motif chemokine 10), interleukin-1α, placental growth factor, and platelet-derived growth factor-BB. Postoperative hemodynamics, biopsy-proven acute rejections, and mortality were similar. No adverse effects were seen in recipients receiving noncardiac solid organ transplants from simvastatin-treated donors. Conclusions: Donor simvastatin treatment reduces biomarkers of myocardial injury after heart transplantation, and—also considering its documented general safety profile—may be used as a novel, safe, and inexpensive adjunct therapy in multiorgan donation. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01160978.

Background: Cancer is currently one of the most important factors affecting the long-term health and survival of heart transplant patients. Material and methods: We calculated the standardized incidence ratios (SIR) for different cancer sites and the cancer-specific standardized mortality ratio (SMR) by linking a cohort of 479 adult heart transplant recipients transplanted in 1985-2014 (4491.6 person-years of follow-up) with data from the national Finnish Cancer Registry until the end of 2015, and with the data from the Statistics Finland's national registry of causes of death. Results: A total of 267 cancers occurred in 143 patients (SIR 6.0; 95% confidence interval (CI) 5.3-6.7). The SIR for overall cancer was considerably higher for men (SIR 6.7; 95% CI 5.9-7.5) than for women (1.4; 95% CI 0.6-2.6). Most frequent cancers were non-melanoma skin cancers (basal cell carcinoma 83 cases, squamous cell skin cancer (SCC) 56 cases), followed by Non-Hodgkin lymphoma (NHL) (36 cases), lung cancer (17), cancer of prostate (16) and cancer of kidney (12). SIRs were highest for SCC (51.9; 95% CI 39.2-67.4), lip cancer (47.4; 95% CI 19.1-97.7), cancer of tongue (26.3; 95% CI 7.2-67.4), and NHL (25.7; 95% CI 18.0-35.6). For most cancers, SIRs increased steadily by time since transplantation. Cancer mortality was three times higher for heart transplant recipients than for the population (SMR 3.1; 95% CI 2.1-4.1). Conclusions: Both cancer incidence and mortality are remarkably increased after heart transplantation, with the relative incidence most elevated for SCC, lip and other oral cancers, and for NHL.

OBJECTIVES Our goal was to study the outcome of patients with cardiogenic shock who were treated with venoarterial extracorporeal membrane oxygenation (VA ECMO), including the subsequent long-term health-related quality of life (HRQoL). METHODS We conducted a retrospective study of 133 consecutive patients treated in a single centre from 2007 to 2016. The HRQoL was studied using the EuroQuol-5 dimensions-3 level questionnaire and the RAND 36-Item Short Form Health Survey at a minimum of 1 year after VA ECMO. RESULTS Of all patients, 66 (49.6%) were weaned from VA ECMO and 16 (12.0%) patients were bridged directly to a transplant, 15 (11.3%) to a ventricular assist device and 1 (0.8%) to a total artificial heart. Survival to discharge was 63.9% and to 1 year, 60.9%. A higher in-hospital mortality rate was independently associated with lower HCO3 at VA ECMO implantation [odds ratio (OR) 1.2/decrease of 1 mmol/l in HCO3 (95% confidence interval 1.1-1.3, P < 0.001)] and with increased need of red blood cells transfused during intensive care [OR 1.9/unit of red blood cells needed/day (95% confidence interval 1.4-2.6, P < 0.001)]. HRQoL measured with the EuroQuol-5 dimensions-3 level questionnaire was equal to the HRQoL of the general population. In the 36-Item Short Form questionnaire, patients reported better emotional well-being and equal energy, pain and general health perception compared to the general population. Limitations were experienced only in physical health. In total, 56% of the patients ≤ 60 years had returned to work. CONCLUSIONS VA ECMO can provide acceptable long-term survival with good HRQoL for selected patients with refractory cardiogenic shock. Timing of patient assessment and of VA ECMO implantation is essential because deeper acidosis is associated with a higher in-hospital mortality rate.

Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Helsinki University Hospital, Finland Background Aortic stenosis (AS) is the most prevalent valvular disease in the developed countries. 4D flow is an emerging cardiac magnetic resonance (CMR) imaging technique, which has been suggested to improve the evaluation of AS severity. The accuracy of peak flow measurement by 4D flow CMR in patients with severe AS has, however, remained unvalidated. Purpose We investigated the reliability of the novel 4D flow CMR technique in measuring transvalvular peak systolic flow in patients with severe aortic valve stenosis. Methods The study included 63 patients clinically evaluated for valve replacement due to severe symptomatic AS. All the patients underwent echocardiography, 2D phase-contrast and 4D flow CMR. CMR was performed on consecutive patients according to international guidelines. Mean age of the patients was 73.8 ± 11.5 years, mean aortic valve area 0.7 ± 0.2 cm², and 40 of the valves were tricuspid and 23 bicuspid. QFlow and QFlow 4D software were used for flow analyses. Bland-Altman analyses and Wilcoxon signed rank sum tests were performed using SPSS software. Results CMR 4D flow analyses underestimated peak flow values when compared with echocardiography (bias -1.1 m/s, limits of agreement ± 1.5 m/s) and with 2D flow analyses (bias -1.2 m/s, limits of agreement ± 1.7 m/s). The difference between values obtained by 4D flow (median 3.1 m/s, range 1.5 – 4.9 m/s) and echocardiography (median 4.3 m/s, range 2.1 – 6.1 m/s) as well as by 2D flow (median 4.3 m/s, range 2.0 – 8.4 m/s) were statistically significant (p < 0,001). The difference between 2D flow analyses and echocardiography remained statistically insignificant (bias 0.05 m/s, limits of agreement ± 1.6 m/s). Conclusions We found that 4D flow analysis significantly underestimates systolic peak flow values in patients with severe AS. This may be due to intra-voxel averaging of the narrow jets. In contrast to previous assumptions, traditional 2D flow technique may therefore outperform 4D flow in measuring valvular peak flow by CMR in patients with severe AS. This should be taken into consideration when assessing disease severity by CMR. Abstract Figure. Peak systolic flow in AS patients (n = 63)

Funding Acknowledgements Type of funding sources: None. Background Global longitudinal strain (GLS) by echocardiography is a sensitive method for measuring left ventricular (LV) function, and of better prognostic value in valvular heart disease than ejection fraction (EF). Cardiac magnetic resonance imaging (CMR) is the most accurate method for measuring LV volume and EF, but GLS has not been possible to measure by CMR until recently. Purpose This study compares GLS obtained by CMR and echocardiography in patients with severe aortic valve stenosis. Normal values for GLS by CMR are reported as well. Methods GLS was measured in 32 patients with severe aortic valve stenosis with speckle tracking echocardiography, using GE Vivid E95 (n = 15) and Philips EPIQ (n = 17) ultrasound machines, as well as with CMR (Avanto 1.5T FIT, Siemens Medical Solutions). For normal values, GLS was measured by CMR in 9 healthy controls. Endo- and epicardial borders of two, three and four chamber cine images were traced for CMR GLS using dedicated software (Qstrain 2.0, Medis, NL). Both CMR and Vivid E95 measured midmyocardial strain, whereas the EPIQ AutoStrain method measures endomyocardial strain. Absolute values of GLS are reported. Pearson correlation coefficient was calculated and paired Student’s t-test was used for comparisons. Results A significant correlation (r = 0.45, p = 0.01) was found between echocardiographic and CMR GLS (Figure). GLS by Vivid E95 had a very good correlation with CMR GLS (r = 0.84, p = 0.0001), whereas GLS by Philips EPIQ did not correlate significantly (r = 0.14, p = 0.01). In patients with aortic stenosis and healthy controls, the average GLS by CMR was 18.3 ± 3% and 20.9 ± 2% respectively. The average GLS by CMR was comparable to that obtained by GE Vivid E95 (17.3 ± 4% vs. 17.2 ± 3%, p = 0.92), and higher than by Philips EPIQ (19.2 ± 2% vs. 15.4 ± 2%, p Conclusion This study shows that GLS by CMR is feasible and correlates with GLS obtained by echocardiography, especially when quantifying midmyocardial strain. Echocardiographic GLS values based on endomyocardial strain were lower. Patient characteristics Age 75 ± 14 y NYHA 1 1 (3 %) NYHA 2 20 (67 %) NYHA 3 8 (27 %) NYHA 4 1 (3 %) CMR EF 66 ± 8 % AVA 0.7 ± 0.2 cm² NYHA = NYHA class of symptoms, EF = ejection fraction by CMR, AVA = aortic valve area by echocardiography Abstract Figure. GLS by CMR vs. Echocardiography

BACKGROUND: Cardiac allograft vasculopathy (CAV) is characterized by diffuse thickening of the arterial intima. Statins reduce the incidence of CAV, but despite the use of statins, CAV remains one of the leading causes of long-term death after heart transplant. Inhibitors of proprotein convertase subtilisin-kexin type 9 (PCSK9) substantially reduce cholesterol levels but have not been tested in heart transplant recipients.METHODS: The Cholesterol lowering with EVOLocumab to prevent cardiac allograft Vasculopathy in De-novo heart transplant recipients (EVOLVD) trial (ClinicalTrials.gov Identifier: NCT03734211) is a randomized, double-blind trial designed to test the effect of the PCSK9 inhibitor evolocumab on coronary intima thickness in heart transplant recipients. Adults who have received a cardiac transplant within the past 4 - 8 weeks are eligible. Exclusion criteria include an estimated glomerular filtration rate < 20 mL/min/1.73 m2 , renal replacement therapy, or contraindications to coronary angiography with intravascular ultrasound. 130 patients will be randomized (1:1) to 12-months' treatment with evolocumab or matching placebo. The primary endpoint is the coronary artery intima thickness as measured by intravascular ultrasound.CONCLUSION: The EVOLVD trial is a randomized clinical trial designed to show whether treatment with the PCSK9 inhibitor evolocumab can ameliorate CAV over the first year after heart transplant.

Background: The use of venoarterial extracorporeal membrane oxygenation in cardiogenic shock keeps increasing, but its cost-utility is unknown. Methods: We studied retrospectively the cost-utility of venoarterial extracorporeal membrane oxygenation in a five-year cohort of consequent patients treated due to refractory cardiogenic shock or cardiac arrest in a transplant centre in 2013–2017. In our centre, venoarterial extracorporeal membrane oxygenation is considered for all cardiogenic shock patients potentially eligible for heart transplantation, and for selected postcardiotomy patients. We assessed the costs of the index hospitalization and of the one-year hospital costs, and the patients’ health-related quality of life (response rate 71.7%). Based on the data and the population-based life expectancies, we calculated the amount and the costs of quality-adjusted life years gained both without discount and with an annual discount of 3.5%. Results: The cohort included 102 patients (78 cardiogenic shock; 24 cardiac arrest) of whom 67 (65.7%) survived to discharge and 66 (64.7%) to one year. The effective costs per one hospital survivor were 242,303€. Median in-hospital costs of the index hospitalization per patient were 129,967€ (interquartile range 150,340€). Mean predicted number of quality-adjusted life years gained by the treatment was 20.9 (standard deviation 9.7) without discount, and the median cost per quality-adjusted life year was 7474€ (interquartile range 10,973€). With the annual discount of 3.5%, 13.0 (standard deviation 4.8) quality-adjusted life years were gained with the cost of 12,642€ per quality-adjusted life year (interquartile range 15,059€). Conclusions: We found the use of venoarterial extracorporeal membrane oxygenation in refractory cardiogenic shock and cardiac arrest justified from the cost-utility point of view in a transplant centre setting.

Ischemia-reperfusion injury may compromise the short-term and long-term prognosis after heart transplantation. Experimental studies show that simvastatin administered to the organ donor is vasculoprotective and inhibits cardiac allograft ischemia-reperfusion injury.Eighty-four multiorgan donors were randomly assigned to receive 80 mg of simvastatin (42 donors) via nasogastric tube after declaration of brain death and upon acceptance as a cardiac donor, or to receive no simvastatin (42 donors). The primary efficacy end point was postoperative plasma troponin T and I levels during the first 24 hours after heart transplantation. Secondary end points included postoperative hemodynamics, inflammation, allograft function, rejections and rejection treatments, and mortality. Results: Organ donor simvastatin treatment significantly reduced the heart recipient plasma levels of troponin T by 34% (14 900 ± 12 100 ng/L to 9800 ± 7900 ng/L, P=0.047), and troponin I by 40% (171 000 ± 151 000 ng/L to 103 000 ± 109 000 ng/L, P=0.023) at 6 hours after reperfusion, the levels of NT-proBNP (N-terminal pro-B-type natriuretic peptide) by 36% (32 800 ± 24 300 ng/L to 20 900 ± 15 900 ng/L; P=0.011) at 1 week, and the number of rejection treatments with hemodynamic compromise by 53% within the first 30 days (P=0.046). Donor simvastatin treatment did not affect donor lipid levels but was associated with a specific transplant myocardial biopsy gene expression profile, and a decrease in recipient postoperative plasma levels of CXCL10 (C-X-C motif chemokine 10), interleukin-1α, placental growth factor, and platelet-derived growth factor-BB. Postoperative hemodynamics, biopsy-proven acute rejections, and mortality were similar. No adverse effects were seen in recipients receiving noncardiac solid organ transplants from simvastatin-treated donors.Donor simvastatin treatment reduces biomarkers of myocardial injury after heart transplantation, and-also considering its documented general safety profile-may be used as a novel, safe, and inexpensive adjunct therapy in multiorgan donation.URL: https://www.clinicaltrials.gov. Unique identifier: NCT01160978.

Background Cytomegalovirus (CMV) remains an important pathogen in solid organ transplant patients. Objective We executed a hybrid prophylactic and pre-emptive valganciclovir (VGCV) prophylaxis to prevent CMV infection in heart transplant patients with anti-thymocyte globulin (ATG) induction and retrospectively evaluated the efficacy and safety of this regimen. Methods Hundred adult heart transplant patients between 2004 and 2010 were included. Recipients with CMV serostatus D+/R- received VGCV 900 mg OD for 6 months and 94.2% (81/86) of R+ recipients received a low-dose 450 mg OD for 3 months. Blood CMV was monitored until 3 months after cessation of the prophylaxis. Results All patients accomplished the prophylaxis. The overall incidence of CMV disease was 4% (4/100) and it was more frequent in D+/R- patients (P = .001). Three of eighty-six (3.5%) of R+ patients had CMV infection (one CMV disease) while on prophylaxis, 2/3 were still on the original significantly reduced renal dose though. There was one late CMV disease in both D+/R- and R+ groups. Ganciclovir/VGCV treatment was successful in all patients. Conclusions The hybrid strategy with low-dose VGCV in R+ patients with ATG was efficient and safe. The good treatment results indicate that the regimen did not lead to a clinically relevant resistance. Optimal renal dosage is essential throughout prophylaxis.

Teema : elinsiirrot. English summary

Purpose Cardiac allograft vasculopathy (CAV) is a unique form of accelerated atherosclerosis that is characterized by a diffuse, progressive thickening of the arterial intima of the allograft coronaries. CAV accounts for 30% of deaths occurring beyond the first year after heart transplantation. It is partly caused by immunological factors, partly brought about by established risk factors for atherosclerosis, such as elevated LDL cholesterol levels. Evolocumab is a fully humanized monoclonal antibody that inhibits the enzyme proprotein convertase subtilisin-kexin type 9 (PCSK9), thereby reducing LDL cholesterol levels by as much as 70 %. The EVOLVD trial is designed to test the hypothesis that treatment with evolocumab can ameliorate CAV in heart transplant recipients. Methods The EVOLVD trial is a randomized, controlled double-blind trial designed to test the efficacy and safety of one year's treatment with evolocumab in de novo heart transplant recipients. The trial will be conducted at the Nordic transplantation sites in Norway, Denmark, Sweden, and Finland. We aim to randomize 130 recently transplanted patients in a 1:1 fashion to receive monthly subcutaneous injections of 420 mg evolocumab or matching placebo supplied by the manufacturer. The trial is powered to detect a 0.05 mm between-group difference in the change in the intima thickness as measured by coronary intravascular ultrasound (IVUS). Secondary objectives are to assess the impact of treatment on cholesterol levels, renal function, inflammation, cardiac function as assessed by biomarkers and echocardiography, quality of life, and safety and tolerability. All participants must provide written, informed consent. Exclusion criteria include contraindications to study medication, inability to perform coronary angiography with IVUS, and an estimated glomerular filtration rate Results Applications have been submitted to regulatory authorities. We aim to recruit patients from November 2018 through December 2020, with last patient, last visit in January 2022. Conclusion The EVOLVD trial is a randomized, controlled, double blind study designed to assess the efficacy and safety of the PCSK9 inhibitor evolocumab in de novo heart transplant recipients. We expect results to be available in January 2022.

Apelin is a newly discovered inotropic peptide tentatively linked up with the pathophysiology of heart failure (HF). To further assess the role of apelin in HF, we measured its transcardiac arteriovenous gradients in patients with left ventricular pressure overload with or without HF and in patients with structurally normal hearts. Blood samples from the aortic root and coronary sinus were drawn from 49 adult patients undergoing preoperative cardiac catheterization for severe aortic valve stenosis (AS). Similar samples were taken from 12 control patients with structurally normal hearts undergoing electrophysiological studies. Plasma apelin was determined by enzyme immunoassay. In the control group, apelin decreased from a median of 0.39 (0.16–1.94) ng/ml in the aortic root to 0.18 (0.13–1.04) ng/ml in the coronary sinus ( P = 0.004). In AS patients free of HF ( n = 33), apelin concentration remained unaltered across the heart, but in those with HF ( n = 15) apelin rose from a median of 0.26 (0.20–0.82) ng/ml in the aorta to 0.45 (0.24–1.17) ng/ml in the coronary sinus ( P = 0.002). The transcardiac apelin gradients differed statistically highly significantly across the three groups ( P = 0.00005), and each of the two-group differences was also statistically significant ( P < 0.05). In conclusion, left ventricular pressure overload changes the transcardiac arteriovenous differences of circulating apelin. Although normal hearts extract apelin from the coronary blood, hearts failing due to left ventricular pressure overload release apelin into the circulation. Loss of cardiac apelin may be involved in the mechanisms of HF development in AS.

Post-operative renal failure is a common and potentially hazardous complication after heart transplantation (HTx). In this study we characterized pre- and post-operative risk factors for acute renal failure requiring renal replacement therapy (RRT).Ninety-three patients underwent orthotopic HTx between 2000 and 2007. The risk factors for RRT during the early post-operative period and predictors contributing to impaired renal function within the first post-transplant year were analyzed by regression analysis. The impact of pre-operative renal failure and early post-operative RRT on renal function within 1 year were studied.Before HTx, 55% of patients (51 of 93) had normal renal function or mild renal failure (glomerular filtration rate [GFR]60 ml/min/1.73 m(2)). Before discharge from the hospital, 25% (23 of 93) developed acute renal failure and required RRT. Of these, 16% (8 of 51) had pre-operatively normal renal function or mild renal failure, and 36% (15 of 42) had moderate or severe renal failure (GFR60 ml/min/1.73 m(2); p = 0.02). The prognosticators for early RRT were prolonged graft dysfunction, re-admission to the operating room due to post-operative bleeding, poor diuresis during surgery (1,000 ml), pre-operative pacemaker implantation, intubation time24 hours, pre-operative GFR60 ml/min/1.73 m(2), post-operative troponin T6 microg/liter and pre-operative use of angiotensin receptor blocker.Pre-operative renal failure is a significant risk factor for RRT during the immediate post-operative period and requires aggressive treatment. Patients with pre-operative renal failure secondary to severe heart failure and acute post-operative renal failure requiring RRT tend to recover within the first year post-HTx.

The pathogenesis of aortic valve stenosis (AS) is characterized by the accumulation of LDL-derived cholesterol in the diseased valves. Since LDL particles also contain plant sterols, we investigated whether plant sterols accumulate in aortic valve lesions. Serum samples were collected from 82 patients with severe AS and from 12 control subjects. Aortic valves were obtained from a subpopulation of 21 AS patients undergoing valve surgery and from 10 controls. Serum and valvular total cholesterol and noncholesterol sterols were measured by gas-liquid chromatography. Noncholesterol sterols, including both cholesterol precursors and sterols reflecting cholesterol absorption, were detected in serum samples and aortic valves. The higher the ratios to cholesterol of the cholesterol precursors and absorption markers in serum, the higher their ratios in the stenotic aortic valves (r = 0.74, P < 0.001 for lathosterol and r = 0.88, P < 0.001 for campesterol). The valvular ratio to cholesterol of lathosterol correlated negatively with the aortic valve area (r = −0.47, P = 0.045), suggesting attenuation of cholesterol synthesis with increasing severity of AS. The higher the absorption of cholesterol, the higher the plant sterol contents in stenotic aortic valves. These findings suggest that local accumulation of plant sterols and cholesterol precursors may participate in the pathobiology of aortic valve disease.

Objective Myocardial gene and cellular therapies have revived the use of porcine ischemic heart models. Commonly applied ameroid-obstruction produces inconsistent coronary stenoses and myocardial lesions, whereas abrupt coronary occlusion causes arrhythmias and sudden death. To produce a constant myocardial lesion after adaptation to ischemia, we surgically modified the ameroid-model by ligation. As a pilot study for further cell therapy research, the spontaneous myocardial response is described. Materials and methods Simultaneously with ameroid application, a loose loop of nonabsorbable thread was placed around the left circumflex artery (LCx) on 11 domestic piglets. Three weeks later, the loop was tightened. Coronary arteriograms with Rentrop collateral grading from 0 to 3, and 99mTc-single photon emission computerized tomography studies were performed 1 to 5 wk after ligation. At autopsy, the hearts were analyzed macroscopically, histologically, and with von Willebrandt factor-staining. Results LCx-banding was well-tolerated in nine animals, of which angiographic occlusion was gained in eight. Postmortem analysis revealed a 5 to 10 cm 2 transmural or subendocardial lateral myocardial infarction in all except one heart. One week after occlusion, LCx showed well-developed collateral filling (Rentrop-grade 2.7 ± 0.4), which remained unchanged at 5 wk. On single photon emission computerized tomography-scans, lateral wall perfusion increased spontaneously between 1 and 5 wk ( P = 0.02), and von Willebrandt factor revealed clusters of neovascularization at the borders of infarct areas. Conclusions This new modification of ameroid model standardizes myocardial lesion, which might reduce animal number in preclinical studies, thus having ethical aspect. The remarked potential for spontaneous recovery in ischemic porcine myocardium should be considered in preclinical therapeutic studies.

In experimental aortic stenosis (AS), blockade of the renin-angiotensin system attenuates AS-related left ventricular (LV) dysfunction and improves survival. We tested whether candesartan, an angiotensin II type 1 receptor blocker, favorably influences LV structure and function and improves exercise capacity in AS patients. Fifty-one patients with severe AS were randomized to receive candesartan (target dose 16 mg/d) or placebo. Eight patients discontinued treatment and the remaining 43 patients underwent echocardiography, walking test, and measurement of plasma N-terminal B-type natriuretic peptide (Nt-proBNP) before and after an average of 5-month treatment. No statistically significant changes in LV diameters, mass, or function were seen. The median 6-minute walking distance decreased from 390 to 368 m with candesartan (P = 0.003) and from 380 to 370 m with placebo (P = 0.523), reflecting natural progression of AS. Concomitantly, median Nt-proBNP increased from 319 to 414 ng/L with candesartan (P = 0.170) and from 413 to 561 ng/L with placebo (P = 0.035). No change with candesartan was statistically significantly different from the corresponding change with placebo. In conclusion, candesartan was well tolerated but had no favorable effects on the LV or effort tolerance. The benefits found in experimental AS of blocking the renin-angiotensin system could not be reproduced in patients with severe AS.

Kupari M, Eriksson S, Turto H, Lommi J, Pettersson K (Helsinki University Central Hospital, Helsinki; and University of Turku, Turku; Finland). Leakage of cardiac troponin I in aortic valve stenosis. J Intern Med 2005; 258; 231-237. Objective. Degeneration and death of cardiomyocytes contribute to the genesis of heart failure (HF) in aortic valve stenosis (AS). We studied whether the ongoing myocyte damage in AS can be detected from circulating cardiac troponin I (cTnI) concentrations. Design and setting. A cross-sectional cohort study in a university hospital. Subjects and methods. We examined 131 adult patients undergoing echocardiography and cardiac catheterization for isolated AS. Blood was sampled from the aortic root and, in a subset of 49 patients, also from the coronary sinus for the determination of cTnI using a sensitive immunoanalysis. Results. Seventy-three patients (56%) had detectable aortic cTnI (≥5 ng L -1 ) with 30 of them (23% of the total group) having cTnI above the reference limit in healthy subjects (>14 ng L -1 ). Patients with detectable cTnI had a higher prevalence of HF than those with undetectable cTnI (42% vs. 19%, P = 0.004). Plasma cTnI rose from the aorta to the coronary sinus by ≥5 ng L -1 in 13 of 49 patients with AS (27%) versus in none of 12 control patients free of structural heart disease (P= 0.044). AS patients with transcardiac cTnI gradients >5 ng L -1 had lower left ventricular (LV) ejection fractions than AS patients with gradients

Background Plasma B-type natriuretic peptide (BNP), as well as the N-terminal part of the prohormone (Nt-BNP), are frequently elevated in aortic valve stenosis (AS). Yet, their release from the heart into the circulation has never been directly studied in AS. Aim To assess the release of Nt-BNP in AS with focus on the identification of its main determinants. Methods We studied 49 adult patients undergoing preoperative cardiac catheterization for isolated AS. Blood was sampled from the aortic root and the coronary sinus for Nt-BNP determination by immunoassay. Results The mean (±S.E.) transcardiac Nt-BNP step-up averaged 79±53 pmol/l in 11 control patients free of structural heart disease, 75±32 pmol/l in 31 AS patients free of heart failure (HF), 236±62 pmol/l in 8 AS patients with diastolic HF (ejection fraction ≥50%, pulmonary wedge pressure >14 mm Hg) and 469±66 pmol/l in 7 AS patients with systolic HF (ejection fraction 14 mm Hg) (p

Aims In aortic stenosis (AS), left ventricular (LV) hypertrophy is considered a compensatory response helping maintain systolic function. Recent research in experimental AS suggests, however, that LV hypertrophy is not necessary to sustain LV contractions but may in fact be maladaptive. The present work aimed to clarify the role of LV hypertrophy in AS-related heart failure (HF) in man. Methods and results We studied 137 adult patients with isolated AS undergoing pre-operative echocardiography and cardiac catheterization. HF was diagnosed by the European criteria and LV hypertrophy by sex-specific limits of echocardiographic LV mass. The higher the LV mass was, the poorer was the LV ejection fraction (b ¼ 20.26, P , 0.001, linear regression) and the greater the likelihood of HF independent of the severity of AS (P , 0.001, logistic regression). In the subgroup of critical AS (valve area ,0.4 cm 2 /m 2 , n ¼ 85), patients with absent LV hypertrophy (n ¼ 19) had better preserved ejection fraction (mean+ SE, 64+3 vs. 57 + 2%, P ¼ 0.045) and less HF (16 vs. 48%, P ¼ 0.025) than patients with LV hypertrophy (n ¼ 66). Conclusion In isolated AS, increased LV mass predicts the presence of systolic dysfunction and HF independent of the severity of valvular obstruction. LV hypertrophy may be maladaptive rather than beneficial in AS in man.

Background: The pregnancy hormone relaxin has been raised as a new compensatory mediator of cardiac origin in heart failure (HF). We set out to assess the role of relaxin in pressure overload-induced human HF. Methods: We studied 129 adult patients undergoing cardiac catheterization for isolated aortic valve stenosis (AS). Blood was sampled from the aortic root and, in a subset of 49 patients, from the coronary sinus for the determination of plasma relaxin by enzyme immunoassay. HF was diagnosed when the patient had dyspnea or fatigue on ordinary effort in association with pulmonary wedge pressure >14 mm Hg at catheterization. Results: Forty-one patients had HF, which was systolic (ejection fraction

s S303 undetermined, the ability of OCT to differentiate CAD from CAV may have therapeutic implications.

To characterize fuel utilization of patients with congestive heart failure (CHF), we measured serum free fatty acid (FFA), counterregulatory hormone concentrations, whole body substrate oxidation rates (indirect calorimetry), and the turnover and oxidation rates of FFA ([1-(14)C]-palmitate infusion) in 7 patients with CHF and in 7 cardiac patients without CHF after an overnight fast. Plasma glucose and serum insulin concentrations were comparable, whereas serum FFA, blood ketone body, and fasting blood lactate (p

Objectives Increased activity of pro-inflammatory cytokines in the circulation has been observed in many, though not all, patients with congestive heart failure. To identify the predictors of cytokine activation in congestive heart failure, we assessed the relationship of peripheral and hepatic venous cytokines to central haemodynamics, neuroendocrine status and intermediary metabolism in patients with moderate or severe congestive heart failure. Patients and methods Concentrations of tumour necrosis factor-α, soluble tumour necrosis factor-receptor II and interleukin 6 were measured from peripheral and hepatic venous plasma in 58 adult cardiac patients, of whom 44 had congestive heart failure, undergoing heart catheterization, echocardiography and assessment of selected neuroendocrine and metabolic characteristics. Results Peripheral venous soluble tumour necrosis factor-receptor II was directly related to NYHA class (rs=0·46 P >0·001) and inversely to 6-min walking distance (rs−0·46, P >0·001). Peripheral venous tumour necrosis factor-α was related to 6-min walking distance (rs=−0·37, P >0·01), but like soluble tumour necrosis factor-receptor II, was unrelated to other haemodynamic and neuroendocrine measurements. Peripheral venous interleukin 6 correlated with NYHA class (rs=0·66, P >0·001) and 6-min walking distance (rs −0·52, P >0·001). In addition, interleukin 6 was related to right atrial pressure (rs0·55, P >0·001 pulmonary artery wedge pressure (rs=−0·50, P >0·001 and left ventricular ejection fraction (rs=−0·39, P >0·01); in multivariate analysis, only right atrial pressure was an independent predictor of interleukin 6 concentration ( P >0·001). Comparisons between patients with and without congestive heart failure showed significantly higher hepatic venous tumour necrosis factor-α, soluble tumour necrosis factor-receptor II and interleukin 6 in the heart failure group; the differences in peripheral venous cytokines were less consistent. Conclusions In cardiac patients, increased plasma tumour necrosis factor-α and soluble tumour necrosis factor-receptor II are associated with symptoms of heart failure and poor exercise capacity, while the most important predictor of increased interleukin 6 is elevated systemic venous pressure. Different but still unknown mechanisms may be responsible for the increased release of cytokines in congestive heart failure.

Various aspects must be anticipated in the planning of first aid in the massive orienteering contest Jukola-relay. Spreading of the event to a wide forest terrain area, beyond the reach of roads, poses a challenge for the evacuation of injured persons. The communication chains must be secured. In addition to the competition center, first aid points must be devised at various off-road points. Capable volunteers must be recruited in sufficient numbers. Establishing a temporary, health center standard emergency preparedness for approximately 50 000 people necessitates the acquisition of equipment and medicines for emergency care. Preparations must be made for the treatment of injuries and attacks of illness among the competitors, the audience and the volunteers.

Myocardial fibrosis predisposes to heart failure in aortic valve stenosis. The study aim was to determine the value of: (i) circulating collagen metabolites as biomarkers of left ventricular fibrosis and heart failure in aortic stenosis; and (ii) myocardial fibrosis as a predictor of postoperative outcome.Among a total of 132 patients (mean age 68 +/- 10 years) with severe aortic stenosis, measurements were made of circulating N-terminal propeptide of procollagen I (PINP), C-terminal telopeptide of collagen I (CITP) and N-terminal propeptide of procollagen III (PIIINP). Cardiac catheterization, echocardiography and a 6-min walk test were also performed. The aorta-to-coronary sinus concentration gradients of collagen metabolites were determined in 45 patients. Patients free from coronary artery disease (n = 85) underwent left ventricular biopsies for the assessment of myocardial fibrosis, one-year postoperative echocardiography and a 6-min walk test, and a long-term follow up for mortality.Neither peripheral collagen metabolites nor their transcardiac concentration gradients correlated with the extent of myocardial fibrosis. PIIINP demonstrated a net release from the heart, while PINP and CITP showed consistent falls in transcardiac concentrations that suggested extraction rather than release by the heart. Peripheral PIIINP correlated directly with the pulmonary wedge pressure (r = 0.50, p0.001) and inversely with the left ventricular ejection fraction (r = -0.40, p = 0.00001) and 6-min walk (r = -0.29, p = 0.001). Similar associations with heart failure were found for CITP, but not for PINP. One-year postoperative changes in exercise capacity and left ventricular mass and function were independent of myocardial fibrosis, as was mortality over a median of 8.8 years.Circulating collagen metabolites are not reliable surrogate measures of myocardial fibrosis in aortic stenosis, despite CITP and PIIINP being associated strongly with heart failure and left ventricular dysfunction. The results of surgery, including long-term survival, appear independent of the extent of myocardial fibrosis.

Objectives. The present study was designed to assess whether blood ketone bodies are elevated in congestive heart failure (CHF) and whether ketonemia is related to the hemodynamic and neurohumoral abnormalities of CHF. Background. In CHF, consumption of the body's fat stores may become abnormally high, contributing to the development of cardiac cachexia. Increased mobilization of free fatty acids could, in theory, augment ketogenesis, but whether patients with CHF are prone to ketosis remains unknown. Methods. Forty-five patients with chronic CHF (mean age [±SD] 57 ± 13 years) and 14 control subjects free of CHF (mean age 53 ± 13 years) underwent invasive and noninvasive cardiac studies and determination of blood ketone bodies (acetoacetate plus beta-hydroxybutyrate), circulating free fatty acids, glucose, lactate, insulin, glucagon, growth hormone, cortisol, norepinephrine, N-terminal proatrial natriuretic peptide, tumor necrosis factor-alpha and interleukin-6 after an overnight fast. Results. Patients with CHF had elevated blood ketone bodies (median 267 μmol/liter, range 44 to 952) compared with control subjects (median 150 μmol/liter, range 31 to 299, p < 0.05). In the total study group, blood ketone bodies were related to pulmonary artery wedge pressure (rs = 0.45, p < 0.001), left ventricular ejection fraction (rs = −0.37, p < 0.01), right atrial pressure (rs = 0.36, p < 0.01) and circulating concentrations of free fatty acids (rs = 0.52, p < 0.001), glucose (rs = −0.39, p < 0.01), norepinephrine (rs = 0.45, p < 0.001), growth hormone (rs = 0.30, p < 0.05) and interleukin-6 (rs = 0.27, p < 0.05). In multivariate analysis, left ventricular ejection fraction, serum free fatty acids and serum glucose were independent predictors of ketonemia. Conclusions. Blood ketone bodies are elevated in CHF in proportion to the severity of cardiac dysfunction and neurohormonal activation. This may be at least partly attributable to increased free fatty acid mobilization in response to augmented neurohormonal stimulation. Additional studies are needed to identify the detailed mechanisms and clinical implications of CHF ketosis.

The influence of body posture on atrial sensing was examined in a single-lead VDD pacemaker in 16 patients. At implantation, a position was searched for the floating atrial bipolar sensor to obtain an adequate atrial signal amplitude. After 1-12 months the atrial signals were measured by programming the sensitivity in five postures: supine, sitting, and standing and lying on the right and left sides. The group mean amplitudes of the atrial signal were equal in all postures, and comparable to the supine value (1.01 +/- 0.51 mV). However, the values within each individual varied considerably according to position, by a range of 0.46 +/- 0.41 mV on average. Testing only supine did not always predict decent sensing when upright, e.g., in 3 patients the atrial signal decreased more than 0.5 mV. In 24-hour ambulatory electrocardiography, with the sensitivity (0.15-0.30 mV) set to cover all postures, atrial beats were undersensed not at all in 4 patients, < 0.01% in 6 patients, and < 0.1% in the remaining 6 patients. Thus, with a floating atrial electrode, sensitivity testing in various postures is advisable to ascertain proper sensing function.

Background— Giant-cell myocarditis often escapes diagnosis until autopsy or transplantation and has defied proper treatment trials for its rarity and deadly behavior. Current therapy rests on multiple-drug immunosuppression but its prognostic influence remains poorly known. We set out to analyze (1) our experience in diagnosing giant-cell myocarditis and (2) the outcome of patients on combined immunosuppression. Methods and Results— We reviewed the histories, diagnostic procedures, details of treatment, and outcome of 32 consecutive patients with histologically verified giant-cell myocarditis treated in our hospital since 1991. Twenty-six patients (81%) were diagnosed by endomyocardial or surgical biopsies and 6 at autopsy or post-transplantation. Twenty-eight (88%) patients underwent endomyocardial biopsy. The sensitivity of transvenous endomyocardial biopsy increased from 68% (19/28 patients) to 93% (26/28) after up to 2 repeat procedures. The 26 biopsy-diagnosed patients were treated with combined immunosuppression (2–4 drugs) including cyclosporine in 20 patients. The Kaplan-Meier estimates of transplant-free survival from symptom onset were 69% at 1 year, 58% at 2 years, and 52% at 5 years. Of the transplant-free survivors, 10/17 (59%) experienced sustained ventricular tachyarrhythmias during follow-up and 3 received intracardiac defibrillator shocks for ventricular tachycardia or fibrillation. Conclusions— Repeat endomyocardial biopsies are frequently needed to diagnose giant-cell myocarditis. On contemporary immunosuppession, two thirds of patients reach a partial clinical remission characterized by freedom from severe heart failure and need of transplantation but continuing proneness to ventricular tachyarrhythmias.

Concern regarding recurrence of pre-transplant (Tx) malignancy has disqualified patients from Tx. Because this has been poorly studied in lung and heart Tx recipients our aim was to investigate the influence of pre-Tx malignancy on post-Tx recurrence and long-term survival, focusing on pre-operative cancer-free intervals.From our lung and heart Tx programs (1983 to 2011) we retrospectively identified 111 (lung, 37; heart, 74) of 3,830 recipients with 113 pre-Tx malignancies. The patients were divided into 3 groups by pre-Tx cancer-free interval: Group I,12 months (n = 24); Group II, ≥12 to60 months (n = 18); and Group III, ≥60 months (n = 71).Mean age at pre-Tx malignancy was 35±18 years. Mean post-Tx follow-up time was 70±63 months (range, 0-278 months), and malignancy recurrence was 63% in Group I, 26% in Group II, and 6% in Group III. Kaplan-Meier analysis of freedom from post-Tx recurrence revealed the following differences among the groups: Group I vs II, p = 0.08; II vs III, p = 0.002; and I vs III, p0.001. Overall survival (51 deaths) was significantly poorer in Group I than in Groups II and III (p = 0.044). Survival between Groups II and III did not differ significantly (p = 0.93).Cancer-free survival of ≥5 years pre-Tx is associated with the lowest recurrence. However, recurrence is related to the time the patients were cancer-free, as seen in Groups I and II.

In severe, acute or chronic heart failure, the heart and the circulation can be mechanically supported, if the patient's life is in danger despite maximal drug therapy, and other cardiologic or heart surgery treatment options or a suitable heart transplant are not available. Long-term prognosis of those treated with mechanical support has improved in the 2000's. This is based on technically advanced equipment, improved treatment practices, properly targeted patient selection and more accurate timing of therapy.

Objective. The first successful pregnancy after heart transplantation was reported in 1988. Worldwide experience with heart and heart/lung transplanted (H-HLTx) pregnant women is limited. To expand this knowledge the collaborating Nordic thoracic transplant centers wanted to collect information on all such pregnancies from their centers. Design. Information was retrospectively collected on all H-HLTx pregnancies in the Nordic countries. Results. A total of 25 women have had 42 pregnancies and all survived the gestation. Minor complications were increasing incidence of proteinuria, hypertension and diabetes. Major problems were two rejections (early post partum), two severe renal failures, seven pre-eclampsias and 17 abortions. Five women died two to 12 years after delivery. Of 25 live born children, one was born with cancer and one died early after inheriting the mother's cardiomyopathi. Conclusion. Pregnancy after H-HLTx can be successful for both mother and child. There are, however, many obstacles which should be addressed. Respecting the couple's desire for children the attitude should be carefully, not too optimistic, after proper pre-pregnant information and counseling. Delivery should preferably take place at the transplant center. (Less)

Background Heart transplantation (HTx) ameliorates the self-perceived health-related quality of life (HRQoL) of patients with terminal heart disease; gastrointestinal (GI) symptoms, due to obligatory immunosuppression, may contribute to impaired HRQoL post-HTx. Methods In this cross-sectional, exploratory study we aimed to investigate association between GI symptoms and HRQoL. The study consisted of 167 patients who had undergone HTx between 1985 and 2006 in Finland. Short-Form 36 (SF-36) Quality of Life and Gastrointestinal Symptom Rating Scale (GSRS) questionnaires were sent to the patients at the end of 2006 for capturing data on the HRQoL of HTx recipients. Results Higher or equal SF-36 scores describing the HRQoL dimensions compared with the Finnish age- and gender-matched reference population were as follows: physical functioning, 60.5%; role-physical, 67.5%; bodily pain, 62.6%; general health, 64.0%; vitality, 68.1%; social functioning, 68.1%; role-emotional, 70.0%; and mental health, 70.4%. The prevalence of troublesome GI symptoms (GSRS score >1) per GSRS dimension was 53.9% for diarrhea, 91.0% for indigestion, 60.6% for constipation, 73.4% for abdominal pain, 46.4% for reflux and 95.8% for any GI symptom. Diabetes contributed to the presence of diarrhea (odds ratio [OR]: 3.00; 95% confidence interval [CI]: 1.12 to 8.00), use of prednisolone to indigestion (OR: 3.21; 95% CI: 1.05 to 9.79) and increased age to constipation (OR: 1.04; 95% CI: 1.02 to 1.07). Conclusions HRQoL after HTx is relatively good and comparable to the age- and gender-matched reference population. HRQoL is vulnerable to side-effects caused by the obligatory post-HTx immunosuppressive regimen, where GI symptoms play a major but clearly an underestimated role.

The aim of this study was to evaluate the effect of myoblast transplantation on left ventricular function, perfusion, and scar formation after compromised coronary flow.A coronary vessel with Ameroid-induced stenosis was ligated and skeletal muscle was biopsied for isolation and cultivation of myoblasts. Two weeks after ligation, animals were randomly selected to receive intramyocardial injections of 2 x 10(6) myoblasts or vehicle. Fifteen animals survived the whole study period (n=9 and n=6, respectively). All animals underwent cardiac magnetic resonance imaging (MRI) and angiography pretreatment and four weeks posttreatment.Peak filling rate of the left ventricle improved in the myoblast group (p=0.0048), but not in the control group. Peak ejection rate and duration of diastole improved only in the myoblast group (p=0.049 and p=0.0039, respectively). Ejection fraction or local thickening did not change. Fibrosis and perfusion were similar in both groups, but more microvessels were present histologically in the myoblast group.In this preclinical study, autologous myoblast transplantation improved ischemic heart function via enhanced diastolic filling of the left ventricle.

Aims In aortic stenosis (AS), adverse remodelling of the valves may depend on altered local regulation of pro- and antifibrotic systems. We have recently shown that angiotensin-converting enzyme (ACE), which generates profibrotic angiotensin II and inactivates antifibrotic bradykinin (BK), is upregulated in stenotic aortic valves. Here, we analyse the expression of neutral endopeptidase (NEP), another profibrotic and BK-degrading enzyme, and of BK receptors in aortic valves in AS. Methods and results Stenotic aortic valves ( n = 86) were obtained at valve replacement surgery and control valves ( n = 13) at cardiac transplantation. Expression levels of NEP and BK type 1 and 2 receptors (BK-1R and BK-2R) in aortic valves and in isolated valvular myofibroblasts were analysed by real-time PCR and immunohistochemistry, and NEP activity was quantified by autoradiography. NEP, BK-1R, and BK-2R mRNA levels were higher in stenotic than in non-stenotic valves ( P < 0.05 for each) and the respective proteins localized to valvular endothelial cells and myofibroblasts. In stenotic valves, the proteolytic activity of NEP was significantly increased (4.5-fold, P < 0.001), and tumour necrosis factor-α induced the expression of NEP in cultured myofibroblasts. Finally, treatment of cultured myofibroblasts with an NEP inhibitor (phosphoramidon) downregulated the expression of profibrotic transforming growth factor-β1, whereas addition of BK decreased the expression of collagens I and III which was reversed by a BK-2R antagonist. Conclusion NEP activity is increased in stenotic aortic valves in parallel with increased expression of BK-receptors. The upregulation of NEP and BK-1R have the potential to promote valvular fibrosis and remodelling while the increase in BK-2R may represent a compensatory antifibrotic response. These findings add novel pathogenic insight and raise potential new therapeutic targets in AS.

To examine the role of the complement system, a source of powerful proinflammatory mediators, in aortic valve stenosis (AS).Stenotic aortic valves (n=24) were obtained at valve replacement surgery, and non-stenotic (n=12) and early sclerotic (n=4) valves at cardiac transplantations. The terminal complement complex C5b-9 was stained by immunohistochemistry. Expression of the anaphylatoxin receptors C3aR and C5aR was studied in the valves by immunohistochemistry and RT-PCR, and in isolated valve myofibroblasts after stimulation with potential AS-accelerating factors (TNF-alpha and cigarette smoke) by RT-PCR. Cultured myofibroblasts were exposed to C3a, and their secretion of proinflammatory cytokines was assessed by ELISA. C5b-9 was found already in early aortic valve lesions, and its deposition was augmented in advanced stenotic valves. In stenotic valves, expression of C3aR mRNA was upregulated (p0.05) and strong staining of C3aR and C5aR was detected. Myofibroblasts in stenotic, but not in control valves, expressed C3aR, and, in isolated myofibroblasts, TNF-alpha and cigarette smoke induced C3aR mRNA expression (p0.05 for both). Stimulation of myofibroblasts with C3a resulted in enhanced secretion of MCP-1 (p0.001), IL-6 (p=0.003), and IL-8 (p=0.03).In stenotic aortic valves, complement is activated leading to generation of the anaphylatoxins C3a and C5a. Upregulation of C3aR in the valves as a result of inflammation and external risk factors, such as cigarette smoke, leads to an inflammatory response in aortic valve myofibroblasts. Complement activation in stenotic valves emerges as a novel pathogenic component of AS and may serve as a therapeutic target in this disease.

Idiopathic giant-cell myocarditis (IGCM) is a rare and highly malignant form of inflammatory heart disease of unknown origin. Pathognomonic histological features are the presence of multinucleated giant cells and a widespread lymphocytic inflammatory infiltration in association with myocyte necrosis.1 IGCM predominantly affects previously healthy young and middle-aged people. Association with autoimmune disorders has been described in 19% of cases.2 Clinically, IGCM often shows a rapid onset of symptoms followed by a fulminant course resulting in congestive heart failure, progressive heart block and ventricular arrhythmias. The response to treatment is poor, and affected patients are often referred to cardiac transplantation.2 Although IGCM is highly associated with ventricular tachycardia,3 the features of ventricular arrhythmias have not been dealt with. We characterise the type of ventricular tachycardias, the recognition of which might initiate measures to promptly diagnose and treat IGCM. Clinical, electrocardiographic, echocardiographic and histopathological data were extracted from the medical records of nine patients diagnosed with IGCM in Helsinki University Hospital, Helsinki, Finland, between 1991 and 2004. On the basis of electrocardiographic recordings and intracardiac electrophysiological studies, ventricular tachycardias were classified as monomorphic or polymorphic, and the morphological pattern of monomorphic ventricular tachycardia was categorised as right bundle branch block (RBBB) or left bundle branch block (LBBB), and superior or inferior axis in the frontal plane. In electrophysiological studies, programmed ventricular stimulation was carried out from …

Objective— To investigate the possible role of elastolytic cathepsins S, K, and V and their endogenous inhibitor cystatin C in adverse extracellular matrix remodeling of stenotic aortic valves. Methods and Results— Stenotic aortic valves were collected at valve replacement surgery and control valves at cardiac transplantations. The expression of cathepsins S, K, and V and cystatin C was studied by conventional and real-time polymerase chain reaction and by immunohistochemistry. Total cathepsin activity in the aortic valves was quantified by a fluorometric microassay. When compared with control valves, stenotic valves showed increased mRNA expression of cathepsins S, K, and V ( P P P Conclusions— Stenotic aortic valves show increased expression and activity of elastolytic cathepsins S, K, and V. These cathepsins may accelerate the destruction of aortic valvular extracellular matrix, so promoting the progression of aortic stenosis.

Left ventricular (LV) stroke work loss (SWL) is an index of aortic stenosis (AS) severity based on the energy loss concept. Traditionally known as an invasive measurement, SWL has also been determined noninvasively using Doppler echocardiography. The present work was done to compare the echocardiographic estimate against the standard invasive SWL.We determined SWL in 113 adult patients with AS at cardiac catheterization (mean gradient as percentage of the LV mean systolic pressure) and by Doppler echocardiography (mean gradient as percentage of the sum of systolic cuff blood pressure and mean gradient). SWL averaged 26.5+/-0.6% by echocardiography vs 30.9+/-0.8% by catheterization (p0.0000001). The underestimation by echocardiography was the worse the higher the invasive SWL was (p0.00001). Echocardiographic SWL exceeding 25% (previously suggested cutoff) had a sensitivity of 64% and specificity of 74% to identify severe AS (Gorlin valve area0.5 cm(2)/m(2)). Several patients with severe AS by valve area had echocardiographic SWL suggesting only mild AS.In AS, echocardiography gives a biased estimate of LV SWL with marked underestimation in severe disease. Echocardiographic SWL may confuse rather than improve the assessment of AS in clinical practice.

Background Osteoprotegerin (OPG) and the receptor activator of nuclear factor-kB ligand (RANKL), two cytokines regulating bone remodeling, have recently been raised as potential pathogenetic factors in cardiovascular diseases. We have studied circulating and myocardial OPG and RANKL in patients having severe aortic stenosis (AS) with or without heart failure (HF). Methods We studied 131 adults with AS. Blood was sampled from the aortic root, coronary sinus, and femoral vein at cardiac catheterization. LV myocardial biopsies were taken at surgery. Plasma OPG and soluble (s)RANKL were analyzed by ELISA, and myocardial OPG and RANKL by RT-PCR and immunohistochemistry. Results Circulating OPG was elevated in AS patients with HF, the association being independent of age, sex, and presence of coronary artery disease (β=0.17, p=0.033). Elevated plasma OPG decreased after valve replacement in patients with preoperative HF (p=0.0005). Relative to its concentration in the aortic root, plasma OPG was reduced in the coronary sinus (p

AIMS Aortic stenosis (AS) is characterized by extensive remodelling of the valves, including infiltration of inflammatory cells, extracellular matrix degradation, and fibrosis. The molecular mechanisms behind this adverse remodelling have remained obscure. In this article, we study whether cathepsin G, an angiotensin II (Ang II)-forming elastolytic enzyme, contributes to progression of AS. METHODS AND RESULTS Stenotic aortic valves (n = 86) and control valves (n = 17) were analysed for cathepsin G, transforming growth factor-beta1 (TGF-beta1), and collagens I and III with RT-PCR and immunohistochemistry. Valvular collagen/elastin ratio was quantified by histochemistry. In stenotic valves, cathepsin G was present in mast cells and showed increased expression (P < 0.001), which correlated positively (P < 0.001) with the expression levels of TGF-beta1 and collagens I and III. TGF-beta1 was also present in mast cell-rich areas and cathepsin G induced losartan-sensitive TGF-beta1 expression in cultured fibroblasts. Collagen/elastin ratio was increased in stenotic valves (P < 0.001) and correlated positively with smoking (P = 0.02). Nicotine in cigarette smoke activated mast cells and induced TGF-beta1 expression in cultured fibroblasts. Fragmented elastin was observed in stenotic valves containing activated cathepsin G-secreting mast cells and in normal valves treated with cathepsin G. CONCLUSION In stenotic aortic valves, mast cell-derived cathepsin G may cause adverse valve remodelling and AS progression.