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1.  Peripheral venous congestion causes inflammation, neurohormonal, and endothelial cell activation 
European Heart Journal  2013;35(7):448-454.
Aims
Volume overload and venous congestion are typically viewed as a consequence of advanced and of acute heart failure (HF) and renal failure (RF) although it is possible that hypervolaemia itself might be a critical intermediate in the pathophysiology of these diseases. This study aimed at elucidating whether peripheral venous congestion is sufficient to promote changes in inflammatory, neurohormonal, and endothelial phenotype similar to those observed in HF and RF.
Methods
To experimentally model peripheral venous congestion, we developed a new method (so-called venous stress test) and applied the methodology on 24 healthy subjects (14 men, age 35 ± 2 years). Venous arm pressure was increased to ∼30 mmHg above the baseline level by inflating a tourniquet cuff around the dominant arm (test arm). Blood and endothelial cells (ECs) were sampled from test and control arm (lacking an inflated cuff) before and after 75 min of venous congestion, using angiocatheters and endovascular wires. Magnetic beads coated with EC-specific antibodies were used for EC separation; amplified mRNA was analysed by Affymetrix HG-U133 Plus 2.0 Microarray.
Results
Plasma interleukin-6 (IL-6), endothelin-1 (ET-1), angiotensin II (AII), vascular cell adhesion molecule-1 (VCAM-1), and chemokine (C-X-C motif) ligand 2 (CXCL2) were significantly increased in the congested arm. A total of 3437 mRNA probe sets were differentially expressed (P < 0.05) in venous ECs before vs. after testing, including ET-1, VCAM-1, and CXCL2.
Conclusion
Peripheral venous congestion causes release of inflammatory mediators, neurohormones, and activation of ECs. Overall, venous congestion mimicked, notable aspects of the phenotype typical of advanced and of acute HF and RF.
doi:10.1093/eurheartj/eht456
PMCID: PMC3924182  PMID: 24265434
Congestive heart failure; Endothelium; Endothelin; Inflammation
2.  Natriuretic peptides in cardiovascular diseases: current use and perspectives 
European Heart Journal  2013;35(7):419-425.
The natriuretic peptides (NPs) family, including atrial, B-type, and C-type NPs, is a group of hormones possessing relevant haemodynamic and anti-remodelling actions in the cardiovascular (CV) system. Due to their diuretic, natriuretic, vasorelaxant, anti-proliferative, and anti-hypertrophic effects, they are involved in the pathogenic mechanisms leading to major CV diseases, such as heart failure (HF), coronary artery disease, hypertension and left ventricular hypertrophy, and cerebrovascular accidents. Blood levels of NPs have established predictive value in the diagnosis of HF, as well as for its prognostic stratification. In addition, they provide useful clinical information in hypertension and in both stable and unstable coronary artery disease. Structural abnormalities of atrial natriuretic peptide gene (NPPA), as well as genetically induced changes in circulating levels of NPs, have a pathogenic causal link with CV diseases and represent emerging markers of CV risk. Novel NP-based therapeutic strategies are currently under advanced clinical development, as they are expected to contribute to the future management of hypertension and HF.
The present review provides a current appraisal of NPs’ clinical implications and a critical perspective of the potential therapeutic impact of pharmacological manipulation of this class of CV hormones.
doi:10.1093/eurheartj/eht466
PMCID: PMC4023301  PMID: 24227810
Natriuretic peptides; Cardiovascular diseases; Genetics; Natriuretic peptides analogues; NEP inhibitors; ARNi
3.  Monocyte subset accumulation in the human heart following acute myocardial infarction and the role of the spleen as monocyte reservoir 
European Heart Journal  2013;35(6):376-385.
Aims
Monocytes are critical mediators of healing following acute myocardial infarction (AMI), making them an interesting target to improve myocardial repair. The purpose of this study was a gain of insight into the source and recruitment of monocytes following AMI in humans.
Methods and results
Post-mortem tissue specimens of myocardium, spleen and bone marrow were collected from 28 patients who died at different time points after AMI. Twelve patients who died from other causes served as controls. The presence and localization of monocytes (CD14+ cells), and their CD14+CD16– and CD14+CD16+ subsets, were evaluated by immunohistochemical and immunofluorescence analyses. CD14+ cells localized at distinct regions of the infarcted myocardium in different phases of healing following AMI. In the inflammatory phase after AMI, CD14+ cells were predominantly located in the infarct border zone, adjacent to cardiomyocytes, and consisted for 85% (78–92%) of CD14+CD16– cells. In contrast, in the subsequent post-AMI proliferative phase, massive accumulation of CD14+ cells was observed in the infarct core, containing comparable proportions of both the CD14+CD16– [60% (31–67%)] and CD14+CD16+ subsets [40% (33–69%)]. Importantly, in AMI patients, of the number of CD14+ cells was decreased by 39% in the bone marrow and by 58% in the spleen, in comparison with control patients (P = 0.02 and <0.001, respectively).
Conclusions
Overall, this study showed a unique spatiotemporal pattern of monocyte accumulation in the human myocardium following AMI that coincides with a marked depletion of monocytes from the spleen, suggesting that the human spleen contains an important reservoir function for monocytes.
doi:10.1093/eurheartj/eht331
PMCID: PMC3916776  PMID: 23966310
Acute myocardial infarction; Inflammation; Monocytes; Spleen; Bone marrow
4.  Ischaemic cardiac outcomes in patients with atrial fibrillation treated with vitamin K antagonism or factor Xa inhibition: results from the ROCKET AF trial 
European Heart Journal  2013;35(4):233-241.
Aims
We investigated the prevalence of prior myocardial infarction (MI) and incidence of ischaemic cardiovascular (CV) events among atrial fibrillation (AF) patients.
Methods and results
In ROCKET AF, 14 264 patients with nonvalvular AF were randomized to rivaroxaban or warfarin. The key efficacy outcome for these analyses was CV death, MI, and unstable angina (UA). This pre-specified analysis was performed on patients while on treatment. Rates are per 100 patient-years. Overall, 2468 (17%) patients had prior MI at enrollment. Compared with patients without prior MI, these patients were more likely to be male (75 vs. 57%), on aspirin at baseline (47 vs. 34%), have prior congestive heart failure (78 vs. 59%), diabetes (47 vs. 39%), hypertension (94 vs. 90%), higher mean CHADS2 score (3.64 vs. 3.43), and fewer prior strokes or transient ischaemic attacks (46 vs. 54%). CV death, MI, or UA rates tended to be lower in patients assigned rivaroxaban compared with warfarin [2.70 vs. 3.15; hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.73–1.00; P = 0.0509]. CV death, MI, or UA rates were higher in those with prior MI compared with no prior MI (6.68 vs. 2.19; HR 3.04, 95% CI 2.59–3.56) with consistent results for CV death, MI, or UA for rivaroxaban compared with warfarin in prior MI compared with no prior MI (P interaction = 0.10).
Conclusion
Prior MI was common and associated with substantial risk for subsequent cardiac events. Patients with prior MI assigned rivaroxaban compared with warfarin had a non-significant 14% reduction of ischaemic cardiac events.
doi:10.1093/eurheartj/eht428
PMCID: PMC3896862  PMID: 24132190
Atrial fibrillation; Myocardial infarction; Coronary artery disease; Outcomes; Factor Xa; Rivaroxaban; Warfarin
5.  Clinical course of atrial fibrillation in older adults: the importance of cardiovascular events beyond stroke 
European Heart Journal  2013;35(4):250-256.
Aims
Atrial fibrillation increases the risks of stroke, heart failure, and death, and anticoagulation therapy increases the risk of gastrointestinal haemorrhage. However, the relative event rates for these outcomes are not well described. We sought to define the risks of major clinical events in older adults after a new diagnosis of atrial fibrillation.
Methods and results
We undertook a population-based, retrospective cohort study of a nationally representative sample of fee-for-service Medicare beneficiaries 65 years or older with incident atrial fibrillation diagnosed between 1999 and 2007. The main outcome measures were mortality and hospitalization or emergency department care for heart failure, myocardial infarction, stroke, or gastrointestinal haemorrhage. Among 186 461 patients with atrial fibrillation and no recent hospitalizations for heart failure, myocardial infarction, stroke, or gastrointestinal haemorrhage, mortality was the most frequent of these major clinical events (19.5% at 1 year; 48.8% at 5 years). By 5 years, 13.7% of patients were hospitalized for heart failure, 7.1% developed new-onset stroke, and 5.7% had gastrointestinal haemorrhage. Myocardial infarction was less frequent (3.9% at 5 years). Rates of mortality, heart failure, myocardial infarction, stroke, and gastrointestinal bleeding increased with older age and higher CHADS2 scores. Among 44 479 patients with previous events, the 5-year risk of death was greatest among patients with recent bleeding events (70.1%) and stroke (63.7%) and lowest among those with recent myocardial infarction (54.9%).
Conclusion
After the diagnosis of incident atrial fibrillation in older adults, mortality was the most frequent major outcome during the first 5 years. Among non-fatal cardiovascular events, heart failure was the most common event.
doi:10.1093/eurheartj/eht483
PMCID: PMC3896863  PMID: 24282186
Atrial fibrillation; Heart failure; Outcome assessment (health care); Mortality
6.  Beta-adrenergic adaptation in paediatric idiopathic dilated cardiomyopathy 
European Heart Journal  2012;35(1):33-41.
Background
Although the pathophysiology and treatment of adult heart failure (HF) are well studied, HF in children remains poorly understood. In adults, adrenergic receptor (AR)-mediated adaptation plays a central role in cardiac abnormalities in HF, and these patients respond well to β-blocker (BB) therapy. However, in children with HF, there is a growing body of literature suggesting a lack of efficacy of adult HF therapies. Due to these unanticipated differences in response to therapy and the paucity of data regarding the molecular adaptation of the paediatric heart, we investigated the molecular characteristics of HF in children.
Methods and results
Explanted hearts from adults and children with idiopathic dilated cardiomyopathy and non-failing controls were used in the study. Our results show that the molecular characteristics of paediatric HF are strikingly different from their adult counterparts. These differences include: (i) down-regulation of β1- and β2-AR in children, whereas β2-AR expression is maintained in adults; (ii) up-regulation of connexin43 in children, whereas down-regulation is observed in adults; (iii) no differences in phosphatase expression, whereas up-regulation is observed in adults; (iv) no decrease in the phosphorylation of phospholamban at the Ser16 or Thr17 sites in children, which are known characteristics of adult HF.
Conclusion
There is a different adaptation of β-AR and adrenergic signalling pathways in children with HF compared with adults. Our results begin to address the disparities in cardiovascular research specific to children and suggest that age-related differences in adaptation could influence the response to therapy. These findings could lead to a paradigm shift in the contemporary management of children with HF.
doi:10.1093/eurheartj/ehs229
PMCID: PMC3877432  PMID: 22843448
Paediatric dilated cardiomyopathy; β-Adrenergic receptor; CaMK; Phosphatase; Fetal gene programme
7.  Abrogated transforming growth factor beta receptor II (TGFβRII) signalling in dendritic cells promotes immune reactivity of T cells resulting in enhanced atherosclerosis 
European Heart Journal  2012;34(48):3717-3727.
Aims
The importance of transforming growth factor beta (TGFβ) as an immune regulatory cytokine in atherosclerosis has been established. However, the role of TGFβ signalling in dendritic cells (DCs) and in DC-mediated T cell proliferation and differentiation in atherosclerosis is unknown.
Methods and results
Here, we investigated the effect of disrupted TGFβ signalling in DCs on atherosclerosis by using mice carrying a transgene resulting in functional inactivation of TGFβ receptor II (TGFβRII) signalling in CD11c+ cells (Apoe−/−CD11cDNR). Apoe−/−CD11cDNR mice exhibited an over two-fold increase in the plaque area compared with Apoe−/− mice. Plaques of Apoe−/−CD11cDNR mice showed an increase in CD45+ leucocyte content, and specifically in CD3+, CD4+ and CD8+ cells, whereas macrophage content was not affected. In lymphoid organs, Apoe−/−CD11cDNR mice had equal amounts of CD11c+ cells, and CD11c+CD8+ and CD11c+CD8− subsets, but showed a subtle shift in the CD11c+CD8− population towards the more inflammatory CD11c+CD8−CD4− DC subset. In addition, the number of plasmacytoid-DCs decreased. Maturation markers such as MHCII, CD86 and CD40 on CD11chi cells did not change, but the CD11cDNR DCs produced more TNFα and IL-12. CD11c+ cells from CD11cDNR mice strongly induced T-cell proliferation and activation, resulting in increased amounts of effector T cells producing high amounts of Th1 (IFN-γ), Th2 (IL-4, IL-10), Th17 (IL-17), and Treg (IL-10) cytokines.
Conclusion
Here, we show that loss of TGFβRII signalling in CD11c+ cells induces subtle changes in DC subsets, which provoke uncontrolled T cell activation and maturation. This results in increased atherosclerosis and an inflammatory plaque phenotype during hypercholesterolaemia.
doi:10.1093/eurheartj/ehs106
PMCID: PMC3869966  PMID: 22613345
Atherosclerosis; Inflammation; TGFβ; Dendritic cell
8.  Transforming growth factor-β: transforming plaque to stability 
European Heart Journal  2012;34(48):3684-3686.
doi:10.1093/eurheartj/ehs228
PMCID: PMC3869967  PMID: 22843445
9.  Vitamin D and cardiovascular disease: is the evidence solid? 
European Heart Journal  2013;34(48):3691-3698.
Vitamin D deficiency, prevalent in 30–50% of adults in developed countries, is largely due to inadequate cutaneous production that results from decreased exposure to sunlight, and to a lesser degree from low dietary intake of vitamin D. Serum levels of 25-hydroxyvitamin D (25-OH D) <20 ng/mL indicate vitamin D deficiency and levels >30 ng/mL are considered optimal. While the endocrine functions of vitamin D related to bone metabolism and mineral ion homoeostasis have been extensively studied, robust epidemiological evidence also suggests a close association between vitamin D deficiency and cardiovascular morbidity and mortality. Experimental studies have demonstrated novel actions of vitamin D metabolites on cardiomyocytes, and endothelial and vascular smooth muscle cells. Low 25-OH D levels are associated with left ventricular hypertrophy, vascular dysfunction, and renin–angiotensin system activation. Despite a large body of experimental, cross-sectional, and prospective evidence implicating vitamin D deficiency in the pathogenesis of cardiovascular disease, a causal relationship remains to be established. Moreover, the cardiovascular benefits of normalizing 25-OH D levels in those without renal disease or hyperparathyroidism have not been established, and questions of an epiphenomenon where vitamin D status merely reflects a classic risk burden have been raised. Randomized trials of vitamin D replacement employing cardiovascular endpoints will provide much needed evidence for determining its role in cardiovascular protection.
doi:10.1093/eurheartj/eht166
PMCID: PMC3924041  PMID: 23751422
Vitamin D; Vascular risk factors; Cardiovascular disease
11.  T1 mapping and survival in systemic light-chain amyloidosis 
European Heart Journal  2014;36(4):244-251.
Aims
To assess the prognostic value of myocardial pre-contrast T1 and extracellular volume (ECV) in systemic amyloid light-chain (AL) amyloidosis using cardiovascular magnetic resonance (CMR) T1 mapping.
Methods and results
One hundred patients underwent CMR and T1 mapping pre- and post-contrast. Myocardial ECV was calculated at contrast equilibrium (ECVi) and 15 min post-bolus (ECVb). Fifty-four healthy volunteers served as controls. Patients were followed up for a median duration of 23 months and survival analyses were performed. Mean ECVi was raised in amyloid (0.44 ± 0.12) as was ECVb (mean 0.44 ± 0.12) compared with healthy volunteers (0.25 ± 0.02), P < 0.001. Native pre-contrast T1 was raised in amyloid (mean 1080 ± 87 ms vs. 954 ± 34 ms, P < 0.001). All three correlated with pre-test probability of cardiac involvement, cardiac biomarkers, and systolic and diastolic dysfunction. During follow-up, 25 deaths occurred. An ECVi of >0.45 carried a hazard ratio (HR) for death of 3.84 [95% confidence interval (CI): 1.53–9.61], P = 0.004 and pre-contrast T1 of >1044 ms = HR 5.39 (95% CI: 1.24–23.4), P = 0.02. Extracellular volume after primed infusion and ECVb performed similarly. Isolated post-contrast T1 was non-predictive. In Cox regression models, ECVi was independently predictive of mortality (HR = 4.41, 95% CI: 1.35–14.4) after adjusting for E:E′, ejection fraction, diastolic dysfunction grade, and NT-proBNP.
Conclusion
Myocardial ECV (bolus or infusion technique) and pre-contrast T1 are biomarkers for cardiac AL amyloid and they predict mortality in systemic amyloidosis.
doi:10.1093/eurheartj/ehu444
PMCID: PMC4301598  PMID: 25411195
ECV; Amyloid; CMR; Cardiomyopathy; Heart failure; T1 mapping
12.  Human autopsy study of drug-eluting stents restenosis: histomorphological predictors and neointimal characteristics 
European Heart Journal  2013;34(42):3304-3313.
Aims
Restenosis in drug-eluting stents (DESs) occurs infrequently, however, it remains a pervasive clinical problem. We interrogated our autopsy registry to determine the underlying mechanisms of DES restenosis, and further we investigated the neointimal characteristics of DESs and compared with bare metal stents (BMSs).
Methods and results
Coronary lesions from patients with DES implants (n = 82) were categorized into four groups based on cross-sectional area narrowing: patent (<50%), intermediate (50–74%), restenotic (≥75% with residual lumen), and total occlusion (organized thrombus within the stent). Restenosis and occlusion were significantly dependent on the total stented length: restenosis (26.7 mm) and occlusion (25.7 mm) compared with patent DESs (17.3 mm). Further, restenotic and occluded lesions were located more distally in the coronary arteries and had greater vessel injury and uneven strut distribution suggesting local drug gradient. Multivariate analysis revealed that normalized maximum inter-strut distance was associated with DES restenosis (OR: 17.4, P = 0.04) while medial tear length was a predictor of DES occlusion (OR: 5.1, P = 0.03). No differences were observed between different DESs (sirolimus-, paclitaxel-, and everolimus-eluting stents) for restenosis and occlusion. Further, neointimal compositions of restenotic DESs demonstrated greater proteoglycan deposition and less smooth muscle cellularity over time, when compared with BMS with greater cell density and collagen deposition.
Conclusions
Our study indicates the impacts of inadequate drug concentration due to wider inter-strut distance and vessel injury as primary mechanisms of DES restenosis and occlusion, respectively. Moreover, the differences in neointimal compositions between DESs and BMSs might serve as a potential target for the suppression of late neointima growth via inhibition of proteoglycans in DESs.
doi:10.1093/eurheartj/eht241
PMCID: PMC3819590  PMID: 23824827
Drug-eluting stent; Restenosis; Neointima; Histology; Human autopsy
13.  Endothelial dysfunction over the course of coronary artery disease 
European Heart Journal  2013;34(41):3175-3181.
The vascular endothelium regulates blood flow in response to physiological needs. Endothelial dysfunction is closely related to atherosclerosis and its risk factors, and it constitutes an intermediate step on the progression to adverse events throughout the natural history of coronary artery disease (CAD), often affecting clinical outcomes. Understanding the relation of endothelial function with CAD provides an important pathophysiological insight, which can be useful both in clinical and research management. In this review, we summarize the current knowledge on endothelial dysfunction and its prognostic influence throughout the natural history of CAD, from early atherosclerosis to post-transplant management.
doi:10.1093/eurheartj/eht351
PMCID: PMC3814514  PMID: 24014385
Endothelial dysfunction; Coronary heart disease; Heart failure; Heart transplant; Acetylcholine
14.  International comparison of treatment and long-term outcomes for acute myocardial infarction in the elderly: Minneapolis/St. Paul, MN, USA and Göteborg, Sweden 
European Heart Journal  2013;34(41):3191-3197.
Aims
International studies provide an opportunity to compare treatment approaches and outcomes. The present study compares elderly hospitalized acute myocardial infarction (AMI) patients in Minneapolis/St. Paul, USA (MSP) and Göteborg, Sweden (GB).
Methods and results
A population-based sample of hospitalized AMI (ICD-9 410) patients aged ≥75 in MSP and GB in 2001–02 was abstracted by trained nurses. Mortality was ascertained from medical records and death certificates. Demographics, cardiovascular procedures, and prescription medications were compared using sex-specific generalized linear models. Adjusted hazard ratios (HR) were calculated with Cox regression. In MSP 839 (387 men, 452 women) and in GB 564 (275 men, 289 women) patients were identified. Age was similar (men: MSP 83 ± 7, GB 82 ± 5; women: MSP 84 ± 6, GB 84 ± 6) yet MSP patients had more previous cardiovascular comorbidities and procedures (PCI/CABG). Guideline-based medication use was high in both locations. MSP patients were significantly more likely to undergo PCI (men: MSP 33%, GB 7%; women: MSP 30%, GB 7%). Survival at 7.5 years was 27.8% among MSP patients (men: 26.6%, women: 28.8%) and 17.2% among GB patients (men: 17.5%, women: 17.0%). After adjustment for baseline characteristics and guideline-based therapies, survival was higher among MSP men [HR: 0.66, 95% confidence interval (CI): 0.50–0.88] and women (HR: 0.49, 95% CI: 0.36–0.67) compared with GB.
Conclusion
In MSP and GB, guideline-based therapy use was high. However, PCI use was markedly higher in MSP. Long-term survival was better among elderly men and women in MSP compared with GB possibly related to greater utilization of PCI.
doi:10.1093/eurheartj/eht196
PMCID: PMC3814513  PMID: 23801823
Acute myocardial infarction; Elderly; International comparison
16.  Effect of aliskiren on post-discharge outcomes among diabetic and non-diabetic patients hospitalized for heart failure: insights from the ASTRONAUT trial 
Maggioni, Aldo P. | Greene, Stephen J. | Fonarow, Gregg C. | Böhm, Michael | Zannad, Faiez | Solomon, Scott D. | Lewis, Eldrin F. | Baschiera, Fabio | Hua, Tsushung A. | Gimpelewicz, Claudio R. | Lesogor, Anastasia | Gheorghiade, Mihai | Ramos, Silvina | Luna, Alejandra | Miriuka, Santiago | Diez, Mirta | Perna, Eduardo | Luquez, Hugo | Pinna, Jorge Garcia | Castagnino, Jorge | Alvarenga, Pablo | Ibañez, Julio | Blumberg, Eduardo Salmon | Dizeo, Claudio | Guerrero, Rodolfo Ahuad | Schygiel, Pablo | Milesi, Rodolfo | Sosa, Carlos | Hominal, Miguel | Marquez, Lilia Lobo | Poy, Carlos | Hasbani, Eduardo | Vico, Marisa | Fernandez, Alberto | Vita, Nestor | Vanhaecke, Johan | De Keulenaer, Gilles | Striekwold, Harry | Vervoort, Geert | Vrolix, Mathias | Henry, Philippe | Dendale, Paul | Smolders, Walter | Marechal, Patrick | Vandekerckhove, Hans | Oliveira, Mucio | Neuenschwande, Fernando | Reis, Gilmar | Saraiva, Jose | Bodanese, Luiz | Canesin, Manoel | Greco, Oswaldo | Bassan, Roberto | Marino, Roberto Luis | Giannetti, Nadia | Moe, Gordon | Sussex, Bruce | Sheppard, Richard | Huynh, Thao | Stewart, Robert | Haddad, Haissam | Echeverria, Luis | Quintero, Adalberto | Torres, Adriana | Jaramillo, Mónica | Lopez, Mónica | Mendoza, Fernan | Florez, Noel | Cotes, Carlos | Garcia, Magali | Belohlavek, Jan | Hradec, Jaromir | Peterka, Martin | Gregor, Pavel | Monhart, Zdenek | Jansky, Petr | Kettner, Jiri | Reichert, Petr | Spinar, Jindrich | Brabec, Tomas | Hutyra, Martin | Solar, Miroslav | Pietilä, Mikko | Nyman, Kai | Pajari, Risto | Cohen, Ariel | Galinier, Michel | Gosse, Philippe | Livarek, Bernard | Neuder, Yannick | Jourdain, Patrick | Picard, François | Isnard, Richard | Hoppe, Uta | Kaeaeb, Stefan | Rosocha, Stefan | Prondzinsky, Roland | Felix, Stephan | Duengen, Hans-Dirk | Figulla, Hans-Reiner | Fischer, Sven | Behrens, Steffen | Stawowy, Philipp | Kruells-Muench, Juergen | Knebel, Fabian | Nienaber, Christoph | Werner, Dierk | Aron, Wilma | Remppis, Bjoern | Hambrecht, Rainer | Kisters, Klaus | Werner, Nikos | Hoffmann, Stefan | Rossol, Siegbert | Geiss, Ernst | Graf, Kristof | Hamann, Frank | von Scheidt, Wolfgang | Schwinger, Robert | Tebbe, Ulrich | Costard-Jaeckle, Angelika | Lueders, Stephan | Heitzer, Thomas | Leutermann-Oei, Marie-Louise | Braun-Dullaeus, Ruediger | Roehnisch, Jens-Uwe | Muth, Gerhard | Goette, Andreas | Rotter, Achim | Ebelt, Henning | Olbrich, Hans-Georg | Mitrovic, Veselin | Hengstenberg, Christian | Schellong, Sebastian | Zamolyi, Karoly | Vertes, Andras | Matoltsy, Andras | Palinkas, Attila | Herczeg, Bela | Apro, Dezso | Lupkovics, Geza | Tomcsanyi, Janos | Toth, Kalman | Mathur, Atul | Banker, Darshan | Bharani, Anil | Arneja, Jaspal | Khan, Aziz | Gadkari, Milind | Hiremath, Jagdish | Patki, Nitin | Kumbla, Makund | Santosh, M.J. | Ravikishore, A.G. | Abhaichand, Rajpal | Maniyal, Vijayakukmar | Nanjappa, Manjunath | Reddy, P. Naveen | Chockalingam, Kulasekaran | Premchand, Rajendra | Mahajan, Vijay | Lewis, Basil | Wexler, Dov | Shochat, Michael | Keren, Andre | Omary, Muhamad | Katz, Amos | Marmor, Alon | Lembo, Giuseppe | Di Somma, Salvatore | Boccanelli, Alessandro | Barbiero, Mario | Pajes, Giuseppe | De Servi, Stefano | Greco, Dott Cosimo | De Santis, Fernando | Floresta, Agata | Visconti, Luigi Oltrona | Piovaccari, Giancarlo | Cavallini, Claudio | Di Biase, Matteo | Masini, Dott Franco | Vassanelli, Corrado | Viecca, Maurizio | Cangemi, Dott Francesco | Pirelli, Salvatore | Borghi, Claudio | Volpe, Massimo | Branzi, Angelo | Percoco, Dott Giovanni | Severi, Silvia | Santini, Alberto | De Lorenzi, Ettore | Metra, Marco | Zacà, Valerio | Mortara, Andrea | Tranquilino, Francisco P. | Babilonia, Noe A. | Ferrolino, Arthur M. | Manlutac, Benjamin | Dluzniewski, Miroslaw | Dzielinska, Zofia | Nowalany-Kozie, Ewa | Mazurek, Walentyna | Wierzchowiecki, Jerzy | Wysokinski, Andrzej | Szachniewicz, Joanna | Romanowski, Witold | Krauze-Wielicka, Magdalena | Jankowski, Piotr | Berkowski, Piotr | Szelemej, Roman | Kleinrok, Andrzej | Kornacewicz-Jac, Zdzislawa | Vintila, Marius | Vladoianu, Mircea | Militaru, Constantin | Dan, Gheorghe | Dorobantu, Maria | Dragulescu, Stefan | Kostenko, Victor | Vishnevsky, Alexandr | Goloschekin, Boris | Tyrenko, Vadim | Gordienko, Alexander | Kislyak, Oxana | Martsevich, Sergey | Kuchmin, Alexey | Karpov, Yurii | Fomin, Igor | Shvarts, Yury | Orlikova, Olga | Ershova, Olga | Berkovich, Olga | Sitnikova, Maria | Pakhomova, Inna | Boldueva, Svetlana | Tyurina, Tatiana | Simanenkov, Vladimir | Boyarkin, Mikhail | Novikova, Nina | Tereschenko, Sergey | Zadionchenko, Vladimir | Shogenov, Zaur | Gordeev, Ivan | Moiseev, Valentin | Wong, Raymond | Ong, Hean Yee | Le Tan, Ju | Goncalvesova, Eva | Kovar, Frantisek | Skalina, Ivan | Kasperova, Viera | Hojerova, Silvia | Szentivanyi, Miroslav | Stancak, Branislav | Babcak, Marian | Kycina, Peter | Poliacik, Pavol | Toth, Peter | Sirotiakova, Jana | de Sa, Esteban Lopez | Bueno, Manuel Gomez | Selles, Manuel Martinez | Cabrera, Jose Angel | Freire, Ramon Bover | Gonzalez Juanatey, Jose Ramon | Comin, Josep | Soriano, FranciscoRidocci | Lopez, Alejandro | Vicho, Raul | Lama, Manuel Geraldia | Schaufelberger, Maria | Brunotte, Richard | Ullman, Bengt | Hagerman, Inger | Cizinsky, Stella | Cherng, Wen-Jin | Yu, Wen-Chung | Kuo, Chi-Tai | Chang, Kuan-Cheng | Lai, Wen-Ter | Kuo, Jen-Yuan | Ural, Dilek | Badak, Ozer | Akin, Mustafa | Yigit, Zerrin | Yokusoglu, Mehmet | Yilmaz, Mehmet | Abaci, Adnan | Ebinc, Haksun | Perlman, Richard | Parish, David | Bergin, James | Burnham, Kenneth | Brown, Christopher | Lundbye, Justin | Williams, Celeste | Eisen, Howard | Juneman, Elizabeth | Joseph, Susan | Peberdy, Mary Ann | Peura, Jennifer | Gupta, Vishal | Habet, Kalim | French, William | Mody, Freny | Graham, Susan | Hazelrigg, Monica | Chung, Eugene | Dunlap, Stephanie | Nikolaidis, Lazaros | Najjar, Samer | Katz, Richard | Murali, Srinivas | Izzo, Joseph L. | Callister, Tracy | Phillips, Roland | Lippolis, Nicholas | Winterton, John | Meymandi, Sheba | Heilman, Karl | Oren, Ron | Zolty, Ronald | Brottman, Michael | Gunawardena, D.R. | Adams, Kirkwood | Barnard, Denise | Klapholz, Marc | Fulmer, James
European Heart Journal  2013;34(40):3117-3127.
Aims
The objective of the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) was to determine whether aliskiren, a direct renin inhibitor, would improve post-discharge outcomes in patients with hospitalization for heart failure (HHF) with reduced ejection fraction. Pre-specified subgroup analyses suggested potential heterogeneity in post-discharge outcomes with aliskiren in patients with and without baseline diabetes mellitus (DM).
Methods and results
ASTRONAUT included 953 patients without DM (aliskiren 489; placebo 464) and 662 patients with DM (aliskiren 319; placebo 343) (as reported by study investigators). Study endpoints included the first occurrence of cardiovascular death or HHF within 6 and 12 months, all-cause death within 6 and 12 months, and change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) at 1, 6, and 12 months. Data regarding risk of hyperkalaemia, renal impairment, and hypotension, and changes in additional serum biomarkers were collected. The effect of aliskiren on cardiovascular death or HHF within 6 months (primary endpoint) did not significantly differ by baseline DM status (P = 0.08 for interaction), but reached statistical significance at 12 months (non-DM: HR: 0.80, 95% CI: 0.64–0.99; DM: HR: 1.16, 95% CI: 0.91–1.47; P = 0.03 for interaction). Risk of 12-month all-cause death with aliskiren significantly differed by the presence of baseline DM (non-DM: HR: 0.69, 95% CI: 0.50–0.94; DM: HR: 1.64, 95% CI: 1.15–2.33; P < 0.01 for interaction). Among non-diabetics, aliskiren significantly reduced NT-proBNP through 6 months and plasma troponin I and aldosterone through 12 months, as compared to placebo. Among diabetic patients, aliskiren reduced plasma troponin I and aldosterone relative to placebo through 1 month only. There was a trend towards differing risk of post-baseline potassium ≥6 mmol/L with aliskiren by underlying DM status (non-DM: HR: 1.17, 95% CI: 0.71–1.93; DM: HR: 2.39, 95% CI: 1.30–4.42; P = 0.07 for interaction).
Conclusion
This pre-specified subgroup analysis from the ASTRONAUT trial generates the hypothesis that the addition of aliskiren to standard HHF therapy in non-diabetic patients is generally well-tolerated and improves post-discharge outcomes and biomarker profiles. In contrast, diabetic patients receiving aliskiren appear to have worse post-discharge outcomes. Future prospective investigations are needed to confirm potential benefits of renin inhibition in a large cohort of HHF patients without DM.
doi:10.1093/eurheartj/eht342
PMCID: PMC3800848  PMID: 23999456
Aliskiren; Diabetes; Outcomes; Post-discharge
17.  Adherence to antihypertensive therapy prior to the first presentation of stroke in hypertensive adults: population-based study 
European Heart Journal  2013;34(38):2933-2939.
Aims
Antihypertensive drug therapy is a major strategy of stroke prevention among hypertensive patients. The aim of this study was to estimate the excess risk of stroke associated with non-adherence to antihypertensive drug therapy among hypertensive patients.
Methods and results
We conducted a population-based study using records from Finnish national registers for 1 January 1995 to 31 December 2007. Of the 73 527 hypertensive patients aged 30 years or older and without pre-existing stroke or cardiovascular disease, 2144 died from stroke and 24 560 were hospitalized due to stroke during the follow-up. At the 2- and 10-year follow-up after the start of continuous antihypertensive medication, non-adherent patients had 3.81 [95% confidence interval (CI) 2.85–5.10] and 3.01 (95% CI: 2.37–3.83) times higher odds of stroke death when compared with the adherent patients. The corresponding odds ratio (OR) for stroke hospitalization was 2.74 (95% CI: 2.35–3.20) at Year 2 and 1.71 (95% CI: 1.49–1.96) at Year 10. In the stroke-event year, the ORs were higher, 5.68 (95% CI: 5.05–6.39) for stroke death and 1.87 (95% CI: 1.72–2.03) for hospitalization. Among those using agents acting on the renin–angiotensin system combined with diuretics or β-blockers, these ORs were 7.49 (95% CI: 5.62–9.98) and 3.91 (95% CI: 3.23–4.75), respectively. The associations between non-adherence and stroke followed a dose–response pattern—the poorer the adherence, the greater the risk of death and hospitalization due to stroke.
Conclusion
These data suggest that poor adherence to antihypertensive therapy substantially increases near- and long-term risk of stroke among hypertensive patients.
doi:10.1093/eurheartj/eht219
PMCID: PMC3791393  PMID: 23861328
Adherence; Antihypertensive therapy; Stroke; Hypertension; Mortality
18.  Repeated episodes of thrombosis as a potential mechanism of plaque progression in cardiac allograft vasculopathy 
European Heart Journal  2013;34(37):2905-2915.
Aims
The pathogenesis of cardiac allograft vasculopathy (CAV) remains complex and may involve multiple mechanisms. We tested the hypothesis that the multilayer (ML) appearance, an intravascular ultrasound (IVUS) finding suggestive of repetitive thrombosis, is associated with plaque progression in heart transplant (HTx) recipients.
Methods and results
Our study population consisted of 132 HTx recipients undergoing at least two grayscale and virtual histology (VH)-IVUS examinations. A retrospective serial analysis was performed between the first (baseline) and the last (follow-up) IVUS data during a median follow-up of 3.0 years. The subjects were divided into two groups based on the presence of the ML appearance on the baseline IVUS. At baseline, subjects with ML appearance (n = 38) had a longer time elapsed since transplant, larger vessel volume, and larger plaque volume than those without (n = 94) (all P < 0.01). Intraluminal thrombi and plaque ruptures were identified only in subjects with ML appearance (P < 0.01 vs. those without). More subjects with ML appearance at baseline developed subsequent ML formation compared with those without [21 (55%) vs. 22 (23%), P < 0.01] during follow-up. There was an increase in plaque volume, necrotic core volume, and dense calcium volume in subjects with ML appearance (all P < 0.01 vs. those without). Multivariable linear regression analysis showed that ML appearance was a potential predictor of plaque progression (regression coefficient 0.28, 95% CI 0.10–0.45, P < 0.01).
Conclusions
The current study demonstrates that a finding of ML appearance, indicative of repeated episodes of mural thrombosis, is not infrequent in asymptomatic HTx recipients and possibly contributes to progression of CAV.
doi:10.1093/eurheartj/eht209
PMCID: PMC3787274  PMID: 23782648
Cardiac allograft vasculopathy; Thrombosis; Plaque progression; Intravascular ultrasound
19.  Midlife blood pressure change and left ventricular mass and remodelling in older age in the 1946 British birth cohort study† 
European Heart Journal  2014;35(46):3287-3295.
Aims
Antecedent blood pressure (BP) may contribute to cardiovascular disease (CVD) independent of current BP. Blood pressure is associated with left ventricular mass index (LVMI) which independently predicts CVD. We investigated the relationship between midlife BP from age 36 to 64 and LVMI at 60–64 years.
Methods and results
A total of 1653 participants in the British 1946 Birth Cohort underwent BP measurement and echocardiography aged 60–64. Blood pressure had previously been measured at 36, 43, and 53 years. We investigated associations between BP at each age and rate of change in systolic blood pressure (SBP) between 36–43, 43–53, and 53–60/64 years on LVMI at 60–64 years. Blood pressure from 36 years was positively associated with LVMI. Association with SBP at 53 years was independent of SBP at 60–64 years and other potential confounders (fully adjusted β at 53 years = 0.19 g/m2; 95% CI: 0.11, 0.27; P < 0.001). Faster rates of increase in SBP from 43 to 53 years and 53 to 60/64 years were associated with increased LVMI. Similar relationships were seen for diastolic, pulse, and mean pressure. Rate of increase in SBP between 43–53 years was associated with largest change in LVMI (β at 43–53 years = 3.12 g/m2; 95% CI: 1.53, 4.72; P < 0.001). People on antihypertensive medication (43 years onwards) had greater LVMI even after adjustment for current BP (β at 43 years = 12.36 g/m2; 95% CI: 3.19, 21.53; P = 0.008).
Conclusion
Higher BP in midlife and rapid rise of SBP in 5th decade is associated with higher LVMI in later life, independent of current BP. People with treated hypertension have higher LVMI than untreated individuals, even accounting for their higher BP. Our findings emphasize importance of midlife BP as risk factor for future CVD.
doi:10.1093/eurheartj/ehu389
PMCID: PMC4258225  PMID: 25246483
Blood pressure; Left ventricular mass; Left ventricular hypertrophy; Echocardiography
20.  Heart rate reduction by If-inhibition improves vascular stiffness and left ventricular systolic and diastolic function in a mouse model of heart failure with preserved ejection fraction 
European Heart Journal  2012;34(36):2839-2849.
Aims
In diabetes mellitus, heart failure with preserved ejection fraction (HFPEF) is a significant comorbidity. No therapy is available that improves cardiovascular outcomes. The aim of this study was to characterize myocardial function and ventricular-arterial coupling in a mouse model of diabetes and to analyse the effect of selective heart rate (HR) reduction by If-inhibition in this HFPEF-model.
Methods and results
Control mice, diabetic mice (db/db), and db/db mice treated for 4 weeks with the If-inhibitor ivabradine (db/db-Iva) were compared. Aortic distensibility was measured by magnetic resonance imaging. Left ventricular (LV) pressure–volume analysis was performed in isolated working hearts, with biochemical and histological characterization of the cardiac and aortic phenotype. In db/db aortic stiffness and fibrosis were significantly enhanced compared with controls and were prevented by HR reduction in db/db-Iva. Left ventricular end-systolic elastance (Ees) was increased in db/db compared with controls (6.0 ± 1.3 vs. 3.4 ± 1.2 mmHg/µL, P < 0.01), whereas other contractility markers were reduced. Heart rate reduction in db/db-Iva lowered Ees (4.0 ± 1.1 mmHg/µL, P < 0.01), and improved the other contractility parameters. In db/db active relaxation was prolonged and end-diastolic capacitance was lower compared with controls (28 ± 3 vs. 48 ± 8 μL, P < 0.01). These parameters were ameliorated by HR reduction. Neither myocardial fibrosis nor hypertrophy were detected in db/db, whereas titin N2B expression was increased and phosphorylation of phospholamban was reduced both being prevented by HR reduction in db/db-Iva.
Conclusion
In db/db, a model of HFPEF, selective HR reduction by If-inhibition improved vascular stiffness, LV contractility, and diastolic function. Therefore, If-inhibition might be a therapeutic concept for HFPEF, if confirmed in humans.
doi:10.1093/eurheartj/ehs218
PMCID: PMC3858102  PMID: 22833515
Heart rate reduction; Ventricular-arterial coupling; Diastolic dysfunction; HFPEF; Vascular stiffness
21.  Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060 
European Heart Journal  2013;34(35):2746-2751.
Aims
Since atrial fibrillation (AF) is associated with increased risks of cardiovascular and cerebrovascular complications, estimations on the number of individuals with AF are relevant to healthcare planning. We aimed to project the number of individuals with AF in the Netherlands and in the European Union from 2000 to 2060.
Methods and results
Age- and sex-specific AF prevalence estimates were obtained from the prospective community-based Rotterdam Study. Population projections for the Netherlands and the European Union were obtained from the European Union's statistics office. In the age stratum of 55–59 years, the prevalence of AF was 1.3% in men (95% CI: 0.4–3.6%) and 1.7% in women (95% CI: 0.7–4.0%). The prevalence of AF increased to 24.2% in men (95% CI: 18.5–30.7%), and 16.1% in women (95% CI: 13.1–19.4%), for those >85 years of age. This age- and sex-specific prevalence remained stable during the years of follow-up. Furthermore, we estimate that in the European Union, 8.8 million adults over 55 years had AF in 2010 (95% CI: 6.5–12.3 million). We project that this number will double by 2060 to 17.9 million (95% CI: 13.6–23.7 million) if the age- and sex-specific prevalence remains stable.
Conclusion
We estimate that from 2010 to 2060, the number of adults 55 years and over with AF in the European Union will more than double. As AF is associated with significant morbidities and mortality, this increasing number of individuals with AF may have major public health implications.
doi:10.1093/eurheartj/eht280
PMCID: PMC3858024  PMID: 23900699
Atrial fibrillation; Epidemiology
22.  Increased risk of coronary heart disease among individuals reporting adverse impact of stress on their health: the Whitehall II prospective cohort study 
European Heart Journal  2013;34(34):2697-2705.
Aim
Response to stress can vary greatly between individuals. However, it remains unknown whether perceived impact of stress on health is associated with adverse health outcomes. We examined whether individuals who report that stress adversely affects their health are at increased risk of coronary heart disease (CHD) compared with those who report that stress has no adverse health impact.
Methods and results
Analyses are based on 7268 men and women (mean age: 49.5 years, interquartile range: 11 years) from the British Whitehall II cohort study. Over 18 years of follow-up, there were 352 coronary deaths or first non-fatal myocardial infarction (MI) events. After adjustment for sociodemographic characteristics, participants who reported at baseline that stress has affected their health ‘a lot or extremely’ had a 2.12 times higher (95% CI 1.52–2.98) risk of coronary death or incident non-fatal MI when compared with those who reported no effect of stress on their health. This association was attenuated but remained statistically significant after adjustment for biological, behavioural, and other psychological risk factors including perceived stress levels, and measures of social support; fully adjusted hazard ratio: 1.49 (95% CI 1.01–2.22).
Conclusions
In this prospective cohort study, the perception that stress affects health, different from perceived stress levels, was associated with an increased risk of coronary heart disease. Randomized controlled trials are needed to determine whether disease risk can be reduced by increasing clinical attention to those who complain that stress greatly affects their health.
doi:10.1093/eurheartj/eht216
PMCID: PMC3766148  PMID: 23804585
Epidemiology; Stress; Coronary heart disease; Prospective studies
23.  Coronary atherosclerosis with vulnerable plaque and complicated lesions in transplant recipients: new insight into cardiac allograft vasculopathy by optical coherence tomography 
European Heart Journal  2013;34(33):2610-2617.
Aims
Cardiac allograft vasculopathy (CAV) is a major limitation to long-term survival following cardiac transplantation. Conventional imaging modalities such as angiography and intravascular ultrasound fail to characterize CAV plaque morphology. Our aim was to characterize CAV in vivo using the high spatial resolution of intracoronary optical coherence tomography (OCT).
Methods and results
We prospectively enrolled 53 cardiac transplant patients to undergo OCT of the left anterior descending coronary artery (LAD) in addition to annual CAV screening by coronary angiography and intravascular ultrasound (IVUS). The proximal 30 mm of the LAD was divided into three segments of 10 mm each (n = 156). Segments with CAV plaque on IVUS were analysed by OCT for specific CAV morphological characteristics within the framework of three groups according to follow-up time after heart transplantation: (i) 0–3 months (n = 18), (ii) 12–36 months (n = 55), and (iii) ≥48 months (n = 83). The prevalence of atherosclerotic characteristics such as eccentric plaques, calcification, and lipid pools increased from 6, 0, and 6% in group 1 to 78, 42, and 61% in group 3, respectively (all P < 0.001). The prevalence of vulnerable plaque features such as thin-cap fibroatheroma, macrophages, and microchannels increased from 0% in group 1 to 12, 29, and 33% in group 3, respectively (P = 0.19, P = 0.006, and P = 0.003). Complicated coronary lesions such as intimal laceration, intraluminal thrombus, and layered complex plaque increased from 0% in group 1 to 18, 19, and 57% in group 3 (P = 0.009, P < 0.001, and P < 0.001). Plaque rupture was identified in 4% of group 3 segments.
Conclusion
The current study gives new insight into CAV that extends far beyond the current concept of concentric and fibrosing vasculopathy, that is, the development of atherosclerosis with vulnerable plaque and complicated coronary lesions.
doi:10.1093/eurheartj/eht236
PMCID: PMC3758840  PMID: 23801824
Cardiac allograft vasculopathy; Transplant; Optical coherence tomography; Atherosclerosis; Vulnerable plaque; Thrombus
24.  Long-term clinical effects of ventricular pacing reduction with a changeover mode to minimize ventricular pacing in a general pacemaker population 
European Heart Journal  2014;36(3):151-157.
Aim
Right ventricular pacing (VP) has been hypothesized to increase the risk in heart failure (HF) and atrial fibrillation (AF). The ANSWER study evaluated, whether an AAI-DDD changeover mode to minimize VP (SafeR) improves outcome compared with DDD in a general dual-chamber pacemaker population.
Methods and results
ANSWER was a randomized controlled multicentre trial assessing SafeR vs. standard DDD in sinus node disease (SND) or AV block (AVB) patients. After a 1-month run-in period, they were randomized (1 : 1) and followed for 3 years. Pre-specified co-primary end-points were VP and the composite of hospitalization for HF, AF, or cardioversion. Pre-specified secondary end-points were cardiac death or HF hospitalizations and cardiovascular hospitalizations. ANSWER enrolled 650 patients (52.0% SND, 48% AVB) at 43 European centres and randomized in SafeR (n = 314) or DDD (n = 318). The SafeR mode showed a significant decrease in VP compared with DDD (11.5 vs. 93.6%, P < 0.0001 at 3 years). Deaths and syncope did not differ between randomization arms. No significant difference between groups [HR = 0.78; 95% CI (0.48–1.25); P = 0.30] was found in the time to event of the co-primary composite of hospitalization for HF, AF, or cardioversion, nor in the individual components. SafeR showed a 51% risk reduction (RR) in experiencing cardiac death or HF hospitalization [HR = 0.49; 95% CI (0.27–0.90); P = 0.02] and 30% RR in experiencing cardiovascular hospitalizations [HR = 0.70; 95% CI (0.49–1.00); P = 0.05].
Conclusion
SafeR safely and significantly reduced VP in a general pacemaker population though had no effect on hospitalization for HF, AF, or cardioversion, when compared with DDD.
doi:10.1093/eurheartj/ehu336
PMCID: PMC4297468  PMID: 25179761
Dual-chamber pacing; Minimization of ventricular pacing; Heart failure; Atrial fibrillation; Randomized controlled trial; SafeR
25.  EuroEco (European Health Economic Trial on Home Monitoring in ICD Patients): a provider perspective in five European countries on costs and net financial impact of follow-up with or without remote monitoring 
European Heart Journal  2014;36(3):158-169.
Aim
Remote follow-up (FU) of implantable cardiac defibrillators (ICDs) allows for fewer in-office visits in combination with earlier detection of relevant findings. Its implementation requires investment and reorganization of care. Providers (physicians or hospitals) are unsure about the financial impact. The primary end-point of this randomized prospective multicentre health economic trial was the total FU-related cost for providers, comparing Home Monitoring facilitated FU (HM ON) to regular in-office FU (HM OFF) during the first 2 years after ICD implantation. Also the net financial impact on providers (taking national reimbursement into account) and costs from a healthcare payer perspective were evaluated.
Methods and results
A total of 312 patients with VVI- or DDD-ICD implants from 17 centres in six EU countries were randomised to HM ON or OFF, of which 303 were eligible for data analysis. For all contacts (in-office, calendar- or alert-triggered web-based review, discussions, calls) time-expenditure was tracked. Country-specific cost parameters were used to convert resource use into monetary values. Remote FU equipment itself was not included in the cost calculations. Given only two patients from Finland (one in each group) a monetary valuation analysis was not performed for Finland. Average age was 62.4 ± 13.1 years, 81% were male, 39% received a DDD system, and 51% had a prophylactic ICD. Resource use with HM ON was clearly different: less FU visits (3.79 ± 1.67 vs. 5.53 ± 2.32; P < 0.001) despite a small increase of unscheduled visits (0.95 ± 1.50 vs. 0.62 ± 1.25; P < 0.005), more non-office-based contacts (1.95 ± 3.29 vs. 1.01 ± 2.64; P < 0.001), more Internet sessions (11.02 ± 15.28 vs. 0.06 ± 0.31; P < 0.001) and more in-clinic discussions (1.84 ± 4.20 vs. 1.28 ± 2.92; P < 0.03), but with numerically fewer hospitalizations (0.67 ± 1.18 vs. 0.85 ± 1.43, P = 0.23) and shorter length-of-stay (6.31 ± 15.5 vs. 8.26 ± 18.6; P = 0.27), although not significant. For the whole study population, the total FU cost for providers was not different for HM ON vs. OFF [mean (95% CI): €204 (169–238) vs. €213 (182–243); range for difference (€−36 to 54), NS]. From a payer perspective, FU-related costs were similar while the total cost per patient (including other physician visits, examinations, and hospitalizations) was numerically (but not significantly) lower. There was no difference in the net financial impact on providers [profit of €408 (327–489) vs. €400 (345–455); range for difference (€−104 to 88), NS], but there was heterogeneity among countries, with less profit for providers in the absence of specific remote FU reimbursement (Belgium, Spain, and the Netherlands) and maintained or increased profit in cases where such reimbursement exists (Germany and UK). Quality of life (SF-36) was not different.
Conclusion
For all the patients as a whole, FU-related costs for providers are not different for remote FU vs. purely in-office FU, despite reorganized care. However, disparity in the impact on provider budget among different countries illustrates the need for proper reimbursement to ensure effective remote FU implementation.
doi:10.1093/eurheartj/ehu339
PMCID: PMC4297469  PMID: 25179766
Implantable cardioverter defibrillator; Remote monitoring; Devices; Follow-up; Health economics

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