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1.  Quantification of Left Ventricular Torsion and Diastolic Recoil Using Cardiovascular Magnetic Resonance Myocardial Feature Tracking 
PLoS ONE  2014;9(10):e109164.
Objectives
Cardiovascular magnetic resonance feature tracking (CMR-FT) offers quantification of myocardial deformation from routine cine images. However, data using CMR-FT to quantify left ventricular (LV) torsion and diastolic recoil are not yet available. We therefore sought to evaluate the feasibility and reproducibility of CMR-FT to quantify LV torsion and peak recoil rate using an optimal anatomical approach.
Methods
Short-axis cine stacks were acquired at rest and during dobutamine stimulation (10 and 20 µg·kg−1·min−1) in 10 healthy volunteers. Rotational displacement was analysed for all slices. A complete 3D-LV rotational model was developed using linear interpolation between adjacent slices. Torsion was defined as the difference between apical and basal rotation, divided by slice distance. Depending on the distance between the most apical (defined as 0% LV distance) and basal (defined as 100% LV distance) slices, four different models for the calculation of torsion were examined: Model-1 (25–75%), Model-2 (0–100%), Model-3 (25–100%) and Model-4 (0–75%). Analysis included subendocardial, subepicardial and global torsion and recoil rate (mean of subendocardial and subepicardial values).
Results
Quantification of torsion and recoil rate was feasible in all subjects. There was no significant difference between the different models at rest. However, only Model-1 (25–75%) discriminated between rest and stress (Global Torsion: 2.7±1.5°cm−1, 3.6±2.0°cm−1, 5.1±2.2°cm−1, p<0.01; Global Recoil Rate: −30.1±11.1°cm−1s−1,−46.9±15.0°cm−1s−1,−68.9±32.3°cm−1s−1, p<0.01; for rest, 10 and 20 µg·kg−1·min−1 of dobutamine, respectively). Reproducibility was sufficient for all parameters as determined by Bland-Altman analysis, intraclass correlation coefficients and coefficient of variation.
Conclusions
CMR-FT based derivation of myocardial torsion and recoil rate is feasible and reproducible at rest and with dobutamine stress. Using an optimal anatomical approach measuring rotation at 25% and 75% apical and basal LV locations allows effective quantification of torsion and recoil dynamics. Application of these new measures of deformation by CMR-FT should next be explored in disease states.
doi:10.1371/journal.pone.0109164
PMCID: PMC4186780  PMID: 25285656
2.  Excessive Supraventricular Ectopic Activity Is Indicative of Paroxysmal Atrial Fibrillation in Patients with Cerebral Ischemia 
PLoS ONE  2013;8(6):e67602.
Background
Detecting paroxysmal atrial fibrillation (PAF) in patients with cerebral ischemia is challenging. Frequent premature atrial complexes (PAC/h) and the longest supraventricular run on 24-h-Holter (SV-run24 h), summarised as excessive supraventricular ectopic activity (ESVEA), may help selecting patients for extended ECG-monitoring, especially in combination with echocardiographic marker LAVI/a’ (left atrial volume index/late diastolic tissue Doppler velocity).
Methods
Retrospective analysis from the prospective monocentric observational trial Find-AF (ISRCTN-46104198). Patients with acute stroke or TIA were enrolled at the University Hospital Göttingen, Germany. Those with sinus rhythm at presentation received 7-day Holter-monitoring. ESVEA was quantified in one 24-hour interval free from PAF. Echocardiographic parameters were assessed prospectively.
Results
PAF was detected in 23/208 patients (11.1%). The median was 4 [IQR 1; 22] for PAC/h and 5 [IQR 0; 9] for SV-run24 h. PAF was more prevalent in patients with ESVEA: 19.6% vs. 2.8% for PAC/h >4 vs. ≤4 (p<0.001); 17.0% vs. 4.9% for SV-run24 h >5 vs. ≤5 beats (p = 0.003). Patients with PAF showed more supraventricular ectopic activity: 29 PAC/h [IQR 9; 143] vs. 4 PAC/h [1]; [14] and longest SV-run24 h = 10 [5]; [21] vs. 0 [0; 8] beats (both p<0.001). Both markers discriminated between the PAF- and the Non-PAF-group (area under receiver-operator-characteristics-curve 0.763 [95% CI 0.667; 0.858] and 0.716 [0.600; 0.832]). In multivariate analyses log(PAC/h) and log(SV-run24 h) were independently indicative of PAF. In Patients with PAC/h ≤4 and normal LAVI/a’ PAF was excluded, whereas those with PAC/h >4 and abnormal LAVI/a’ showed high PAF-rates.
Conclusions
ESVEA discriminated PAF from non-PAF beyond clinical factors including LAVI/a’ in patients with cerebral ischemia. Normal LAVI/a’+PAC/h ≤4 ruled out PAF, while prevalence was high in those with abnormal LAVI/a’+PAC/h >4.
doi:10.1371/journal.pone.0067602
PMCID: PMC3695922  PMID: 23840747
3.  Age-dependent yield of screening for undetected atrial fibrillation in stroke patients: the Find-AF study 
Journal of Neurology  2013;260(8):2042-2045.
Diagnosis of paroxysmal atrial fibrillation (AF) in stroke patients is challenging, but highly clinically relevant. The percentage of stroke patients with permanent AF increases with age, but limited data are available for the age-dependent yield of paroxysmal AF by Holter monitoring. Patients with acute cerebral ischemia were included into the prospective observational Find-AF study. Patients free from AF at presentation received 7 day Holter monitoring. We calculated the percentage of otherwise undetected paroxysmal AF and the number needed to screen for age groups under 60 years, and in 5 year clusters from the age of 60 up to 85 and older. 272 patients were included, 43 (15.8 %) had AF at admission, 33 patients with paroxysmal AF were identified by 7 day Holter (n = 29) or medical history (n = 4).The yield of 7 day Holter ECG clearly increased with older age (p = 0.004): <60 years: 5 %, 60–64 years: 5 %, 65–69 years: 7 %, 70–74 years: 11 %, 75–79 years: 13 %, 80–84 years: 25 %, ≥85 years: 39 %. The number needed to screen (NNS) to find one patient with paroxysmal AF decreased with age: ≤60 years: 18, 60–64 years: 20, 65–69 years: 14, 70–74 years: 9, 75–79 years: 8, 80–84 years: 4, ≥85 years: 3, respectively. In patients <65 years, all AF cases were detected by Holter ECG. The percentage of paroxysmal AF in stroke patients increases with age. The 7 day Holter ECG is most efficient in elderly patients.
doi:10.1007/s00415-013-6935-x
PMCID: PMC3734596  PMID: 23632947
Age; Paroxysmal atrial fibrillation; Screening; Stroke; Atrial fibrillation; Cohort study
4.  A simple score for rapid risk assessment of non-high-risk pulmonary embolism 
Clinical Research in Cardiology  2012;102(1):73-80.
Objective
We tested whether bedside testing for H-FABP is, alone or integrated in combination models, useful for rapid risk stratification of non-high-risk PE.
Methods
We prospectively studied 136 normotensive patients with confirmed PE. H-FABP was determined using a qualitative bedside-test showing a positive result for plasma concentration >7 ng/ml.
Results
Overall, 11 patients (8.1 %) had an adverse 30-day outcome. Of 58 patients (42.6 %) with a positive H-FABP bedside-test, 9 (15.5 %) had an unfavourable course compared to 2 of 78 patients (2.6 %) with a negative test result (p = 0.009). Logistic regression analysis indicated a sevenfold increased risk for an adverse outcome (95 % CI, 1.45–33.67; p = 0.016) for patients with a positive H-FABP bedside-test. Additive prognostic information were obtained by a novel score including the H-FABP bedside-test (1.5 points), tachycardia (2 points), and syncope (1.5 points) (OR 11.57 [2.38–56.24]; p = 0.002 for ≥3 points). Increasing points were associated with a continuous exponential increase in the rate of an adverse 30-day outcome (0 % for patients with 0 points and 44.4 % for ≥5 points). Notably, this simple score provided similar prognostic value as the combination of the H-FABP bedside-test with echocardiographic signs of right ventricular dysfunction (OR 12.73 [2.51–64.43]; p = 0.002).
Conclusions
Bedside testing for H-FABP appears a useful tool for immediate risk stratification of non-high-risk patients with acute PE, who may be at increased risk of an adverse outcome, in particular if integrated in a novel score without the need of echocardiographic examination.
doi:10.1007/s00392-012-0498-1
PMCID: PMC3536952  PMID: 23011575
Bedside-test; Biomarker; Combination models; Heart-type fatty acid-binding protein (H-FABP); Risk stratification; Pulmonary embolism
5.  Oral health status of patients with acute coronary syndrome – a case control study 
BMC Oral Health  2012;12:17.
Background
The aim of this investigation was to assess the state of oral health of patients with acute coronary syndrome (ACS) and to compare this with that of a provably healthy control group (H).
Methods
33 patients who were receiving treatment as inpatients following acute myocardial infarction or unstable angina pectoris took part in the study (ACS-group). A healthy control group (H-group) made up of blood donors, was formed following matching for age, gender, and smoking habit with the study patient group.
The dental investigation consisted of the dental status (DMF-T), a plaque-Index (PI), an assessment of gingival inflammation (GI) and periodontal situation (Periodontal Screening Index: PSR®/PSI), and attachment loss (AL). Statistical evaluation: t-test, Mann–Whitney-test and chi- squared test (level of significance p < 0.05).
Results
The mean DMF-T of the ACS-group (18.7 ± 6.8) and the H-group (19.4 ± 5.1) showed no difference (p = 0.7). Although, in the ACS-group the average loss of teeth (M-T: 8.4 ± 5.2) was higher than in the H-group (M-T: 5.8 ± 6.6) the difference was not significant (p = 0.2). Whereas with the PI no difference between the two groups was found (p = 0.9), the ACS-group showed significantly more signs of inflammation (GI) than the H-group (p = 0.045). In the case of PSR®/PSI, there was no difference between the two groups (p = 0.7). With regard to AL, no difference was revealed between ACS- and H-group (p = 0.2).
Conclusion
Although, the state of oral health of the ACS-group differed only insignificantly from that of control, patients with ACS showed more signs of gingival inflammation and a higher loss of teeth.
doi:10.1186/1472-6831-12-17
PMCID: PMC3444382  PMID: 22727119
Oral health; Oral hygiene; Gingival inflammation; Periodontitis; Acute coronary syndrome; Acute myocardial infarction; Unstable angina pectoris
6.  Natriuretic Peptides for the Detection of Paroxysmal Atrial Fibrillation in Patients with Cerebral Ischemia – the Find-AF Study 
PLoS ONE  2012;7(4):e34351.
Background and Purpose
Diagnosis of paroxysmal atrial fibrillation (AF) can be challenging, but it is highly relevant in patients presenting with sinus rhythm and acute cerebral ischemia. We aimed to evaluate prospectively whether natriuretic peptide levels and kinetics identify patients with paroxysmal AF.
Methods
Patients with acute cerebral ischemia were included into the prospective observational Find-AF study. N-terminal pro brain-type natriuretic peptide (NT-proBNP), brain-type natriuretic peptide (BNP) and N-terminal pro atrial-type natriuretic peptide (NT-proANP) plasma levels were measured on admission, after 6 and 24 hours. Patients free from AF at presentation received 7 day Holter monitoring. We prospectively hypothesized that patients presenting in sinus rhythm with NT-proBNP>median were more likely to have paroxysmal AF than patients with NT-proBNP
Results
281 patients were included, of whom 237 (84.3%) presented in sinus rhythm. 220 patients naïve to AF with an evaluable prolonged Holter ECG were analysed. In patients with NT-proBNP>median (239 pg/ml), 17.9% had paroxysmal AF in contrast to 7.4% with NT-proBNP<239 pg/ml (p = 0.025). The ratio of early (0 h) to late (24 h) plasma levels of NT-proBNP showed no difference between both groups. For the detection of paroxysmal atrial fibrillation, BNP, NT-proBNP and NT-proANP at admission had an area under the curve in ROC analysis of 0.747 (0.663–0.831), 0.638 (0.531–0.744) and 0.663 (0.566–0.761), respectively. In multivariate analysis, BNP was the only biomarker to be independently predictive for paroxysmal atrial fibrillation.
Conclusions
BNP is independently predictive of paroxysmal AF detected by prolonged ECG monitoring in patients with cerebral ischemia and may be used to effectively select patients for prolonged Holter monitoring.
doi:10.1371/journal.pone.0034351
PMCID: PMC3324530  PMID: 22509292
Clinical Research in Cardiology  2012;101(7):553-563.
Background
Transcatheter aortic valve implantation (TAVI) has recently developed into an acceptable alternative to conventional surgery in high-risk patients. However, information on the identification of patients gaining most benefit from this procedure is still limited. The aim of this study was to evaluate safety and efficacy of TAVI in different patient cohorts.
Methods
Between August 2008 and December 2010, 180 high-risk patients underwent TAVI at our institution (97 transapical and 83 transfemoral approaches). Periprocedural complications as well as mortality and incidence of MACCE during follow-up were recorded.
Results
Mean age was 82 ± 5 years, and mean logistic EuroScore 27 ± 14%. In the total cohort, 30-day mortality was 8.9% and 12-month survival (according to Kaplan–Meier-analysis) 72%, with no significant differences between the two approaches. However, a significant difference in survival was obvious after stratification of patients according to logistic EuroScore mortality estimates. Survival proportions at 1 year were 62% in patients with logistic EuroScore >40%, 71% in patients with EuroScore 20–40% and 80% in octogenarians with EuroScore <20% (P = 0.009). Furthermore, the observed median event-free survival as an indicator for morbidity ranged between 315 days in the first, 442 days in the second and 710 days in the third group (P = 0.1).
Conclusions
TAVI proved to be feasible with reproducible results. However, mortality and rehospitalization rates were considerably high in specific patient cohorts, suggesting that the risk-to-benefit ratio of TAVI should be validated individually. In the present study, octogenarians with logistic EuroScore <20% could be identified as candidates apparently gaining high benefit from the procedure.
doi:10.1007/s00392-012-0426-4
PMCID: PMC3377897  PMID: 22350751
Aortic valve; Aortic stenosis; Transcatheter aortic valve implantation; TAVI
Europace  2011;14(3):416-422.
Aims
The EUTrigTreat clinical study has been designed as a prospective multicentre observational study and aims to (i) risk stratify patients with an implantable cardioverter defibrillator (ICD) for mortality and shock risk using multiple novel and established risk markers, (ii) explore a link between repolarization biomarkers and genetics of ion (Ca2+, Na+, K+) metabolism, (iii) compare the results of invasive and non-invasive electrophysiological (EP) testing, (iv) assess changes of non-invasive risk stratification tests over time, and (v) associate arrythmogenomic risk through 19 candidate genes.
Methods and results
Patients with clinical ICD indication are eligible for the trial. Upon inclusion, patients will undergo non-invasive risk stratification, including beat-to-beat variability of repolarization (BVR), T-wave alternans, T-wave morphology variables, ambient arrhythmias from Holter, heart rate variability, and heart rate turbulence. Non-invasive or invasive programmed electrical stimulation will assess inducibility of ventricular arrhythmias, with the latter including recordings of monophasic action potentials and assessment of restitution properties. Established candidate genes are screened for variants. The primary endpoint is all-cause mortality, while one of the secondary endpoints is ICD shock risk. A mean follow-up of 3.3 years is anticipated. Non-invasive testing will be repeated annually during follow-up. It has been calculated that 700 patients are required to identify risk predictors of the primary endpoint, with a possible increase to 1000 patients based on interim risk analysis.
Conclusion
The EUTrigTreat clinical study aims to overcome current shortcomings in sudden cardiac death risk stratification and to answer several related research questions. The initial patient recruitment is expected to be completed in July 2012, and follow-up is expected to end in September 2014.
Clinicaltrials.gov identifier: NCT01209494.
doi:10.1093/europace/eur352
PMCID: PMC3283222  PMID: 22117037
Sudden cardiac death risk stratification; Implantable cardioverter defibrillator; Cardiomyocyte ion metabolism; Ventricular repolarization; Electrocardiogram; Programmed electrical stimulation; Repolarization alternans
Clinical Research in Cardiology  2011;100(9):755-764.
Background
Comorbidities negatively affect prognosis more strongly in heart failure with preserved (HFpEF) than with reduced (HFrEF) ejection fraction. Their comparative impact on physical impairment in HFpEF and HFrEF has not been evaluated so far.
Methods and results
The frequency of 12 comorbidities and their impact on NYHA class and SF-36 physical functioning score (SF-36 PF) were evaluated in 1,294 patients with HFpEF and 2,785 with HFrEF. HFpEF patients had lower NYHA class (2.0 ± 0.6 vs. 2.4 ± 0.6, p < 0.001) and higher SF-36 PF score (54.4 ± 28.3 vs. 54.4 ± 27.7, p < 0.001). All comorbidities were significantly (p < 0.05) more frequent in HFrEF, except hypertension and obesity, which were more frequent in HFpEF (p < 0.001). Adjusting for age and gender, COPD, anemia, hyperuricemia, atrial fibrillation, renal dysfunction, cerebrovascular disease and diabetes had a similar (p for interaction > 0.05) negative effect in both groups. Obesity, coronary artery disease and peripheral arterial occlusive disease exerted a significantly (p < 0.05) more adverse effect in HFpEF, while hypertension and hyperlipidemia were associated with fewer (p < 0.05) symptoms in HFrEF only. The total impact of comorbidities on NYHA (AUC for prediction of NYHA III/IV vs. I/II) and SF-36 PF (r2) in multivariate analyses was approximately 1.5-fold higher in HFpEF, and also much stronger than the impact of a 10% decrease in ejection fraction in HFrEF or a 5 mm decrease in left ventricular end-diastolic diameter in HFpEF.
Conclusion
The impact of comorbidities on physical impairment is higher in HFpEF than in HFrEF. This should be considered in the differential diagnosis and in the treatment of patients with HFpEF.
doi:10.1007/s00392-011-0305-4
PMCID: PMC3167043  PMID: 21416189
Heart failure with preserved ejection fraction; Heart failure with reduced ejection fraction; Comorbidities; Physical impairment
European Journal of Heart Failure  2010;12(12):1309-1316.
Aims
Heart failure with normal ejection fraction (HFnEF) is an important clinical entity that remains incompletely understood. The novel biomarker growth differentiation factor 15 (GDF-15) is elevated in systolic heart failure (HFrEF) and is predictive of an adverse outcome. We investigated the clinical relevance of GDF-15 plasma levels in HFnEF.
Methods and results
A subgroup of patients from the ongoing DIAST-CHF observational trial, with a history of chronic heart failure (CHF) or positive Framingham criteria at presentation, was selected. Patients were classified as having either HFrEF (n = 86) or HFnEF (n = 142) and compared with healthy elderly controls (n = 188) from the same cohort. Growth differentiation factor 15 levels in HFnEF were significantly higher than in controls and similar to those in HFrEF. In multivariate analysis, factors significantly associated with GDF-15 levels were age, sex, estimated glomerular filtration rate (eGFR), presence of HFrEF and HFnEF. Growth differentiation factor 15 correlated with multiple echocardiographic markers of diastolic function and was associated with 6 min walk test performance and SF-36 physical score on multivariate analysis in all patients. When using a classification for HFnEF that did not employ N-terminal pro brain natriuretic peptide (NT-proBNP) as a diagnostic criterion, the diagnostic properties of GDF-15 for detecting HFnEF tended to be superior to those of NT-proBNP, and a combination significantly improved diagnostic accuracy.
Conclusion
Growth differentiation factor 15 is elevated in HFnEF to a similar degree as in HFrEF. It is independently associated with impairment in exercise capacity and in physical components of quality of life. Diagnostic precision of GDF-15 is at least as good as that of NT-proBNP and combining both markers improves diagnostic accuracy.
doi:10.1093/eurjhf/hfq151
PMCID: PMC2990410  PMID: 20837635
Heart failure; Diastolic heart failure; Biological markers; Growth differentiation factor 15; Diagnosis; Cross-sectional studies
European Heart Journal  2009;30(24):3027-3036.
Aims
We tested the hypothesis that, in heart failure with normal ejection fraction (HFNEF), diastolic dysfunction is accentuated at increasing heart rates, and this contributes to impaired frequency-dependent augmentation of cardiac output.
Methods and results
In 17 patients with HFNEF (median age 69 years, 13 female) and seven age-matched control patients, systolic and diastolic function was analysed by pressure–volume loops at baseline heart rate and during atrial pacing to 100 and 120 min−1. At baseline, relaxation was prolonged and end-diastolic left ventricular stiffness was higher in HFNEF, whereas all parameters of systolic function were not different from control patients. This resulted in smaller end-diastolic volumes, higher end-diastolic pressure, and a lower stroke volume and cardiac index in HFNEF vs. control patients. During pacing, frequency-dependent upregulation of contractility indices (+dP/dtmax and Ees) occurred similarly in HFNEF and control patients, but frequency-dependent acceleration of relaxation (dP/dtmin) was blunted in HFNEF. In HFNEF, end-diastolic volume and stroke volume decreased with higher heart rates while both remained unchanged in control patients.
Conclusion
In HFNEF, frequency-dependent upregulation of cardiac output is blunted. This results from progressive volume unloading of the left ventricle due to limited relaxation reserve in combination with increased LV passive stiffness, despite preserved force–frequency relation.
doi:10.1093/eurheartj/ehp341
PMCID: PMC2792717  PMID: 19720638
Diastolic function; Heart failure; Pressure volume loops; Force–frequency relation
Background and purpose
Clinical scores are recommended for predicting cardiovascular risk in patients with cerebral ischaemia to inform secondary prevention. Blood biomarkers may improve prediction beyond clinical scores.
Methods
Within the observational Find-AF trial (ISRCTN46104198), 197 patients >18 years of age with cerebral ischaemia and without atrial fibrillation had blood sampled at baseline. The predictive value of five biomarkers for a combined vascular endpoint (acute coronary syndrome, stroke, cardiovascular death) and all-cause mortality was determined, alone and in addition to the Essen Stroke Risk Score (ESRS), Stroke Prognostic Instrument 2 (SPI-2) and National Institutes of Health Stroke Scale (NIH-SS).
Results
There were 23 vascular events (11.7%) and 13 deaths (6.6%) to 1 year follow-up. In multivariate analyses of all markers, only high-sensitivity troponin T (hsTropT) remained independently predictive for vascular events (p=0.045) and all-cause mortality (p=0.004). hsTropT was higher in patients with a vascular event (median 12.7 ng/ml vs 5.1 ng/ml), and patients with hsTropT above the median of 6.15 ng/ml had vascular events more frequently (HR 3.86, p=0.008). For prediction of vascular events as well as all-cause mortality, hsTropT significantly improved multivariate Cox regression models with ESRS, SPI-2 or NIH-SS. The c-statistic increased non-significantly from 0.695 (ESRS) or 0.710 (hsTropT) to 0.747 (ESRS+hsTropT) and from 0.699 (SPI-2) to 0.763 (SPI-2+hsTropT). No patient with a low-risk ESRS and an hsTropT below the median had a vascular event or died.
Conclusions
hsTropT predicts vascular events and all-cause mortality in patients with acute cerebral ischaemia and improves prediction beyond established clinical scores.
doi:10.1136/jnnp-2012-303360
PMCID: PMC3623028  PMID: 23355808
Stroke; Cardiology; Cerebrovascular Disease

Results 1-13 (13)