Methylated free-circulating HPP1 DNA is an early response marker in patients with metastatic colorectal cancer.

Detection of methylated free-circulating DNA (mfcDNA) for hyperplastic polyposis 1 (HPP1) in blood is correlated with a poor prognosis for patients with metastatic colorectal cancers (mCRC). Here, we analyzed the plasma levels of HPP1 mfcDNA in mCRC patients treated with a combination therapy containing a fluoropyrimidine, oxaliplatin and bevacizumab to test whether HPP1 mfcDNA is a suitable prognostic and response biomarker. From 467 patients of the prospective clinical study AIO-KRK-0207, mfcDNA was isolated from plasma samples at different time points and bisulfite-treated mfcDNA was quantified using methylation specific PCR. About 337 of 467 patients had detectable levels for HPP1 mfcDNA before start of treatment. The detection was significantly correlated with poorer overall survival (OS) (HR = 1.86; 95%CI 1.37-2.53). About 2-3 weeks after the first administration of combination chemotherapy, HPP1 mfcDNA was reduced to non-detectable levels in 167 of 337 patients. These patients showed a better OS compared with patients with continued detection of HPP1 mfcDNA (HR HPP1(sample 1: pos/ sample 2: neg) vs. HPP1(neg/neg) = 1.41; 95%CI 1.00-2.01, HPP1(neg,pos/pos) vs. HPP1(neg/neg) = 2.60; 95%CI 1.86-3.64). Receiver operating characteristic analysis demonstrated that HPP1 mfcDNA discriminates well between patients who do (not) respond to therapy according to the radiological staging after 12 or 24 weeks (AUC = 0.77 or 0.71, respectively). Detection of HPP1 mfcDNA can be used as a prognostic marker and an early marker for response (as early as 3-4 weeks after start of treatment compared with radiological staging after 12 or 24 weeks) to identify patients who will likely benefit from a combination chemotherapy with bevacizumab.

Implantable cardiac monitors in high-risk post-infarction patients with cardiac autonomic dysfunction and moderately reduced left ventricular ejection fraction: Design and rationale of the SMART-MI trial.

BACKGROUND: Most deaths after myocardial infarction (MI) occur in patients with left ventricular ejection fraction (LVEF) >35%, for whom no specific prophylactic strategies exist. Deceleration capacity (DC) of heart rate and periodic repolarization dynamics (PRD) are noninvasive electrophysiological markers depending on the vagal and sympathetic tone. The combination of abnormal DC and/or PRD identifies a new high-risk group among postinfarction patients with LVEF 36%-50%. This new high-risk group has similar characteristics with respect to prognosis and patient numbers to those of the established high-risk group identified by LVEF ≤ 35%. STUDY DESIGN: The SMART-MI trial is an investigator-initiated randomized prospective multicenter trial that tests the efficacy of implantable cardiac monitors (ICM) in this new high-risk group. The study will enroll approximately 1,600 survivors of acute MI with sinus rhythm and an LVEF of 35%-50% in 17 centers in Germany who will be tested for presence of cardiac autonomic dysfunction. Four hundred patients with either abnormal DC (≤2.5 ms) and/or PRD (≥5.75deg2) will be randomized in a 1:1 fashion to intensive follow-up via telemonitoring using an ICM device (experimental arm) or conventional follow-up (control arm). For the ICM arm, specific treatment paths have been developed according to current guidelines. OUTCOMES: The primary end point is time to detection of predefined serious arrhythmic events during follow-up, including atrial fibrillation ≥6minutes, nonsustained ventricular tachycardia (cycle length≤320 ms; ≥40 beats), atrioventricular block ≥IIb, and sustained ventricular tachycardia/ventricular fibrillation. The median follow-up period is 18months with a minimum follow-up of 6months. The effect of remote monitoring on clinical outcomes will be tested as secondary outcome measure (ClinicalTrials.gov NCT02594488).

Impact of moderate altitude exposure on cardiovascular risk.

Acute exposure to extreme altitude increases arterial stiffness by activation of the sympathetic and endothelin system as well as hypoxia-induced reactive oxygen species production. Beyond a certain individual threshold, these physiological adaptations represent a relevant cardiovascular risk factor. In this pilot study we investigated to what extent temporary exposure to moderate altitude, as present during hiking, skiing or in aeroplanes, leads to changes in vascular tone. Pulse wave parameters of 8 healthy individuals were assessed with a BR-102 plus pulse wave analyser (Schiller, Germany) at baseline (521 m) and after 24 h exposure to moderate altitude (2650 m). We identified a significant increase in heart rate (61 vs. 68/min, p = 0.021) as well as changes in central (35.6 vs. 41.4 mmHg, p = 0.024) and peripheral pulse pressure (44.7 vs. 52.6 mmHg, p = 0.006). Amplitudes of forward (21.6 vs. 25.4 mmHg, p = 0.012) and backward pulse waves (15.3 vs. 17.6 mmHg, p = 0.043) were significantly elevated. Pulse wave velocity showed no significant change from 5.8 m/s at baseline to 6.1 m/s at moderate altitude (p = 0.056). We show that temporary exposure to moderate altitude leads to mild changes in vascular tone reflected by pulse pressure and pulse wave amplitude in healthy adults. Although the observed effects were mild in our study, it indicates that adaptation capacity is of crucial importance and any restrictions by disease or simply with the process of ageing demand increased awareness, even in moderate altitude.

Periodic repolarization dynamics as a risk predictor after myocardial infarction: Prospective validation study.

BACKGROUND: Periodic repolarization dynamics (PRD) is a novel electrocardiographic phenomenon that refers to sympathetic activity-associated low-frequency modulations of cardiac repolarization. Retrospective post-myocardial infarction (MI) studies revealed that increased PRD indicates an increased risk of subsequent death. OBJECTIVE: This is the first prospective study to validate PRD in patients after MI receiving up-to-date treatment. METHODS: Four hundred fifty-five survivors of MI (age ≤80 years) in sinus rhythm were enrolled. PRD was assessed from 20-minute electrocardiographic recordings (2048 Hz) and prospectively dichotomized at 5.75 deg2. Primary and secondary end points were total mortality and cardiovascular mortality, respectively. Multivariable analyses additionally included Global Registry of Acute Coronary Events score (dichotomized at >140), left ventricular ejection fraction (dichotomized at ≤35%), diabetes mellitus, and deceleration capacity of heart rate (dichotomized at ≤2.5 ms). The prognostic power of PRD was evaluated using receiver operating characteristic curve analysis, Cox regression analysis, and the integrated discrimination improvement index. RESULTS: During a median follow-up period of 27 months, 47 patients died. Twenty-three of these deaths were classified as cardiovascular. Increased PRD was significantly associated with both end points, yielding areas under receiver operating characteristic curves of 69.3% (60.2%-77.8%) and 79.1% (69.7%-86.7%) for total mortality and cardiovascular mortality, respectively (P < .001 for both). In multivariable analysis, increased PRD indicated a 2.2- and 9.5-fold risk of total mortality and cardiovascular mortality (P = .024 and P = .003, respectively). Addition of PRD to the models significantly improved the integrated discrimination improvement index for total (P = .047) and cardiovascular mortality (P = .007). CONCLUSION: PRD is a strong and independent predictor of total mortality and cardiovascular mortality in patients after MI treated with contemporary therapy.

Dynamic Changes of Cardiac Repolarization Instability during Exercise Testing.

INTRODUCTION: Physical exercise triggers efferent cardiac sympathetic activation. Here, we tracked the spatiotemporal properties of cardiac repolarization on a beat-to-beat basis throughout a standardized exercise test and hypothesized a detectable change at the point of the anaerobic threshold (AT). METHODS: The study included 20 healthy adults (age 35.3 ± 6.7 yr) undergoing a standardized incremental exercise test on a cycle ergometer. During exercise testing, high-resolution (2000 Hz) ECG monitoring in Frank lead configuration was performed. Three-dimensional beat-to-beat repolarization instability (dT°) was assessed by a novel vector-based method according to a previously published technology. In parallel, the lactate threshold (LT) was detected according to Dickhuth and Mader. RESULTS: We could identify a characteristic pattern of dT° signal during exercise testing. With increasing physical activity, dT° increased concordantly to heart rate. At an average of 164 ± 38 W, dT° and heart rate abruptly showed a discordant behavior, characterized by a transient drop of dT°. The maximal discordance between dT° and heart rate was defined as ATdT° and highly significantly correlated with LTDickhuth (r = 0.841, P < 0.001) and LTMader (r = 0.819, P < 0.001), which were at 156 ± 39 and 172 ± 46 W, respectively. The characteristic of dT° could not be provoked by fast atrial pacing in the absence of exercise. CONCLUSIONS: Repolarization instability shows a characteristic pattern during standardized exercise in healthy individuals that allows for a noninvasive estimation of AT.