Potential role for clinical calibration to increase engagement with and application of home telemonitoring: a report from the HeartCycle programme

Aims: There is a need for alternative strategies that might avoid recurrent admissions in patients with heart failure. Home Telemonitoring (HTM) to monitor patient’s symptoms from a distance may be useful. This study attempts to assess changes in HTM vital signs in response to daily life activities (variations in medication, salt intake, exercise and stress) and to stablish which variations affect weight, blood pressure (BP) and heart rate (HR). Methods and results: We assessed 76 patients with heart failure (mean age 76 ± 10.8 years, 75% male, mainly in NYHA class II/III and from ischaemic etiology cause). Patients were given a calendar of interventions scheduling activities approximately twice-a-week before measuring their vital signs. Eating salty food or a large meal were the activities that had a significant impact on weight gain (+0.3 kg; p<0.001 and p=0.006, respectively). Exercise and skipping a dose of medication other than diuretics increased heart rate (+3 bpm, p=0.001 and almost +2 bpm, p=0.016, respectively). Conclusions: Our HTM system was able to detect small changes in vital signs related to these activities. Further studies should assess if providing such a schedule of activities might be useful for patient education and could improve long-term adherence to recommended lifestyle changes

Noninvasive assessment of an engineered bioactive graft in myocardial infarction: impact on cardiac function and scar healing

Cardiac tissue engineering, which combines cells and biomaterials, is promising for limiting the sequelae of myocardial infarction (MI). We assessed myocardial function and scar evolution after implanting an engineered bioactive impedance graft (EBIG) in a swine MI model. The EBIG comprises a scaffold of decellularized human pericardium, green fluorescent protein-labeled porcine adipose tissue-derived progenitor cells (pATPCs), and a customized-design electrical impedance spectroscopy (EIS) monitoring system. Cardiac function was evaluated noninvasively by using magnetic resonance imaging (MRI). Scar healing was evaluated by using the EIS system within the implanted graft. Additionally, infarct size, fibrosis, and inflammation were explored by histopathology. Upon sacrifice 1 month after the intervention, MRI detected a significant improvement in left ventricular ejection fraction (7.5%64.9% vs. 1.4%63.7%; p = .038) and stroke volume (11.565.9 ml vs. 364.5 ml; p = .019) in EBIG-treated animals. Noninvasive EIS data analysis showed differences in both impedance magnitude ratio (20.02 6 0.04 per day vs. 20.48 6 0.07 per day; p = .002) and phase angle slope (20.18°60.24° per day vs.23.52°60.84° per day; p = .004) in EBIG compared with control animals. Moreover, in EBIG-treated animals, the infarct size was 48% smaller (3.4%60.6% vs. 6.5%61%; p = .015), less inflammation was found by means of CD25+ lymphocytes (0.65 6 0.12 vs. 1.26 6 0.2; p = .006), and a lower collagen I/III ratio was detected (0.4960.06 vs. 1.6660.5; p = .019). An EBIG composed of acellular pericardium refilled with pATPCs significantly reduced infarct size and improved cardiac function in a preclinical model of MI. Noninvasive EIS monitoring was useful for tracking differential scar healing in EBIG-treated animals, which was confirmed by less inflammation and altered collagen deposit.Peer ReviewedPostprint (published version

Conformational and thermal characterization of left ventricle remodeling post-myocardial infarction

Adverse cardiac remodeling after myocardial infarction (MI) causes impaired ventricular function and heart failure. Histopathological characterization is commonly used to detect the location, size and shape of MI sites. However, the information about chemical composition, physical structure and molecular mobility of peri- and infarct zones post-MI is rather limited. The main objective of this work was to explore the spatiotemporal biochemical and biophysical alterations of key cardiac components post-MI. The FTIR spectra of healthy and remote myocardial tissue shows amides A, I, II and III associated with proteins in freeze-died tissue as major absorptions bands. In infarcted myocardium, the spectrum of these main absorptions was deeply altered. FITR evidenced an increase of the amide A band and the distinct feature of the collagen specific absorption band at 1338cm-1 in the infarct area at 21days post-MI. At 21days post-MI, it also appears an important shift of amide I from 1646cm-1 to 1637cm-1 that suggests the predominance of the triple helical conformation in the proteins. The new spectra bands also indicate an increase in proteoglycans, residues of carbohydrates in proteins and polysaccharides in ischemic areas. Thermal analysis indicates a deep increase of unfreezable water/freezable water in peri- and infarcted tissues. In infarcted tissue is evidenced the impairment of myofibrillar proteins thermal profile and the emergence of a new structure. In conclusion, our results indicate a profound evolution of protein secondary structures in association with collagen deposition and reorganization of water involved in the scar maturation of peri- and infarct zones post-MI

Planetary science and exploration in the deep subsurface: results from the MINAR Program, Boulby Mine, UK

The subsurface exploration of other planetary bodies can be used to unravel their geological history and assess their habitability. On Mars in particular, present-day habitable conditions may be restricted to the subsurface. Using a deep subsurface mine, we carried out a program of extraterrestrial analog research – MINe Analog Research (MINAR). MINAR aims to carry out the scientific study of the deep subsurface and test instrumentation designed for planetary surface exploration by investigating deep subsurface geology, whilst establishing the potential this technology has to be transferred into the mining industry. An integrated multi-instrument suite was used to investigate samples of representative evaporite minerals from a subsurface Permian evaporite sequence, in particular to assess mineral and elemental variations which provide small-scale regions of enhanced habitability. The instruments used were the Panoramic Camera emulator, Close-Up Imager, Raman spectrometer, Small Planetary Linear Impulse Tool, Ultrasonic drill and handheld X-ray diffraction (XRD). We present science results from the analog research and show that these instruments can be used to investigate in situ the geological context and mineralogical variations of a deep subsurface environment, and thus habitability, from millimetre to metre scales. We also show that these instruments are complementary. For example, the identification of primary evaporite minerals such as NaCl and KCl, which are difficult to detect by portable Raman spectrometers, can be accomplished with XRD. By contrast, Raman is highly effective at locating and detecting mineral inclusions in primary evaporite minerals. MINAR demonstrates the effective use of a deep subsurface environment for planetary instrument development, understanding the habitability of extreme deep subsurface environments on Earth and other planetary bodies, and advancing the use of space technology in economic mining

Overlapping Effects of miR-21 Inhibition and Drugs for Idiopathic Pulmonary Fibrosis: Rationale for Repurposing Nintedanib as a Novel Treatment for Ischemia/Reperfusion Injury

ABSTRACT: A specific anti-miR-21 has emerged as an effective treatment for ischemia/reperfusion injury in a pig model of myocardial infarction (MI), but the perspectives for clinical translation are limited. Anti-miR-21 blunts profibrotic pathways, whose excessive activation is detrimental in the post-MI setting. Repurposing antifibrotic drugs approved for other indications is a possible strategy. We compared the molecular effects of anti-miR-21 and the 2 drugs approved for idiopathic pulmonary fibrosis (nintedanib and pirfenidone) through a bioinformatic approach. We report that nintedanib and anti-miR-21 share many targets, including the proto-oncogene Rous sarcoma oncogene cellular homolog. Conversely, pirfenidone and anti-miR-21 do not have common mechanisms of action. In summary, the molecular mechanisms activated by nintedanib are partially overlapping with those elicited by anti-miR-21. Nintedanib could be evaluated in animal studies or clinical trials on MI

Reply: Interleukin-1β and sST2

©2019. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ This document is the Accepted version of a Published Work that appeared in final form inJACC: Cardiovascular Imaging. To access the final edited and published work see https://doi.org/10.1016/j.jacc.2019.05.02

The PCSK9-LDL Receptor Axis and Outcomes in Heart Failure:BIOSTAT-CHF Subanalysis

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds low-density lipoprotein receptor (LDLR), preventing its recycling. PCSK9 is a risk predictor and a biotarget in atherosclerosis progression. Objectives: The aim of this study was to determine whether the PCSK9-LDLR axis could predict risk in patients with heart failure (HF). Methods: The BIOSTAT-CHF (Biology Study to Tailored Treatment in Chronic Heart Failure) is a multicenter, multinational, prospective, observational study that included patients with worsening HF signs and/or symptoms. The primary endpoints were all-cause mortality and the composite of mortality or unscheduled hospitalizations for HF. We implemented Cox proportional hazard regression to determine the simultaneously adjusted effect of PCSK9 and LDLR on both outcomes when added to the previously validated BIOSTAT-CHF risk scores. Results: This study included 2,174 patients (mean age: 68 ± 12 years; 53.2% had a history of ischemic heart disease). Median (interquartile range) PCSK9 and LDLR levels were 1.81 U/ml (1.45 to 2.18) and 2.98 U/ml (2.45 to 3.53), respectively. During follow-up, 569 deaths (26.2%) and 896 (41.2%) composite endpoints were ascertained. A multivariable analysis, which included BIOSTAT-CHF risk scores, LDLR, and statin treatment as covariates, revealed a positive linear association between PCSK9 levels and the risk of mortality (hazard ratio [HR]: 1.24; 95% confidence interval [CI]: 1.04 to 1.49; p = 0.020) and the composite endpoint (HR: 1.21; 95% CI: 1.05 to 1.40; p = 0.010). A similar analysis for LDLR revealed a negative association with mortality (HR: 0.86; 95% CI: 0.76 to 0.98; p = 0.025) and the composite endpoint (HR: 0.92; 95% CI: 0.83 to 1.01; p = 0.087). Including PCSK9 and LDLR improved risk score performance. Conclusions: The PCSK9-LDLR axis was associated with outcomes in patients with HF. Future studies must assess whether PCSK9 inhibition will result in better outcomes in HF

Revascularization for coronary artery disease in diabetes mellitus: Angioplasty, stents and coronary artery bypass grafting

Author Manuscript: 2011 April 14Patients with diabetes mellitus (DM) are prone to a diffuse and rapidly progressive form of atherosclerosis, which increases their likelihood of requiring revascularization. However, the unique pathophysiology of atherosclerosis in patients with DM modifies the response to arterial injury, with profound clinical consequences for patients undergoing percutaneous coronary intervention (PCI). Multiple studies have shown that DM is a strong risk factor for restenosis following successful balloon angioplasty or coronary stenting, with greater need for repeat revascularization and inferior clinical outcomes. Early data suggest that drug eluting stents reduce restenosis rates and the need for repeat revascularization irrespective of the diabetic state and with no significant reduction in hard clinical endpoints such as myocardial infarction and mortality. For many patients with 1- or 2-vessel coronary artery disease, there is little prognostic benefit from any intervention over optimal medical therapy. PCI with drug-eluting or bare metal stents is appropriate for patients who remain symptomatic with medical therapy. However, selection of the optimal myocardial revascularization strategy for patients with DM and multivessel coronary artery disease is crucial. Randomized trials comparing multivessel PCI with balloon angioplasty or bare metal stents to coronary artery bypass grafting (CABG) consistently demonstrated the superiority of CABG in patients with treated DM. In the setting of diabetes CABG had greater survival, fewer recurrent infarctions or need for re-intervention. Limited data suggests that CABG is superior to multivessel PCI even when drug-eluting stents are used. Several ongoing randomized trials are evaluating the long-term comparative efficacy of PCI with drug-eluting stents and CABG in patients with DM. Only further study will continue to unravel the mechanisms at play and optimal therapy in the face of the profoundly virulent atherosclerotic potential that accompanies diabetes mellitus.National Institutes of Health (U.S.) (GM 49039

ESC Heart Failure Association age-adjusted natriuretic peptide thresholds for a new diagnosis of heart failure: diagnostic accuracy study

Background: Natriuretic peptide (NP) testing is an important part of the heart failure (HF) diagnostic pathway. The European Society of Cardiology (ESC) HF guidelines currently recommend a NT-proBNP cut-off <125pg/mL to rule out HF in the community.1 However, NP level increases with age and an NT-proBNP above 125pg/mL is common in older people in the general population. The ESC Heart Failure Association (HFA) recently published a practical algorithm for early diagnosis of HF recommending age-specific rule-in NT-proBNP thresholds: ≥125pg/ml for patients aged under 50 years, ≥250pg/ml for patients aged 50-75 years, and ≥500pg/ml for patients over 75 years (Figure 1).2 Purpose: Our aim was to assess NT-proBNP test performance for HF diagnosis at the ESC HFA age-specific thresholds. Method: We analysed our existing diagnostic accuracy study dataset containing primary care data from the Clinical Practice Research Datalink (CPRD) linked to inpatient Hospital Episode Statistics (HES) inpatient data between 2004 and 2018. NT-proBNP results were taken from the GP record (index test) and the primary outcome (reference standard) was a HF diagnostic code entered in CPRD or HES within six months of the test. NT-proBNP accuracy for HF was assessed by calculating sensitivity, specificity, positive predictive values (PPV), and negative predictive value (NPV). Receiver operating characteristic (ROC) curves were plotted to assess overall test performance. Results: In total, 229,580 patients had an NP test and 21,102 (9.2%) were diagnosed with HF. The current ESC NT-proBNP threshold ≥125pg/mL had sensitivity 94.6% (95% confidence intervals [CI] 94.2 to 95.0), specificity 50.0% (95%CI 49.7 to 50.3), PPV 16.4% (16.1 to 16.6), NPV 98.9% (98.8 to 99.0)). Area under the ROC curve was 0.874 (0.871 to 0.877). Age-specific NT-proBNP thresholds performance: Below 50 years (≥125pg/mL): 32,882 people tested, HF prevalence 3.8%. Sensitivity 83.5 % (81.3 to 85.5), specificity 77.6% (77.2 to 78.1), PPV 13.0% (12.2 to 13.7), NPV 99.2% (99.0 to 99.3). 50 to 75 years ≥250pg/mL: 105,771 people tested, HF prevalence 9.8%. Sensitivity 88.5% (87.9 to 89.1), specificity 67.8% (67.5 to 68.0), PPV 23.1% (22.6 to 23.5), NPV 98.2% (98.1 to 98.3). Above 75 years ≥500pg/mL: 16,694 people tested, HF prevalence 17.5%. Sensitivity 84.4% (83.0 to 85.7), specificity 63.5% (62.7 to 64.3), PPV 32.8% (31.7 to 33.9), NPV 95.0% (94.6 to 95.5). Conclusion: The age-specific NT-proBNP thresholds in the HFA practical algorithm had higher specificity so fewer people without HF would be referred, reducing demand for echocardiography and cardiology assessment overall meaning people with HF could be seen earlier. However, lower sensitivity means some cases of HF would initially be missed. NT-proBNP was a reliable ‘rule-out’ test at population level. The optimal NT-proBNP threshold will depend on the priorities and capacity of the national healthcare system

CGeNArateWeb: a web server for the atomistic study of the structure and dynamics of chromatin fibers

We present CGeNArateWeb, a new web tool for the three-dimensional simulation of naked DNA and protein-bound chromatin fibers. The server allows the user to obtain a dynamic representation of long segments of linear, circular, or protein–DNA segments thanks to a Langevin dynamics coarse-grained (CG) model working with a machine-learning (ML) fitted C1′-resolution Hamiltonian. The CG trajectories can be back-mapped to atomistic resolution using another ML algorithm trained on a large database of molecular dynamics (MD) simulations. The method allows the user to get structural and dynamic information on large (kilobase range) portions of both protein-bound and free DNA, to transform conceptual cartoons into structural and dynamical models. Trajectories are analyzed using an extensive set of nucleic acid-specific analysis tools, and the results are displayed using a powerful and flexible graphic interface. The web tool uses state-of-the-art technologies such as (i) Docker components orchestrated by Docker Swarm, with containers deployed on demand for computations, (ii) WebGL-programmed NGL molecular viewer and the JavaScript plotly library for interactive plots, and (iii) noSQL-MongoDB for storage. The server is accessible at https://mmb.irbbarcelona.org/CGNAW/. The web tool is free and open to all users, and there are no login requirements