C). Validity measures overall are as follows: Garmin Fenix 5 , Jabra Elite Sport , Motiv ring , Scosche Rhythm+ , Suunto Spartan Sport . All photoplethysmography-based (PPG) devices displayed poor heart rate agreement during variable intensity trail running. Until technological advances occur in PPG-based devices allowing for acceptable agreement, heart rate in outdoor environments should be obtained using an ECG-based chest strap that can be connected to a wristwatch or other comparable receiver.Validation of heart rate responses in wearable technology devices is generally composed of laboratory-based protocols that are steady state in nature and as a result, high accuracy measures are returned. However, there is a need to understand device validity in applied settings that include varied intensities of exercise. The purpose was to determine concurrent heart rate validity during trail running. Twenty-one healthy participants volunteered ]: age = 31  years, h The use of wearable technology has steadily increased, and has been the top fitness trend since 2016 as determined by health and fitness professionals throughout the world , and heaWearable technology devices that return heart rate include smart bras , earbudsA limited number of studies have not utilized the treadmill, but engaged participants in unrestricted activities including walking and running , 20–22. As seen from the literature above, agreement between wearable devices and a heart rate criterion measure during running are generally higher during treadmill-based activity , 11, 18 Twenty-one healthy participants volunteered for this study  . Heart rParticipants were outfitted with wearable technology devices and completed a self-paced 3.22 km (two-mile) trail run while concurrently wearing a criterion heart rate strap. Devices were secured to the participant by members of the research team to ensure appropriate fit, and to certify heart rate was obtained by each device. The trail runs were an out-and-back course with the first 1.61 km (1-mile) in a generally uphill direction, and the 1.61 (1-mile) return being generally downhill in nature. Three different trails were utilized which included elevation changes of 48 m , 55m  and 104m . The elevation profiles of these trails are shown in Criterion heart rate: the criterion measure was obtained using the Polar H7 heart rate monitor , which contains a single flexible plastic sensor (2.4 x 27.9 cm), worn concurrently and placed on the sternum. The Polar H7 heart rate receiver has a sample rate of 1000 Hertz and has high agreement with ECG measurements during various exercise modalities  .ECG chest strap device and watch: Suunto Spartan Sport watch —the watch was secured around the right wrist by the strap. Heart rate was obtained through the accompanying heart rate strap that was secured around the sternum just below the Polar H7 monitor. The dimensions are 50 x 50 x 13.8 mm.™ multi-sensor heart rate monitor. The dimensions are 47 x 47 x 15.5 mm.Photoplethysmography-based devices: Garmin Fenix 5 wristwatch —the device was secured to the left wrist by the strap. This device utilizes the Garmin ElevateJabra Elite Sport earbuds —earbuds were secured into the ear canal. The dimensions are 120 x 45 x 179 mm.Motiv ring —a size 10 ring was secured on the finger that provided the best fit, being able to fit over the knuckle and fit snugly on the finger between the proximal interphalangeal and metacarpophalangeal joints. The appropriate finger was self-selected by each participant. The outer housing is composed of a titanium alloy, and employs a green LED optical heart rate sensor.Scosche Rhythm+ forearm band —secured around the forearm by a breathable neoprene band. Sensor size is 54.4 x 48.8 x 14.7 mm.Heart rate data for the Polar H7, Rhythm+ forearm band, Jabra Elite earbuds, and Suunto Spartan Sport were transmitted real time via Bluetooth to a synced iPad mini tablet  and captured into the PerformTek application . The PerformTek application reports heart rate in a second-by-second fashion and allowed the Rhythm+ forearm band, Jabra Elite earbuds, and Suunto Spartan Sport to be time-synced with the Polar H7. Heart rate from the Motiv ring was transmitted via Bluetooth to the synced iPad mini and captured into the Motiv application . Heart rate data from the Garmin Fenix 5 was captured onto the watch during the trail run and synced to the Garmin Connect application on the iPad mini immediately upon return to the trailhead. Heart rate data from the Motiv ring and Garmin Fenix 5 were plotted against the criterion measure to visually confirm time-syncing between devices.C), and Intraclass Correlations (ICC) . Validity was considered if devices met all of the following criteria: MAPE within 5% ). The uphill portion of the run was 11:39 (3:19) min, and the downhill portion was 10:26 (2:17) min. Validity measures for heart rate (bpm) over the entire length of trail run are shown in The purpose of this investigation was to evaluate heart rate validity of several types of wearable technology devices during a variable intensity trail run. We hypothesized that all devices would have acceptable heart rate agreement compared to our criterion over the course of this exercise bout. The main findings are that regardless of device location , PPG-based devices do not provide acceptable heart rate validity during a trail run lasting longer than 20-min. We found that a heart rate strap recorded to a wrist watch (Suunto Spartan Sport), provided acceptable agreement for heart rate utilizing thresholds normally applied to laboratory-based research.The Suunto Spartan Sport device has been evaluated with respect to step count accuracy , and proC = 0.93), and during cycle and treadmill exercise lasting 4.5 min , but not when performing elliptical training  [C = 0.885) than when running was at a generally positive incline . It is possible that greater device motion was experienced in the uphill portion leading to these results, and further investigation is warranted.Forearm PPG heart rate monitors have been utilized in a variety of applications including virtual reality ship handling simulators , during ovement) . Anotherovement) . The curC = 0.316), and these measures are consistent regardless of the incline (either primarily uphill or downhill) of the trail.The Garmin Fenix series is relatively new PPG-based device and as such has limited available literature. In fact, we were only able to find two conference abstracts for the Fenix 3 , 46, andC = 0.293). Future investigations utilizing ring-based wearables should be investigated in a controlled laboratory setting to determine heart rate validity in this environment. A limitation with respect to this device is that the current investigation utilized a single ring size. Additionally, the specific fingers utilized by participants was not recorded and future studies should take this into account.While ring-based wearable devices have been presented in conference abstracts –51, we h2 = 0.98) [C = 0.943; bias = -3.6 bpm, MAPE = 3.53%, rC = 0.861 respectively) [2 = 0.434) [Literature on PPG-based earbud heart rate validity during exercise is beginning to emerge. Investigations have found earbud-based heart rate to be acceptable during resistance training (MAPE = 6.24%) , graded  = 0.98) , and durThe current investigation utilized a variety of commercially available wearable technology devices capable of returning heart rate measures. We observed a range of heart rate agreement in devices during a trail run and as expected found an ECG-based chest strap recording to a wrist worn watch to have the greatest concurrent validity. The PPG-based devices were positioned at various locations on the body, and the forearm strap device displayed the best validity of this class of wearable. Nevertheless, in an outdoor environment, heart rate obtained from the remaining PPG-based devices  were observed to have poor agreement with the criterion measure. Motion artifact is the likely source of error in wearable devices that were found to have low heart rate validity , howeverLaboratory-based research investigations into wearable technology devices have generally utilized specific thresholds for validity measurements, such as ICC above 0.70 and/or MAPE lower than 5% [


AMI led to an increase in LVEDV and LVESV during 6-week, with concomitant elevation of NT-proBNP 3-weeks after AMI. Plasma clusterin levels were increased immediately after AMI and returned to normal levels until 3-weeks. Plasma NGAL, ET-1 and miR29 was significantly elevated at 3 weeks follow-up, miR21 increased after reperfusion and at 3 weeks post-AMI, while circulating neprilysin levels did not change. Elevated plasma clusterin levels 120 min after AMI onset suggest that clusterin might be an additional early biomarker of myocardial ischemia.Clusterin exerts anti-inflammatory, cytoprotective and anti-apoptotic effects. Both an increase and decrease of clusterin in acute myocardial infarction (AMI) has been reported. We aimed to clarify the role of clusterin as a systemic biomarker in AMI. AMI was induced by percutaneous left anterior artery (LAD) occlusion for 90 min followed by reperfusion in 24 pigs. Contrast ventriculography was performed after reperfusion to assess left ventricular ejection fraction (LVEF), left ventricular end diastolic volume (LVEDV) and left ventricular end systolic volume (LVESV) and additional cMRI + late enhancement to measure infarct size and LV functions at day 3 and week 6 post-MI. Blood samples were collected at prespecified timepoints. Plasma clusterin and other biomarkers  were measured by ELISA and qPCR. Gene expression profiles of infarcted and remote region 3 h ( Early diagnosis and therapy of acute myocardial infarction (AMI) are essential to reduce infarct size and improve prognosis ,2,3. CurClusterin  is a heat shock protein-like extracellular protein that is expressed in a variety of human tissues and body fluids . ClusterUp to now, several plasma biomarkers were investigated to be associated with AMI, such as . Neprilysin is a zinc-dependent endopeptidase that has been found in a variety of tissues, e.g., brain, lungs, heart, kidney, testes, adipose tissue, endothelial cells, vascular smooth muscle cells and cardiac myocytes ,19. It iMyocardial ischemia is linked to LV remodelling, a process that is characterised by cardiomyocytes hypertrophy, cardiac fibrosis and deformation of the heart chambers . CardiacBased on contradictory data on the above-mentioned biomarkers in AMI we aimed to further clarify the dynamics of clusterin, neprilysin, NGAL, osteopontin, ET-1, miR21 and miR29 in a preclinical porcine model of reperfused AMI in which duration and extent of myocardial ischemia are standardised and comparable, and associated with cardiac magnetic resonance imaging (cMRI)-derived cardiac function parameter.p < 0.0001, p < 0.0001, p < 0.0001, p = 0.15, To quantify myocardial necrosis as well as left ventricular dysfunction, we assessed infarct size, left ventricular ejection fraction (LVEF), left ventricular end systolic volume (LVESV) and left ventricular end diastolic volume (LVEDV) using cMRI at 3 days as well as 6 weeks after reperfused AMI. Myocardial necrosis (as % of LV) was decreased at 6 weeks as compared to 3 days, most probably due to shrinkage of the scar tissue  and significantly decreased afterwards at day 3 (p = 0.001) and week 3 (p < 0.001)  . Clusterin levels at day 3 and week 3 follow-up did not correlate with the 3 day and 6 week left ventricular function parameters and infarct size.We correlated clusterin 120 min after AMI onset with LV function parameters assessed by contrast ventriculography. Plasma clusterin post AMI was significantly associated with LVEF  and miR21 .Additionally, elevated, clusterin concentration at 120 min post AMI-onset did not correlate with plasma levels of any other assessed biomarker, including Troponin I, type 3  that returned to normal levels already after 3 days, suggesting that it can be a similar and additionally early and high-sensitive biomarker of acute myocardial ischemia as hs-cTn, which increases 2–3 h after ischemia onset and remains elevated several days after AMI. Furthermore, we observed a correlation of plasma clusterin 120 min after AMI onset with LVEF and LVESV. The failure of correlation between clusterin (a molecular chaperone) and TnI levels might be explained by the different intracellular localization, subcellular compartments and molecular interactions, and warrants further investigations.In the current clinical setting, biomarkers play an important role in diagnosis and early treatment modalities of AMI. Even though hs-cTn has improved diagnosis and management of AMI patients, they still feature several drawbacks such as limited specificity and a delay in measurably increased values . DiagnosIn contrast with the other circulating factors (except TnI and miR21), clusterin proved to be a good marker for acute ischemia already 120 min after ischemia onset. This hypothesis is supported by the correlation of post AMI clusterin with LVEF and LVESV assessed by contrast ventriculography 30 min after reperfusion onset. Nevertheless, the mechanism of clusterin release can only be speculated. Clusterin is a heat shock protein-like intra- and extracellular chaperone and its expression is stimulated by cellular stress and tissue injury  ,9,50. ExClusterin expression is also associated with diabetes type II and high cholesterol levels, both being well known risk factors for atherosclerosis and AMI . In our Even though we provide evidence that plasma clusterin levels are regulated during controlled myocardial ischemia, several limitations to our study should be mentioned. Firstly, it is an observation study and no causality effects can be concluded, a mechanistic explanation of clusterin in AMI needs to be elaborated in further studies. Secondly, we measured clusterin levels in a small group of pigs; clinical applicability needs to be evaluated in a larger patient cohort. Third, we investigated clusterin dynamics only during a brief period after myocardial infarction; long term dynamics and a possible prognostic factor for mortality should be the subject of additional studies. Fourth, the current commercially available clusterin ELISA kits showed a relatively large scatter of data, which should be further refined.n = 39, weight 30–35 kg, female) underwent percutaneous coronary intervention (PCI) in order to induce catheter-based reperfused AMI. According to ESC guidelines [Domestic pigs  was inserted. In total, 10,000 IU of heparin sodium were administered via the femoral sheath, and baseline haemodynamics were recorded. Selective angiography of the left coronary artery was performed by using a 6F guiding catheter  with regular contrast media . After a baseline angiogram was analysed, a balloon catheter  (Abbot Vascular) was placed after the origin of the second diagonal branch. To induce AMI, the balloon was inflated with 5 atm for 90 min followed by deflation of the balloon resulting in reperfusion. Wounds were closed and anaesthesia was terminated by withdrawal of isoflurane. In this study, 1 g metamizole was applied intramuscularly (i.m.) as analgesia. Furthermore, 100 mg benzathine benzylpenicilline, 100 mg procaine benzylpenicillin and 200 mg dihydrostreptomycin-sulphate was given i.m. as antibiotic shielding. Heart rate, arterial blood pressure, electrocardiography, O2 saturation and temperature were monitored throughout the procedure.Prior to left anterior descending artery (LAD) occlusion, the pigs received intramuscular injection of 12 mg/kg ketamine hydrochloride, 1 mg/kg xylazine and 0.04 mg/kg atropine as anaesthesia. Anaesthesia were deepened with isoflurane and OThe experiments were conducted at the Institute of Diagnostics and Oncoradiology, University of Kaposvar, Hungary. All animal facilities met the standards of the American Association for Accreditation of Laboratory Animal Care. Animal investigations were executed in accordance with the “Position of the American Heart Association on Research Animal Use” as adopted by the American Heart Association (AHA) on 11 November 1984. The study was approved by the Ethics Committee on Animal Experimentation at the University of Kaposvar, Hungary .g for 10 min and stored at −20 °C until further analyses were performed.Peripheral blood samples were collected before occlusion (pre-AMI), and post-AMI , at 3 days and 3 weeks post AMI. Blood was centrifuged at 2000× Biplane contrast ventriculography was performed 30 min after start of reperfusion, before the end of anaesthesia. Fifty mL contrast medium was infused by an injection pump at a rate of 12 mL/s via a 5F pig-tail catheter. LV volumina  were calculated off-line by using the area-length methods . Magnification correction was calculated from the known internal diameter of the pig-tail catheter and the known distance between the mid chest of the animal and the radiography equipment, documented during the procedure. The end-diastolic and end-systolic contours were digitalized and traced automatically and LVEF was calculated.At 3 days and 6 weeks after artificial myocardial infarction, cMRI + late enhancement (LE) was performed to assess myocardial necrosis, LVEF, LVEDV and LVESV. The cMRI + LE acquisition method and analyses have been described previously . In accoPlasma levels of clusterin , neprilysin , brain natriuretic protein , neutrophil gelatinase-associated lipocalin , osteopontin , endothelin-1  and troponin I, type 3  were assessed using commercially available ELISA Kits, which have been performed according to the manufacturers’ protocol. Absorbance was measured by Wallac Multilabel Counter 1420  at 450 nm. AutoOptical density values obtained at 450 nm (subtracted by plate background measured at 595 nm) were compared to the standard curve calculated from standards with a known concentration of the antigen. Measurements were performed in duplicates.Detailed information is described in the http://primer3.wi.mit.edu/primer3web_help.htm; Microsynth, Balgach, Switzerland). The relative gene expression level was calculated using the ΔCt method . The expression changes were calculated relative to median expression at baseline.Total RNA was isolated from plasma using the miRNeasy Serum/Plasma Kit . The RNA quantity and quality were measured with a nanodrop machine . MiRNA was reverse transcribed to cDNA  and expression was quantified by rtPCR . The primers for the target sequences were designed using Primer3 software version 4.1.0  and IBM SPSS Statistics version 23 . Mixed linear models were used to compare parametric variables and for non-parametric variables after logistic transformation. Parametric variables were expressed as mean ± standard deviation (SD) and compared Student’s paired t-test. A Wilcoxon test and Friedman test were used to compare non-parametric, paired variables and expressed as median and interquartile range (IQR). Bonferroni correction was applied for multiple testing. For correlation of non-parametric variables Spearman’s rank correlation was used. All tests were performed in a two-sided manner. In conclusion, we have shown that plasma clusterin levels are associated with AMI in the early phase. In contrast to previous work, we did not observe sustained elevation of clusterin; however, this may be due to the fact that we could examine clusterin dynamics after AMI isolated from any concomitant diseases that are well known to be associated with altered clusterin expression.


Several studies addressed the association between fragmented QRS (fQRS) on 12-lead EKG and left ventricular (LV) dysfunction in patients with a variety of cardiovascular disorders. We tested such association in healthy individuals.Out of 500 healthy participants without -overt cardiovascular disease from the Shiraz Heart Study cohort, we identified 20 subjects with fQRS (cases) and 20 peers without fQRS (controls). Global LV longitudinal strain (GLS) was measured by speckle tracking echocardiography in the two groups. Comparison was made between case and control groups by using chi-square or independent sample t-test or ANOVA.p = 0.009).Age, gender, ejection fraction, LV volume and dimensions did not differ between the case and the control groups. Overall, 14 subjects out of 40 had reduced GLS (≤20%) and 10 of them (25%) had fQRS. GLS was significantly lower in the group with fQRS than in the control group (19.9 ± 1.8 vs 21.4 ± 1.6; Healthy subjects with fQRS present regional LV systolic dysfunction, assessed by GLS, in the presence of a normal ejection fraction. These data suggest that fQRS may be a promising tool to identify apparently healthy subjects with regional LV systolic dysfunction. Left ventricular (LV) systolic function is an important clinical finding in cardiology. It is applied in prevention, diagnosis, prognostication, and treatment ina variety of cardiovascular conditions. Speckle tracking echocardiography (STE) measures LV systolic function quantitatively through detecting subtle myocardial deformations. Using this technique, the most sensitive and reproducible parameter capable of early detection of malfunctions is the global longitudinal strain (GLS) . The funLess than two decades ago, fragmentation of QRS complex (fQRS) was coined on 12-lead EKG . AbnormaAbout 6–10% of apparent healthy individuals show fQRS . In a geThis nested case-control study was done in the setting of a prospective cohort, Shiraz Heart Study (SHS), which is conducted on general population of Shiraz city aiming to analyze cardiovascular risk factors . The preInclusion criteria were negative past medical history, normal lipid profile, normal blood pressure, normal anthropometric indices as well as non-smokers and non-diabetics. Exclusion criteria were history of CAD, history of major risk factors for CAD , angina pectoris, acute coronary syndrome, cardiomyopathies, receiving any cardiovascular-related medications, implantation of pacemaker, heart valve disease, atrial fibrillation and flutter, rheumatism, renal disease, malignancy, pulmonary hypertension, and chronic obstructive pulmonary disease. Among those who met inclusion and exclusion criteria, random sampling was utilized in order to select 500 subjects.A resting 12-lead EKG has obtained previously from the all the participants as the cohort scheduled procedure . The EKGs of 500 subjects were thoroughly evaluated by two independent cardiologists seeking for QRS fragmentation. Notching in the R or S wave in the absence of a branch block, or an RSR’ pattern additional to the original QRS wave (< 120 ms) were defined as fQRS . Upon diSubjects in the two groups were asked to attend in the clinic. EKGs were repeated in order to find any possible new changes or arrhythmias by an expert who was blinded to grouping. Then, STE was performed with a commercially available ultrasound scanner  with a 2.5-MHz transducer by a single blinded echoman cardiologist. Echocardiograms were obtained in three-, two- and four-chamber apical views at a rate of 50 to 70 frames/s with the patient holding their breath during at least three cardiac cycles. Endocardial borders were automatically marked and tracking was applied to each image. In satisfactory tracking, the entire cardiac wall  was covered. The LV was divided into four segments in 3-chamber view, and six segments in 2- and 4-chamber view, totally 16 segments were assessed. If the segments were marked by the software automatically, the obtained data were recorded. Otherwise, they were corrected manually. Image analysis was done by AFI system.Peak systolic longitudinal strains (LS) of different segments were calculated and then, average LS for each view was produced. GLS was the arithmetic mean of LSs in three apical views. GLS of > 20% was assumed to be normal . Dimensit test or ANOVA when appropriate. P value of less than 0.05 was considered statistically significant.The statistical analysis was done in SPSS for Windows . Categorical variables are expressed as number (percentages) and continuous variables as mean ± standard deviation (SD). Comparison between variables were done using chi square, independent samples The age range of the participants was 40 to 60 years old (mean of 50.3 ± 6.5) and higher prevalence of male subjects (75%). Table . Mean LVGLS was below the normal range (≤20%) in 14 subjects and 10 of these subjects had fQRS. EF and other variables did not differ significantly between those with reduced GLS and peers with normal GLS.In the group with fQRS, this was localized in the inferior leads in 50% of subjects, equally distributed in anterior and lateral leads in the remaining subjects. The position of fragmentation was not significantly associateed with abnormal changes in GLS or EF Table .Table 3When analyzing the LS in different segments, the group with fQRS showed a lower LS than the control group in five segments which included base-, mid-, and apex- of septal, base of anteroseptal and base of inferior. Also, there was significant reduction of LS in apical 4-chamber view, while LS in apical three- and two-chamber views did not differ significantly between case and control groups. Overall, GLS was significantly lower in the group with fQRS than the control group (Table This nested case-control study was designed in order to investigate the association, if any, between fQRS and left ventricular dysfunction in apparently healthy people. Although the correlation between fQRS and cardiac disorders has been demonstrated in several diseased status , 20, butScarring of the myocardium following by zigzag pattern of electrical conduction produces fQRS spikes . fQRS isExistence of fQRS in different EKG leads simply translates into tissue scarring in different segments of the heart and is associated to the higher incidence of cardiac death and hospitalization . SeveritEF, which is a popular tool to estimate LV function, is able to reflect moderate to severe impairment in the ventricles. Also, this parameter suffers several limitations. Of note, EF mostly contributes to the myocardial changes in radial axis while longitudinal deformations are being neglected . Strain In an investigation on patients with systemic sclerosis, fQRS was present while LVEF and LV dimensions were normal. Importantly, GLS was significantly lower in these patients than in the control group . In a cofQRS in individuals with normal EF may be due to the existence of myocardial fibrosis of subclinical scale which in turn boasts fQRS sensitivity , 24. EKGBecause of the rising interest for fQRS in several pathological conditions, we investigated its importance in apparently healthy subjects. In these subjects, fQRS was associated with regional LV systolic dysfunction, assessed by GLS, in the presence of a normal ejection fraction. These data suggest that fQRS should not be considered as an innocent finding in healthy individuals.


Betel-quid (BQ) is a commonly used psychoactive substance that renders a specific cardiotoxicity. The purpose of this study was to investigate the association between BQ chewing and premature ventricular contractions (PVC) in patients with cardiopulmonary symptoms, and examine the potential influences of cardiovascular and chronic diseases on such relationship. Participants were 146 patients with cardiopulmonary symptoms who participated in 24-h Holter electrocardiogram monitoring during 2012–2018 in a hospital serving residents that lived in a BQ high prevalence area. Data on substance uses and medical histories for cardiovascular and chronic diseases were collected. Baron–Kenny method was employed to evaluate possible mediation. In patients with cardiopulmonary symptoms, 36.3% were BQ users and 63.7% were nonusers. Adjusting for covariates, BQ chewing was significantly associated with heart failure and diabetes mellitus (adjusted odds ratio (aOR) = 3.4 and 2.3, respectively), but only heart failure was significantly correlated with a low and high level of PVC. Additionally controlling for the effect of heart failure, the risk of high PVC for BQ users reduced from 3.60 to 2.88; however, the risk for BQ chewers remained significant (95% CI: 1.06–7.84). Heart failure was found to explain 27.7% of the excessive effect of BQ use on high PVC. In conclusion, BQ use is directly associated with an elevated risk of high PVC in patients with cardiopulmonary symptoms. The higher risk might be elevated among patients who suffered heart failure. Given several research limitations, the findings from this study offer future opportunities for validation. DSM-5 criteria for a substance use disorder [N-oxide in oral cavity, which may elevate the risks of developing carcinomas of the upper aerodigestive tracts [Betel-quid (BQ), a mixed chewing product, is made by areca nut, often combined with a leaf of Piper betle smeared with white/red slaked limes, and occasionally tobacco or condiments . Followidisorder ,7. Epidedisorder ,9,10. The tracts ,12,13.Clinical studies in chewers have found that BQ use can affect autonomic nervous function, increase heart rate and face temperature, and induce tachycardia and arrhythmias ,15. In cPremature ventricular contraction (PVC) is a type of ventricular arrhythmia that induces abnormal heartbeats in lower heart chambers. This cardiac dysfunction has been closely linked to the development of cardiomyopathy, heart failure, and mortality from heart disease ,22,23. PIn Taiwan, a large-scale epidemiological survey conducted in the southernmost township reported that residents in Mutan have a very high prevalence of BQ use  . AdditioThis is a hospital-based patient-series investigation carried out in one area hospital serving for Hengchun Peninsula inhabitants in southern Taiwan. There are about 50,000 people living on this Peninsula. Inhabitants who suffered cardiopulmonary symptoms often went to the research hospital or another hospital for treatments, because there is no large-scale medical center within a radius of 70–100 km of the Hengchun Peninsula. Study participants were the patients who came to the cardiovascular outpatient clinics requesting examinations and/or treatments for cardiopulmonary symptoms and agreed to participate in the measurement of 24-h Holter electrocardiogram. The cardiopulmonary symptoms experienced by study participants receiving a Holter monitoring included palpitation (51.4%), chest tightness (29.5%), short of breath (9.6%), and others (9.6%). This study was performed using a backtracking of medical records and secondary data analysis. Research protocol and the exemption of patient informed consent were approved by the Institutional Review Boards of Kaohsiung Medical University Hospital -20180319). During the period between 2012 and 2018, a total of 146 patients aged 35 years were included in this investigation.The interviews with patients were performed by trained interviewers in hospital settings. Data on the use of BQ and cigarette, with regard to the amount daily consumed were collected and recorded in the medical records for each participant. BQ users were the patients who had chewed one or more quids of BQ per day for at least 1 year, and cigarette smokers were the patients who had smoked one or more cigarettes per day for at least 1 year. Substance nonusers were defined as those who never used the two types of substance or used them for less than 1 year.The parameters recoded by a Holter electrocardiogram comprised maximum, minimum, and mean heart rates measured in a 24-h time period, sinus pause more than 1 s, and the amount, frequency, and duration of PVC and premature atrial contraction (PAC). The PVC burden was defined as the percentage of total beats that appeared PVC and the PAC burden was defined as the percentage of total beats that revealed PAC. Heart rate variability was also measured by the Holter electrocardiogram. However, data were available only for 54.1% of the participants (79/146). Echocardiography was performed for 76 patients (52.1%) because of clinical needs. The parameters measured in echocardiography included left atrium diameter, left ventricular diameter, interventricular septum, posterior wall septum of left ventricle, and left ventricular ejection fraction (LVEF).Medical information in regard to cardiovascular disorders, chronic diseases, and drug use were extracted from the measurements of biochemical laboratory, medical diagnosis records, prescribed medications, and echocardiography (if available) by the trained staff who were not aware of the results for substance use and Holter electrocardiogram. Medical histories collected for each participant included the initial date of diagnosis and continued treatments for heart failure, atrial fibrillation, coronary artery disease, stroke, hypertension, dyslipidemia, diabetes mellitus, and chronic kidney disease. The diagnosis of heart failure was according to Framingham criteria . In thos−4) of PVC burden as a cutoff point and divided this parameter into three groups: no PVC, low PVC (PVC < median), and high PVC (PVC ≥ median) burden. Polytomous logistic regression models were employed to estimate adjusted odds ratio (aOR) of low and high PVC burden relative to no PVC, since three outcome groups were defined [Percentage and mean ± standard deviation were, respectively, used to express the distribution of categorical and continuous data, however median and interquartile range were employed for variables with an abnormal distribution. The differences in medians of heart rate, PVC-, and PAC-related parameters between BQ uses and nonusers were examined using Mann–Whitney test. Logistic regression models were employed to evaluate the association between binary outcome and study variables. As PVC burden is a zero-inflated distribution , we used the median . No substantial differences in medians for longest run, minimum/maximum heart rates, PAC, and PAC burden between the two BQ groups were found.p < 0.05). However, the associations of diabetes mellitus with low and high levels of abnormal PVC burden were nonsignificant .As BQ chewing was related to a higher risk of heart failure, we further reviewed particular echocardiographic parameters and heart rate variability for patients who had the available data. As shown in This study presents findings to demonstrate that BQ use is associated with a higher risk of heart failure, diabetes mellitus, and PVC in patients with cardiopulmonary symptoms, and the relationship between BQ chewing and high level of PVC cannot be explained by heart failure. To the best of our knowledge, this is the first report that clarified the association across BQ use, heart failure, and PVCs using a 24-h Holter monitoring.The association between CVD and BQ chewing has been reported in several studies ,34. In aStudies have observed that, compared to chewing gum, BQ chewing increases heart rate, face temperature, tachycardia, and sympathetic dysmodulation with a gradual decrease in vagal modulation ,15. ChiaIn prior studies, frequent PVC has been associated with an increased risk for sudden/total cardiac death in general populations . PVC morExperimental studies have found that the nitrosated derivatives of areca nut alkaloids include a ring-shaped moiety that in configuration is similar to glucose, implying a possibility that BQ use might be diabetogenic . In CD1 In a large-scale population-based investigation, in that numerous cardiometabolic risk factors have been controlled, BQ users were observed to have a 1.3-fold risk of type 2 diabetes . SimilarSympathetic activity can bring about heart rate increasing, systemic vasoconstriction, and enlarged venous tone, then increase ventricular preload and systemic vascular resistance; in response to these, the heart increases ventricular end-diastolic volume and stroke volume . ChronicIn one follow-up study with 102 heart failure patients, 30.4% of patients were observed to have 101–1000 PVCs/24-h and 48% of patients had >1000 PVCs/24-h . ElectroThere are several limitations in this study. First, the cross-sectional nature of this investigation prevents a causal–effect inference about all conclusions. Second, the restricted sample size impedes a detailed evaluation for the relationship across BQ, heart failure, diabetes, and abnormal PVC. The limited samples were also difficult to use to differentiate the effects of other parameters that may link to these study variables. Third, certain cardiometabolic factors, such as risk components for metabolic syndrome, were not collected, which could confound or mediate the specific relationship between BQ use and PVC. Fourth, the type and duration of BQ used by the patients were not available, which prevent a full investigation for BQ characteristics consumed. This study has several advantages. First, all diagnoses for heart failure were confirmed cases and validated by an independent cardiologist who had no knowledge of the study results. Second, high BQ prevalence in study sample improved the power to clarify the study question for BQ consumption. Last, this is the first investigation that used a 24-h Holter electrocardiographic monitoring to examine the association between BQ use and PVC.In patients with cardiopulmonary symptoms, our study provides an understanding about the direct association of BQ use with an elevated risk of high level of PVC due to its cardiotoxicity. The risk might be elevated through multiple medications among patients who suffered heart failure. However, given a limited sample size in this investigation, the findings from this study offer future opportunities for validation.


Knowledge on heparin-induced thrombocytopenia keeps increasing. Recent progress on diagnosis and management as well as several discoveries concerning its pathogenesis have been made. However, many aspects of heparin-induced thrombocytopenia remain partly unknown, and exact application of these new insights still need to be addressed. This article reviews the main new concepts in pathogenesis, diagnosis, and management of heparin-induced thrombocytopenia. Heparin-induced thrombocytopenia (HIT) is a fascinating, complex, and still partially obscure immunological syndrome. It is associated with a very high prothrombotic risk and may cause limb and life-threatening complications. Thus, a rapid accurate clinical and laboratory recognition as well as a prompt and effective management are required. Since its discovery, knowledge on HIT has been impressively growing, and all fields have been evolving: from pathogenesis to diagnostic approaches and management. In this review, we will particularly focus on the most relevant clinical new insights and advances on HIT.The pathophysiology of heparin-induced thrombocytopenia (HIT) is complex and far exceeds simple platelet activation. Its spectrum is broad. Here, we will describe each step of HIT pathophysiology, beginning with antigen formation, followed by immune reaction and antibody synthesis, development of a severe prothrombotic state, and ending with thromboembolism, which has the potential to be life threatening.The HIT antigen is situated on the platelet factor 4 (PF4), a chemokine that is contained in platelet α-granules. PF4 is not immunogenic in its primary form. Conformational PF4 changes are needed to expose a neo-epitope, which is the HIT antigen. These changes occur by the formation of complexes between PF4 and negatively charged molecules, especially heparin and other glycosaminoglycans (GAGs) . The sizInnate and adaptive humoral and cellular reactions lead to anti-PF4/H antibodies synthesis. Briefly, once formed, ULCs activate complement, leading to the deposition of C3/C4 on the complexes. This allows their binding to cluster of differentiation 21  on B cells, which facilitates their activation, antigen transport to secondary lymphoid follicles, and antigen transfer. This culminates in an adaptive humoral immune response and anti-PF4/H antibodies production .The antigenic complex formation occurs on the platelet surface in a dynamic and potentially reversible manner. In presence of PF4, increasing heparin initially leads to an increasing antigen-complex size. HIT antibodies will then bind to these ULCs . With fuMonocytes participate in HIT hypercoagulability. Indeed, PF4 binds monocytes with a higher affinity than platelets. This is due to the different GAGs proportion in their glycocalyx and to a variable PF4 affinity for the different GAGs. Indeed, PF4 binds with decreasing intensity to heparin, heparan sulfate, dermatan sulfate, chondroitin-6-sulfate, and chondroitin-4-sulfate . This faHIT antibodies bind to PF4 on endothelial cells as well ,22, possMoreover, PF4 could bind to extended strings of von Willebrand factor, which have been released from activated or injured endothelial cells, consecutively exposing the HIT antigen on bound PF molecules . This isNeutrophils are thought to play an essential role in HIT hypercoagulability and in thrombosis development. They are activated by P-selectin on platelets and via FcγRIIa  by anti-PF4 and anti-PF4/polyanion antibodies could play a physiologic role in the host immune defense, particularly against Gram-negative bacterial infections. Indeed, bacteria can activate platelets, leading to degranulation and release of PF4 and polyphosphates. PF4 and polyphosphates can successively bind on lipid A on Gram-negative bacteria ,31,32, lAs widely known, not all patients developing HIT antibodies develop HIT, and not all patients with HIT develop thromboembolic complications. The mechanisms underlying these variable responses are not completely understood. However, specific gene polymorphisms could be involved, especially in the risk to develop thromboembolic complications in HIT. Indeed, an association between the polymorphism of FcγRIIIA 158VV  and occuHeparin is the most frequent negatively charged molecule that induces HIT. However, some patients develop symptoms and signs of HIT without exposition to heparin, especially after orthopedic surgery, which is known as spontaneous or autoimmune HIT (aHIT) ,36,37,38To summarize, HIT is a complex immune-mediated pathology. Its mechanisms depend on the concentrations of PF4 and heparin, particularly their ratio to each other and involve platelets, monocytes, endothelial cells, and neutrophils as well. The activation of these cells induces, besides thrombocytopenia, a coagulation cascade activation leading to a severe hypercoagulant state.Making a correct and rapid diagnosis of HIT is challenging and of utmost importance . It requAt the bedside, the cornerstones are thinking of HIT when appropriate  and subsequently assess the clinical pre-test probability of HIT with validated clinical scores. To do so, the 4T score  has been developed , and itsDifferent types of laboratory assays exist. In this review, we will focus on two platelet-activation assays  and the heparin-induced platelet aggregation test (HIPA)), on some broadly available immunoassays (IA) for HIT, and on emerging diagnostic strategies.Two platelet-activation assays using donor washed platelets are considered as diagnostic gold standards for HIT . These aMany laboratory techniques detecting anti-PF4/heparin antibodies exist.Enzyme-linked immunosorbent assays (ELISA) were the first wide available techniques . They arMany other techniques detecting anti-PF4/H antibodies have been developed and studied. In 2016, two very relevant meta-analyses about rapid IA for HIT were published. Nagler et al. identified five tests as highly sensitive and specific for HIT, namely the polyspecific ELISA with an intermediate threshold , particle-gel immunoassay (PaGIA), lateral flow immunoassay (LFIA), polyspecific chemiluminescent immunoassay (CLIA) with a high threshold, and IgG-specific CLIA with a low threshold . Sun et Moreover, both meta-analyses highlighted that combining results of some of the different aforementioned rapid IA might improve diagnostic performance for HIT and thus further improve care in patients with suspected HIT. Additionally, Sun et al. highlighted that combining clinical assessment  with rapid immunoassays in a Bayesian approach was likely to be the most powerful way to estimate an overall likelihood of HIT in real-world clinical practice ,65. In 2Regarding the Bayesian diagnostic approach, Nellen et al. showed in 2012 for the first time ever that the combination of clinical pre-test probability (assessed by the 4T score) with the quantitative result of a rapid immunoassay detecting anti-PF4/heparin antibodies was valuable not only for excluding , but alsRecently, two groups described diagnostic approaches that combine two rapid immunoassays. Our group developed and prospectively validated a Bayesian diagnostic algorithm  based on the 4T score and the combination of IgG-specific CLIA and PaGIA that correctly classifies >95% of patients within a 60 min laboratory work-up time . This alAs described previously, HIT is a complex and severe prothrombotic state. Briefly, current cornerstones of HIT management are (i) immediate cessation of any heparin administration and (ii) introduction of non-heparin therapeutic anticoagulation, such as argatroban or bivalirudin , or danaparoid or fondaparinux  . RecentlExperience with TPE in patients with HIT remains limited, as underscored in 2018 by Cho et al. who performed a national survey (USA) of academic apheresis services regarding practices in managing patients with HIT and found only 15.4% of respondents reporting having performed TPE on patients with HIT during the past year .To date, case reports are the major source of evidence. Additionally, although a single TPE removes about two-thirds of the HIT antibodies , the exaTPE has been described as an effective option for managing HIT in three particular situations . First, In the latest guidelines on HIT management, elucidation of the role of IVIG treatment in acute HIT has been defined as a key research priority for the management of HIT .Regarding safety of IVIG use, a consensus of 15 Canadian hematologists stated in 2007 that IVIG were contraindicated for treatment of HIT because of a potential increased thrombotic risk . HoweverIn clinical practice, many groups have reported favorable experience with this treatment, especially in patients with refractory HIT ,87. ReceInterestingly and in relationship with elements discussed above, in vitro IVIG have been shown to preferentially inhibit heparin-independent platelet-activating antibodies, explaining thus the rationale of their use in aHIT and/or refractory HIT . Even ifA chimeric anti-PF4/H antibody composed of a mouse IgG1 and a human Fc fragment was developed, namely the 5B9. It was obtained after immunization of transgenic mice with heparin and purified human PF4. 5B9 was proven to (i) induce platelet degranulation and release of serotonin when added in whole blood of healthy donors containing UFH  and (ii) induce thrombocytopenia and thrombin generation when administered with UFH to another species of transgenic mice expressing human FcγRIIa and PF4 . Thus, 5B9 was described to fully mimic the effects of human HIT antibodies .Streptococcus pyogenes (IdeS), which cleaves a region that is critical in the interaction of IgG with FcγRIIa and thus disables platelet activation via this pathway [One emerging and appealing option that still needs further study is the IgG-degrading enzyme of  pathway . Kizlik- pathway . Summari pathway . Thus, iOn the one hand, according to Selleng et al.  and WarkTo date, the ASH recommends delaying cardiovascular surgery among these patients. Because of a low level of evidence, there are only suggestions for management strategies in patients requiring immediate cardiovascular surgery .The three main management options in these patients are (i) alternative intraoperative anticoagulation with bivalirudin, (ii) intraoperative anticoagulation with heparin and simultaneous antiaggregation with a potent platelet inhibitor (iloprost or tirofiban), or (iii) intraoperative anticoagulation with heparin and peri-operative plasma exchanges (see above) .Bivalirudin is considered a safe alternative option for intraoperative anticoagulation in patients who undergo cardiovascular surgery when the interdisciplinary team is experienced and familiar with this technique, in particular avoiding blood stasis in the extracorporeal circuit and monitoring bivalirudin .Alternatively, anticoagulation with intraoperative heparin and simultaneous short-acting and reversible anti-aggregation seems to be a valid strategy. In this context, apart from tirofiban   and ilopA novel approach with limited published experience thus far is the use of IVIG to prevent HIT antibodies activating platelets and other cells as well (see above), possibly combined with additional cangrelor, in order to perform cardiovascular surgery with heparin .To date, the ASH recommends with low level of evidence to favor intraoperative heparin for these patients on the basis of a few cases series ,90,91. HIn this review, we described novel insights in the pathophysiology of HIT, recent improvements for the accuracy and speed of its diagnostic work-up, as well as new concepts for its management.The current model of HIT is that of a multi-step immune pathology in response to the simultaneous exposition to an endogenous  and an exogenous molecule , at specific molar ratios. Moreover, the importance of platelets has been well known for years, but the central roles of other cells  and specific receptors have only been recognized a few years ago. The comprehension of the pathophysiology of HIT is key to improve the therapeutic arsenal and the management of patients. This is well shown by the opportunity offered by IVIG and IdeS and their inhibitory effects in the interaction of IgG and FcγRIIa. A further and more precise comprehension of the pathophysiology could allow to develop more specific therapy for HIT.Clinically, the work-up of HIT has improved in the past few years with the emergence of rapid and accurate diagnostic algorithms combining clinical parameters (4T score) and rapid quantitative laboratory assays. It is now possible to rapidly and accurately rule in or out HIT. This drastically improves the management of patients with HIT suspicion.In conclusion, our knowledge about HIT is rapidly improving, which leads to a better management of this pathology and a better prognosis for patients.


Global longitudinal strain (GLS), most commonly measured at the endocardium, has been shown to be superior to left ventricular (LV) ejection fraction (LVEF) for the identification of systolic dysfunction and prediction of outcomes in heart failure (HF). We hypothesized that strains measured at different myocardial layers  will have distinct diagnostic and predictive performance for patients with HF.Layer-specific GLS, layer-specific global circumferential strain (GCS) and global radial strain (GRS) were evaluated by cardiovascular magnetic resonance imaging (CMR) feature tracking in the Alberta HEART study. A total of 453 subjects consisted of healthy controls , at-risk for HF , HF with preserved ejection fraction , HF with mid-range ejection fraction  and HF with reduced ejection fraction . For outcomes analysis, CMR-derived imaging parameters were adjusted with a base model that included age and N-terminal prohormone of b-type natriuretic peptide (NT-proBNP) to test their independent association with 5-year all-cause mortality.GLS_EPI distinguished all groups with preserved LVEF  while GLS_ENDO and all GCS  were similar among these groups. GRS was reduced in HFpEF  and the difference between GLS_EPI and GLS_ENDO were significantly larger in HFpEF as compared to controls. Within the preserved LVEF groups, reduced GRS and GLS_EPI were significantly associated with increased LV mass (LVM) and LVM/LV end-diastolic volume EDV (concentricity). In multivariable analysis, only GLS_AVE and GRS predicted 5-year all-cause mortality , with the strongest association with 5-year all-cause mortality by Akaike Information Criterion analysis and significant incremental value for outcomes prediction beyond LVEF or GLS_ENDO by the likelihood ratio test.Global strains measured on endocardium, epicardium or averaged across the wall thickness are not equivalent for the identification of systolic dysfunction or outcomes prediction in HF. The endocardium-specific strains were shown to have poorest all-around performance. GLS_AVE and GRS were the only CMR parameters to be significantly associated with 5-year all-cause mortality in multivariable analysis. GLS_EPI and GRS, as well as the difference in endocardial and epicardial strains, were sensitive to systolic dysfunction among HF patients with normal LVEF (> 55%), in whom lower strains were associated with increased concentricity. Heart failure (HF) is a complex clinical syndrome with a wide array of characteristic cardiac structural and functional abnormalities . PatientHowever, myocardial structure and function are heterogeneous, with layer-specific fiber orientations ranging from largely circumferential at the mid-wall to more oblique at the endocardium (ENDO) and epicardium (EPI) . There iThe aims of the current study were to compare the utility of global strains assessed at different layers of the myocardium, measured with cardiovascular magnetic resonance imaging (CMR) feature-tracking, to characterize layer-dependence, to detect systolic dysfunction in HFpEF and to predict outcomes in all HF patients, regardless of LVEF.The study was approved by the University of Alberta and University of Calgary Health Research Ethics Boards and all study participants provided written informed consent. We excluded those unable to provide informed consent or with a contraindication to CMR. Patient recruitment and testing has previously been reported . BrieflyAll subjects underwent a CMR examination on 1.5 T CMR scanners  at the University of Alberta or University of Calgary sites, respectively. To quantify cardiac structure and function, the CMR exam included standard balanced steady state free precession (bSSFP) cine imaging, with 10–14 short axis slices covering the entire ventricle, as well as two-chamber, three-chamber and four-chamber long axis views. Typical acquisition parameters: Repetition time/echo time (TR/TE) 2.8/1.4 ms, 50–70 degree flip angle, 8 mm slice thickness with a 2 mm gap for short axis slices, 256 × 192 matrix, 380 × 285 mm field of view, 10 views per segment with 25 or 30 reconstructed cardiac phases over the cardiac cycle. All cardiac images were acquired with electrocardiographic gating within an 8–12 s breath-hold per slice.LV and right ventricular (RV) end-diastolic volume  and end-systolic volume , ejection fraction  and left ventricular mass (LVM) were measured using Syngo Argus,  or CVI42 . Both methods used only short axis slices for volume analysis and papillary muscle was included in the chamber volume. Volumes and LVM were normalized to body surface area (BSA), calculated using idealized weight for the given subject height . Relativ0) to end-systole (L) relative to end-diastolic length, reported as a percentage, (L − L0)/L0*100 (Lagrangian strain), as shown in Fig. Strain was measured from bSSFP short and long axis cine images using a feature tracking approach develop in-house based on b-spline non-rigid registration . The strGLS and GCS strains at all layers were also calculated using commercially available CMR feature tracking software  in a subset of 202 subjects, for a comparison of feature tracking methodology used in current study.Continuous variables were expressed as mean ± standard deviation or median , as appropriate. Categorical variables were expressed as frequency and percentage. For missing data, the data was assumed to be missing at random. Our cohort had missing values for N-terminal prohormone of b-type natriuretic peptide  and creatinine . Multiple imputation by chained equations with 50 imputed data sets was used to generate missing data based on all candidate predictors and outcomes. We averaged results from the 50 imputations .Two sample t-test (or Mann–Whitney U test) or one-way analysis of variances with Bonferroni post-hoc correction (or Dunn’s test) were used to compare continuous variables among groups of patients, as appropriate. Chi-square was used to compare the categorical baseline characteristics. The normal distribution of continuous variables was tested by the Shapiro–Wilk normality test. We applied logarithmic transformation to NT-proBNP and creatinine. Correlation between continuous variables was tested by Pearson correlation.minimum) indicates the best outcomes model. Each compared model included the base model and a single evaluated CMR parameter. For comparison of AIC values (between CMR parameters), Δi = AICi – AICminimum is the difference between Modeli and best fit model. If Δi ≤ 2, there is substantial support for similar predictive performance of the best fit model and the i-th model; for 4 ≤ Δi ≤ 7 there is considerably less support for i-th model; for Δi > 10 there is no support for i-th model [Clinical outcome was all-cause mortality over a 5-year follow-up. Univariable Cox proportional regression was performed for all demographic parameters, cardiovascular risk factors, cardiovascular disease history, concomitant diseases and CMR-derived imaging parameters. Sex and the parameters with univariable p value < 0.2, including age, systolic blood pressure, current smoker, presence of heart failure, coronary artery disease, atrial fibrillation or atrial flutter, chronic obstructive pulmonary disease, log (NT-proBNP) and log (creatinine) entered the forward selection approach based on Akaike Information Criterion (AIC) to build the optimal set of predictors as the base model for adjustment. In the multivariable Cox proportional hazard analysis conventional LV measurements, GRS, and layer-specific strains for GLS, GCS were each adjusted with the base model to test their independent association with the outcome. Additionally, the association of layer-specific strains and conventional LV measurements with clinical outcomes were quantified using the AIC values, where the lowest AIC score . Statistical analyses were performed using STATA . A p-value less than 0.05 was considered significant for all tests.From 466 subjects who underwent CMR exams, 453 subjects with analyzable images were identified: controls (n = 77), at-risk (n = 143), HFpEF (n = 87), HFmrEF (n = 88), and HFrEF (n = 58).For statistical analysis of group differences, two subgroups of subjects were considered, those with preserved LVEF (> 55%), consisting of healthy controls, patients at-risk for HF and HFpEF  and LVM/LVEDV (concentricity) values in HFpEF (top row) and all individuals with preserved LVEF (bottom row), with separate results by sex Fig. . SimilarAmong the 77 healthy controls subjects , male subjects had lower strains than females at all locations except for GCS_ENDO which were similar Table . For bot, with ΔAIC values of 3.5 to 6.1 [2 = 5.1 and 7.4, respectively, both ps < 0.05), by the likelihood ratio test. GRS, from both at short axis and long axis images, had incremental value over LVEF .During a 5-year follow-up for the at-risk and HF subgroups, there were 33 events of all-cause mortality. The base model included age and log (NT-proBNP) for multivariable analysis. After adjustment with the base model, GLS_AVE and GRS (for both LAX and SAX-derived GRS) were the only independent predictors of mortality, with adjusted hazard ratio 1.10, 1.03 and 1.03, respectively, for 1% absolute decrease of strains, all ps < 0.05. LVEF and GLS_ENDO were unable to independently predict outcome Table . Additio5 to 6.1 . The useThe intra-observer reproducibility of all layer-specific strains was excellent; CoV values ranged from 2.7 to 5.4%, with 4.3% for GLS_EPI and 2.7% for GLS_ENDO, and ICC values ranging from 0.97 to 0.99, with 0.98 for GLS_EPI and 0.99 for GLS_ENDO. The inter-observer reproducibility of all layer-specific strains was also excellent; CoV values ranged from 4.9 to 9%, with 4.9% for GLS_EPI and 8.7% for GLS_ENDO, and ICC ranged from 0.92 to 0.98, with 0.92 for GLS_EPI and 0.98 for GLS_ENDO. Comparison of the custom feature tracking software used in the current study and the commercially available CVI42 for all GLS and GCS components in 202 subjects illustrated good agreement between the methods. . Similar to recent studies in healthy subjects , 29, 30 Additionally, indexed LVM and LVM/LVEDV were significantly increased in the HFpEF group as compared to at-risk and healthy controls. Together, these findings describe a HFpEF phenotype with preserved ENDO function, paralleling LVEF, but with increased strain reduction across the wall, potentially associated with increased LVM and concentricity (mass/volume). GRS was also significantly reduced in the HFpEF group as compared to healthy controls, and was shown to be associated with increased concentricity. A similar relationship was observed for GLS_EPI, with more impaired function in those with increased concentricity. These observed associations between strains and structure also exist in comparison of the healthy men and women, where men had larger LVM, larger LVM/LVEDV, lower GLS_EPI, lower GRS and larger differences between ENDO and EPI strains.In the current study, the use of a higher cutoff of 55% for preserved LVEF , 22, as For many of the reported structural and functional parameters that distinguish HFpEF from healthy controls, the values in the at-risk group were intermediate, between the control and HFpEF groups, with significant group differences on post-hoc analysis, suggesting early changes in these parameters may contribute to or be associated with future development of HF.When comparing the three HF groups alone , all CMR parameters were significantly different between all groups, with larger volumes, increased LV mass and reduced strain  from HFpEF to HFrEF. The differences between endocardial and epicardial strains also followed this pattern, with reduced differences between the layers from HFpEF to HFrEF, paralleling the reduction in concentricity (mass/volume).Among all strain components, only GLS_AVE and GRS were significantly predictive of mortality in HF patients and those at risk when including the key factors of age and NT-proBNP in the outcomes model. Both parameters had superior outcomes prediction performance as compared to commonly reported GLS_ENDO , 12, 31.The limited improvement in endocardial-specific strain over LVEF for detection of dysfunction or prognosis might be expected given the strong relationship between volumetric function, from which LVEF is defined, and deformations of the endocardial surface. Recently, Stokke et al. highlighted the direct relationship between endocardial strains and LVEF, and that LV wall thickness becomes a modulator of this relationship when considering average strains, measured across the wall thickness . SpecifiIt should be acknowledged that the conventional strain components, longitudinally or circumferentially, are not along the direction of fiber shortening. Fibers are helically orientated at the ENDO and EPI . It is pSimilar to previous studies , 30, menOur study has a modest sample size and number of events for outcomes analysis, a reflection of the clinical stability of our HF cohort, which may limit the generalizability of the reported findings. However, based on the suggested 10 outcome events per predictor, our use of age, log (NT-proBNP) with each CMR parameter separately (i.e. 3 predictors in the composite model), our observed 33 events  are sufficient. The base model, while only including age and NT-proBNP was established based on AIC forward selection including all cardiovascular disease risk factors and disease history with p-values < 0.2 and is thus robust and representative. Also, age and NT-proBNP have previously been reported to be the strongest predictors of mortality among clinical characteristics in patients with HF or without HF . An addiGlobal strains measured on ENDO, EPI or average across the wall thickness are not equivalent for the identification of dysfunction or outcomes prediction in HF. The endocardium-specific strains were shown to have poorest all-around performance. GLS_AVE and GRS were the only CMR parameters to be significantly associated with 5-year all-cause mortality in multivariable analysis. GLS_EPI, GLS_AVE, GRS and the relative difference in endocardial and epicardial strains differentiated HFpEF patients from healthy controls, and increased LVM and LVM/LVEDV were generally associated with reduced strain in those with preserved LVEF.Additional file 1: Fig. 1. Comparison of feature tracking software (custom software used in the current study versus CVI42) for calculation of layer-specific longitudinal and circumferential strains in a subset of 202 subjects . See Table 2 for abbreviations.


Different techniques have been described to repair post myocardial infarction ventricular septal rupture (VSR), each method may result in residual shunting, bleeding, and suboptimal left ventricular (LV) performance secondary to change in LV geometry. The aim of this report is to describe early and mid-term results of sandwich technique through right ventricle in five consecutive patients.Five consecutive patients (3 women and 2 men) with VSR  underwent surgical repair for postinfarction ventricular septal rupture by sandwich technique performed through right ventricle from August 2012 to April 2019 in our institute. Reconstruction of the septum was performed by two patches of 0.6 mm Gore-Tex on each side of the septal defect through right ventricular incision, according to the method described by Isoda et al. Coronary artery bypass grafting was performed in two patients.The mean aortic clamp time was 90 min . The mean extracorporeal circulation time was 146.6 min . Postoperative intensive care unit (ICU) stay averaged 12 days . There was no hospital mortality. No postoperative residual shunting was detected, and no patient needed re-operation for bleeding. Patients have been followed up for a mean of 24.4 months . There was one death seven days after discharge due to arrhythmia (40 days after surgery).Sandwich technique through right ventricular approach is simple and extendable to all VSRs irrespective of their locations. Residual shunting and bleeding are negligible or zero. It may be considered as standard of repair for patient with post infarction ventricular septal rupture. Ventricular septal rupture (VSR) is a rare but lethal complication of myocardial infarction. It complicates less than 0.5% of patients following acute myocardial infarction . MedicalMany surgical techniques have been described including infarctectomy and closure (Daggett’s technique), infarct exclusion and its modifications (single or double patch) with or without application of surgical glue , and sanMany current techniques do not fulfill this criterion. Isoda et al. have developed a method known as sandwich technique that effectively addresses these problems . They usBased on the encouraging results achieved by Isoda technique, we operated five consecutive patients with the diagnosis of VSR using this method and here we reported the results.We reviewed five consecutive patients with postinfarction ventricular rupture who referred to us from August 2012 to April 2019 for surgical repair at Seyed-al-Shohada Heart Hospital, Urmia, Iran. Steps of the operation were the same for all patients.All patients were supported with intra-aortic balloon pump (IABP) immediately after the diagnosis. The operations were performed on cardiopulmonary bypass and bicaval cannulation. Venous line de-airing was routinely undertaken. Arterial filter (Eurosets) and pre-bypass filter (Eurosets EU 3709) were routinely used. Affinity (3 cases) and Dideco Evo Oxygenators (2 cases) were used. Moderate hypothermia (28 C) was used. During CPB, both lungs were ventilated with 150-200 mL of air to prevent atelectasis. First dose of cardioplegia administered initially into the aortic root as warm induction until heart was arrested and then the rest of it were given through coronary sinus. Next doses of cardioplegia were administered only through coronary sinus.During cardiac arrest, intra-aortic balloon pump (IABP) was set to internal mode to make the flow pulsatile. The operation field was flooded with CO2 to lessen the chance of air emboli. At the conclusion of the operation, warm shot was infused into the coronary sinus, followed by controlled aortic root reperfusion.Surgical technique, right ventricle (RV) was opened about 1.5 to 2 cm lateral and parallel to the left anterior descending coronary artery (LAD) about 5 or 6 cm to fully visualize VSD. In order to expose septal defect, trabeculae were widely cut. Two patches of 0.6 mm Gore-Tex measuring approximately 5 in 5 cm were trimmed at their corners to make them octagon. On average about 10-11 sutures of “25 mm 3-0 prolene” were used, 6 or 7 to sandwich the septum between the patches. These sutures were placed in the following order: left ventricular Gore-Tex patch, LV side of the septum emerging from right ventrivilar side of the septum then to the second (right ventricular) patch. The remaining 4 or 5 sutures were used to anchor LV patch to free wall of the LV about 1.5 cm to the left of LAD being secured with Teflon felts pledgets. Then LV patch was pushed throgh septal defect into the LV cavity. RV patch at its free wall is left intact to be later incorporated with sutures for closing the RV incision with two strip of Teflon felt . In one case saphenous vein graft (SVG) was grafted to obtuse marginal (OM), and in the other one SVG was grafted to OM and posterior descending artery (PDA). In neither case, LAD was graftable. The mean aortic clamp time was 90 min (range of 64 to 157 min). The mean cardiopulmonary bypass (CPB) time was 146.6 min (range of 108 to 240 min).The mean postoperative use of IABP was 2.8 days (range 1 to 5 days). Postoperatively, no residual shunting was detected by echocardiographic study. There was no hospital mortality.One patient died of arrhythmia 40 days after surgery and 7 days after hospital discharge. This case was a 69-year-old diabetic woman received at our center in cardiogenic shock with EF of 20%. IABP was placed and while stabilizing the patient she experienced cardiac arrest due to ventricular fibrillation and underwent resuscitation (CPR), tracheal intubation, and mechanical ventilation. Subsequently, she developed disseminated intravascular coagulation (DIC) and renal failure with creatinine levels reaching 4 mg/dL. After controlling arrhythmia and some improvement in her condition, she underwent surgery. Postoperatively, she had very complicated course of arrhythmia, low cardiac output, pressure ulcers, generalized edema, and respiratory failure; with supportive measures, she survived to discharge with a total hospital stay of 52 days. One week following hospital discharge, she died of arrhythmia. The remaining (80%) are currently alive and in NYHA functional class 2.Before the introduction of thrombolytic therapy, 1% to 2% acute myocardial infarctions (MI) were complicated with ventricular septal defect (VSD), so it is fairly uncommon . With meTiming of operation may be depended on patient’s condition. Patients in cardiogenic shock (50 to 60% of patients) need immediate surgery. Delaying treating patients in cardiogenic shock represents a “failed strategy.” Stable patients represent less than 5% of total, surgery in this group may be safely delayed, allowing necrotic tissue become fibrotic. Patients with intermediate position between shock and stable condition. These patients should be operated on promptly within 12 to 24 h .There are four main surgical techniques to repair VSR, including infarctectomy and closure (Daggett’s technique), infarct exclusion, modified infarct-exclusion technique double patch plus biological glue, and sandwich technique through right ventricular approach.Furukawa et al. reported 12 patients who underwent Daggett’s infarctectomy and septal rupture reconstruction with Dacron patch from 1990 to 1998 with no in-hospital mortality. Coronary artery bypass grafting was performed in 5 patients. In their series, postoperative residual shunt was recognized in 3 patients (25%); none of them was hemodynamically significant, so re-operation was not needed. They reported two late deaths caused by non-cardiac problems [The Komeda type exclusion technique through the left ventricular cavity avoids stitching necrotic myocardium, so minimal or no infarctectomy is needed. A single patch of bovine pericardium is sutured to non-necrotic-ischemic tissue. The right ventricle is not incised. Residual shunting is still a concern and potential change in LV geometry remains, although tearing of the fragile ischemic myocardium may be prevented  Fig. 3)3).Fig. Residual leak is a common problem after surgical repair for VSR. Deja et al. reported this complication in 40% of patients with different surgical techniques. In their study, reoperation was needed in 12% of patients and operative mortality was 35% . Residua(Fig. Isoda et al. introduced a method known as the sandwich technique in which septum is sandwiched between two patches of Gore-Tex anchored together Fig. . Table 3We performed this technique in five consecutive patients. Surgical glue was applied in only one case, although Isoda recommended glue to lessen stress at suture . No patiApproach from RV is superior than LV because LV geometry is better preserved; mitral valve apparatus is less likely to be damaged; bleeding is of lesser concern due to lower pressures of RV; and the septal defect is better visualized, making it easier for placing the patches.The principles of the repair of posterior VSR is quite similar to anterior ones. The incision is about 1-1.5 cm from and parallel to posterior descending artery, large enough to fully visualize the septal defect. It is important to resect obscuring trabeculae .This technique is simple and reproducible, and the LV geometry is not changed. We experienced no residual shunting, no reoperation, and no operative death. In our experience, no significant right heart failure was developed secondary to right ventriculotomy.


In pulmonary arterial hypertension (PAH), progressive right ventricular (RV) dysfunction is believed to be largely secondary to RV ischaemia. A recent pilot study has demonstrated the feasibility of Oxygen-sensitive (OS) cardiovascular magnetic resonance (CMR) to detect in-vivo RV myocardial oxygenation. The aims of the present study therefore, were to assess the prevalence of RV myocardial ischaemia and relationship with RV myocardial interstitial changes in PAH patients with non-obstructive coronaries, and corelate with functional and haemodynamic parameters.We prospectively recruited 42 patients with right heart catheter (RHC) proven PAH and 11 healthy age matched controls. The CMR examination involved standard functional imaging, OS-CMR imaging and native T1 mapping. An ΔOS-CMR signal intensity (SI) index  was acquired at RV anterior, RV free-wall and RV inferior segments. T1 maps were acquired using Shortened Modified Look-Locker Inversion recovery (ShMOLLI) at the inferior RV segment.p = 0.02). The inferior RV ΔOS-CMR SI had a significant correlation to RV inferior wall thickness  and RHC mean pulmonary artery pressure (mPAP) . Compared to healthy controls, patients with PAH had higher native T1 in the inferior RV wall: 1303 (1107–1612) vs 1232 (1159–1288)ms, p = 0.049. In addition, there was a significant difference in the inferior RV T1 values between the idiopathic PAH and systemic sclerosis associated PAH patients: 1242 (1107–1612) vs 1386 (1219–1552)ms, p = 0.007.The inferior RV ΔOS-CMR SI index was significantly lower in PAH patients compared with healthy controls (9.5 (– 7.4–42.8) vs 12.5 (9–24.6)%, Blunted OS-CMR SI suggests the presence of in-vivo microvascular RV dysfunction in PAH patients. The native T1 in the inferior RV segments is significantly increased in the PAH patients, particularly among the systemic sclerosis associated PAH group. Pulmonary arterial hypertension (PAH) is a progressive disorder that affects both the pulmonary vasculature and the heart . It is aOxygen-sensitive (OS) cardiovascular magnetic resonance (OS-CMR), also known as blood oxygen level dependent (BOLD) CMR enables the in-vivo assessment myocardial oxygenation at the tissue level –13. OS-CPatients undergoing treatment in the PAH clinics at two South Australian hospitals were invited to participate in this study. Inclusion criteria included right heart catheter (RHC) proven PAH (defined as pulmonary capillary wedge pressure (PCWP) The full protocol has been described elsewhere ; in brieNative T1 mapping were acquired using Shortened Modified Look-Locker Inversion recovery (ShMOLLI) on a single mid-ventricular short-axis slice as previously described . The ShM42 . The short-axis bSSFP cine images were used to quantify LV and RV systolic function. Standard function parameters were calculated including LV ejection fraction (LVEF), RV ejection fraction (RVEF), cardiac index, and body surface area (BSA) indexed end-diastolic (EDVI), end-systolic (ESVI) volumes for LV/RV and LV indexed myocardial mass. End-diastolic RV mass and volumes was used to calculate RV mass/volume ratio.CMR analysis was performed using cvi42  as previously described [The OS-CMR assessment of the RV and LV was performed using cviescribed . In brieescribed . Reliablescribed , hence aescribed . The meaescribed . As it iescribed . The relescribed .42 (Circle Cardiovascular Imaging). As previously described [The T1-values of the RV were assessed using cviescribed , a ROI cescribed . A mean All analyses were performed using the Stata statistical software version 15.1 . Categorical data are described using frequencies and percentages and continuous data using median and range. Differences between groups in the mean change in myocardial oxygenation response and native T1-values were assessed using Mann–Whitney test. Changes in these same outcomes within patient groups were assessed using the Sign-rank test. Reproducibility of measurements for inter and intra-observers was assessed by using the coefficient of variation and by assessing the absolute and proportional bias. Absolute bias was assessed using a t-test of the differences in the 2 measures versus zero and proportional bias by regressing the differences in the 2 measures on the mean for the 2 measurements. Associations between test parameters were assessed using the Spearman’s rho (ρ) correlation coefficient. A 2-sided Type 1 error rate of alpha = 0.05 was used for assessing statistical significance.The subject characteristics are summarised in Table 2, p = 0.001), RV mass/volume ratio (0.30 (0.22–0.49) vs 0.22 (0.15–0.25), p < 0.001) and inferior RV wall thickness (4 (3–9) vs 3 (2–5)mm, p = 0.002). Table Table  p = 0.02)   and LV lateral wall (9.5 (– 7.4–42.8) vs 11.5 (– 9.2–31.8)%, p = 0.57) of PAH patients.Of the total 42 PAH patients recruited, 40 (95%) patients and all the healthy controls completed the OS-CMR study protocol. The mean RV ΔOS-CMR SI change in the inferior RV segments was significantly lower in PAH group compared to the controls (9.5 (-7.4 – 42.8) vs 12.5 (9 – 24.6)%,02) Fig. a. The gl04) Fig. b. The ΔOp = 0.049  and LV lateral wall (1303 (1107–1612) vs 1301 (1102–1500)ms, p = 0.85) of PAH patients. The inter-observer absolute bias was 2.0, 95% confidence interval (CI) , p = 0.53 and the relative bias was – 0.05, 95% CI , p = 0.41. The intra-observer absolute bias was 9.1, 95% confidence interval (CI) , p = 0.68 and the relative bias was 0.48, 95% CI , p = 0.18.Good quality and analysable RV native T1 maps were obtained from 71% 30/42) PAH patients and 73% (8/11) of controls. Reasons for excluding T1 maps were image artefacts and partial volume effects. Compared to healthy controls, patients with PAH had higher native T1 values in the inferior RV wall: 1303 (1107–1612) vs 1232 (1159–1288)ms, 0/42 PAH p = 0.88  and SScPAH (n = 17) patients was 9.4 (– 5.1–23.6) vs 9.0 (– 7.4- 42.8)%, p < 0.001)     Fig. a. Compar01) Fig. b and mod02) Fig. c. This s91) Fig. D. FurtheThe principal finding from this study is that myocardial oxygenation response to adenosine stress is blunted in patients with PAH compared to healthy controls. The blunted oxygenation response was demonstrated in PAH patients who were stable on pulmonary vasodilator therapy and at an adaptive stage of PAH with non-obstructive epicardial coronaries, and was correlated inversely with RV wall thickness and RHC mPAP. Although we had demonstrated changes to the myocardial interstitium, no clear interaction with myocardial oxygenation was noted. These findings highlight the potential contribution of myocardial ischemia to the pathophysiology of RV dysfunction in PAH, and could subsequently lead to new potential treatment targets, in such patients.In PAH, RV myocardial ischemia is acknowledged to be a significant contributor to adverse remodelling and progressive RV dysfunction . Reduced. had demonstrated that in coronary artery disease, 50% of hypoperfused segments on quantitative myocardial perfusion demonstrate no evidence of deoxygenation [In this study, we have demonstrated a blunted myocardial oxygenation response to vasodilator stress in the inferior RV segment on PAH patients. Specifically our study demonstrates the presence in-vivo myocardial deoxygenation in the adaptive stage of PAH. The findings of in-vivo RV myocardial deoxygenation in PAH are novel because abnormalities in myocardial blood flow or microvascular dysfunction may not necessarily lead to myocardial deoxygenation . Arnold genation . Furthergenation . AlthougThe OS-CMR SI changes in the RV had good correlation with global OS-CMR SI changes seen in the LV, an area of myocardium in which there is good validation with the OS-CMR technique. In our study, the OS-CMR technique has demonstrated significant changes in the inferior RV segment. Thinned myocardium , off-resonance artefacts and image artefacts are known limitations of the OS-CMR technique in the RV . HoweverFurthermore, our study has demonstrated a moderate inverse correlation between RV OS-CMR SI and mPAP. The moderate correlation highlights that there are other pathophysiological factors (such as microvascular ischemia) that affect the RV besides elevated mPAP. Patients with microvascular ischemia often present with typical effort-induced angina, but also with atypical symptoms such as dyspnea on exertion . ExertioIn PAH, the RV adaptation extends to the cardiomyocytes and interstitium altering the cardiac structure and function . AlthougInterestingly our study is the first to have demonstrated a significant difference in the native T1-values between the IPAH and SScPAH. We have used the ShMOLLI sequence in contrast to other studies that have used the MOLLI sequence , 22, 38.Our study only performed a single mid-ventricular slice on OS-CMR imaging rather than the entire ventricle hence there was incomplete coverage of the full RV myocardium. This is unlikely to be of major relevance in RV assessment of PAH which is a global process. While our study had demonstrated in-vivo myocardial deoxygenation in the RV of PAH, we had not performed any direct comparison with myocardial blood flow, an area for future studies. Late-gadolinium enhancement or extracellular volume assessment was not performed due to concerns of patient safety and tolerability during CMR research scan. While OS-CMR sequence has been studied in many conditions , to our Blunted OS-CMR SI suggest the presence of in-vivo microvascular dysfunction in the RV of PAH patients. Future studies are essential to determine the utility of OS-CMR of the RV in predicting progressive RV dysfunction and mortality.Additional file 1: Table S1. Correlation between right ventricular (RV) ΔOS-CMR signal intensity and RV T1-mapping to RV CMR volumetric/functional indices and right heart catheter (RHC) hemodynamic indices.