BackgroundUnlike the relationship with atherosclerotic coronary artery disease, that between low-density lipoprotein cholesterol (LDL-C) and cardiac allograft vasculopathy (CAV) is unclear. Our objectives were to characterize lipid profiles early after heart transplantation (HT) and evaluate the relationship between early LDL-C and the development of CAV.MethodsWe retrospectively reviewed consecutive adults who underwent HT at 2 centres during the time period 2010-2018. The primary outcome was the incidence of angiographic CAV. The relationship between LDL-C and CAV was assessed using Cox proportional hazards and logistic regression models adjusted a priori for clinically important covariates, including recipient and donor age, recipient sex, ischemic time, and pre-HT diabetes.ResultsA total of 386 patients followed for a median (range) of 4.4 (2.8-6.8) years were included. LDL-C at baseline (2.11 ± 0.86 mmol/L) and 1 year after HT (2.20 ± 0.88 mmol/L) was similar (P = 0.21), but it was lower at the end of follow-up (1.89 ± 0.74 mmol/L, P < 0.01). Of 309 patients who underwent angiography, 54% had CAV. The risk of CAV did not vary according to baseline, 1-year, or change from baseline to 1-year LDL-C. The odds of CAV at 1 year were equally likely across LDL-C values (adjusted odds ratio 1.00, 95% confidence interval: 0.61-1.63 for baseline, and adjusted odds ratio 1.25, 95% confidence interval: 0.74-2.10 for 1-year LDL-C).ConclusionsNo association was identified between early LDL-C and the development of CAV. Our findings do not support targeting a specific LDL-C for patients who do not otherwise meet criteria for guideline-recommended LDL-C target levels. Randomized studies are warranted to determine if lipid-lowering to a specific LDL-C target level modifies the risk of CAV.

Inroduction: People with postural tachycardia syndrome (PoTS) experience orthostatic intolerance in association with orthostatic tachycardia.Current demographic data is largely based on North American populations.The aim of this study is to obtain a profile of UK PoTS patients and is the largest study to date.Method: 1005 PoTS patients completed an online survey designed by healthcare professionals, charity trustees and patients.It was distributed by email and social media.Only those from the UK diagnosed by tilt table test (N ¼ 615, 73%) are included in this report.Results: 84% of responders were aged between 18-50 and 93% were female.Cardiologists were usually first to suggest a diagnosis of PoTS (36% of cases) followed by patient, family or friend (24%) and in only 7% did the GP suggest a PoTS diagnosis.The mean time from presenting with symptoms to a healthcare professional to obtaining a PoTS diagnosis was 3.5 years (range 0.5-28 years).The most common presenting symptoms of PoTS were lightheadedness (91%), tiredness (91%), and palpitations (85%).60% reported blackouts or fainting, which is a much higher proportion than previous studies.Half of the patients were told by a medical professional that their PoTS symptoms were due to a psychiatric or psychological problem, the most common of which was anxiety.Co-morbidities included Ehlers-Danlos hypermobility type (also known as EDS III or joint hypermobility syndrome; 48%), low blood pressure (37%), vasovagal syncope (33%) and chronic fatigue syndrome (27%).85% of respondents perceived a reduction in their quality of life.A fifth were wheelchair users and 11% had lost their driving licence.25% had changed their career, 29% reduced their working hours and 38% had stopped working for the foreseeable future due to PoTS symptoms.42% experienced undefined financial problems.Of interest, 66% were engaged in aerobic exercise at least twice a week at the onset of their PoTS symptoms, which challenges previous suggestions that deconditioning may be a contributing trigger.Currently, the main barriers to exercise are fatigue and feeling unwell during or after exercise.Of the 38% referred for lifestyle or exercise advice, only half of their advisors knew what advice to give a PoTS patient.Conclusions: This survey paints a unique picture of this under and misdiagnosed condition and its impact on patients' lives.Findings highlight a need for the education of a range of healthcare professionals on PoTS diagnosis and multidisciplinary management.PoTS should be considered in patients who present with the triad of presyncope, fatigue, and palpitations.Due to the non-specific and multiple symptoms of PoTS, the development of a screening tool may facilitate and expedite diagnosis.

Introduction Feature-tracking (FT) analysis offers a novel, fast and practicable method to calculate strain from routinely acquired steady state free precession (SSFP) images without the need to perform additional tagged sequences. There is no validation of this technique, however, against a reference standard myocardial tagging analysis for any strain parameter other than mid-left ventricular whole slice circumferential strain. In an adult study of patients with dilated cardiomyopathy (DCM) and healthy controls, we sought to validate the FT method (TomTec Imaging systems, Munich) against spatial modulation of magnetisation (SPAMM) tissue tagging analysis (Cardiac Image Modelling Package (CIMTag2D), University of Auckland) for the computation of long axis function. Methods We compared measures of global longitudinal strain from the horizontal long axis view using the two techniques in 45 patients (mean age 44±14 years, male 63%). Normal healthy adults (n=35) were identified from an ongoing prospective, observational research study examining the effects of living kidney donation on cardiovascular structure and function (NCT01028703). Consecutive DCM patients (n=10) were identified after undergoing myocardial tagging for clinically indicated scans. Retrospective off-line analysis was performed on matched tagged and SSFP slices by two independent blinded observers (WEM and RJT). After manually drawing endocardial borders in the end-diastolic frame for each image, the FT software automatically propagated the contour and followed its features (brightness gradient at the tissue-cavity interface, dishomogeneties of the tissue, spatial coherence) throughout the remainder of the cardiac cycle to compute longitudinal strain parameters. Results Longitudinal strain (Ell). Peak systolic FT-Ell (−18.1±5.0%) correlated most strongly with CIMTag-Ell values derived from the subendocardium (−16.7±4.8%) with a Pearson9s correlation coefficient of 0.70 (p<0.001; figure 1A). A Bland Altman plot (figure 1B) showed good agreement with only a small systematic overestimation from FT (mean difference 1.3±3.8%, p=0.03). Whilst in DCM patients peak systolic global Ell values were not significantly different between the two techniques (−9.7±4.5% vs −8.8±3.9%, p=0.44), among healthy controls there was a small but significant difference in Ell values between FT and tagging image analysis (−19.5±3.5% vs −18.0±3.5%, p=0.04; figure 2). Longitudinal strain rate (SR) There was good agreement between the two techniques for peak systolic global longitudinal SR values but with a small tendency towards higher FT values as compared with tagging (mean difference 0.09±0.26 1/s, p=0.04; r=0.64, p<0.001). The weakest correlation between the two techniques was for early diastolic global longitudinal SR but even this relationship was still highly significant (mean difference 0.09±0.26 1/s; r=0.42, p=0.007). Reproducibility testing Intraobserver and interobserver variability for FT-Ell analysis was small (−0.49±1.83% and 0.22±1.13%, respectively). Timed analysis The average time taken for post-processing strain analysis using FT software was significantly less than that required for CIMTag (5.9±0.8 min vs 23.2±3.5 min, p<0.0001). Conclusions FT based assessment of longitudinal strain correlated highly with values derived from tagged images in a population with a wide range of left ventricular function. Furthermore, FT can be performed without the need for additional imaging and lengthy post-processing times.

Background Increasing evidence from clinical outcomes studies suggest that cardiac resynchronisation therapy with defibrillation (CRT-D) is superior to implantable cardioverter defibrillator (ICD) therapy alone in patients with left ventricular dysfunction. Methods We undertook a retrospective analysis of all ICD and CRT-D implants from April 2006 to July 2012. Cost data was obtained on an individual patient basis, derived from financial records of transactions between payers and the provider. Results A total of 921 patients (aged 63±14 years (mean±SD), 49 (91%) male) underwent device implantation: 486 (53%) de novo CRT-D; 381 (41%) single/dual chamber ICD; and, 54 (6%) upgrade from ICD to CRT-D. In the upgrades from ICD to CRT-D, the median time from ICD to CRT-D implantation was 3.2 years. From the time prior to ICD implantation to prior to CRT-D, the LVEF decreased from 30±9.4% to 22±8.7% (p<0.001), the QRS duration increased from 133±34.9 ms to 158±29.3 ms (p=0.0003) and all patients had progressed to NYHA class III. In this upgrade group, the initial ICD implantation cost £846 864 (34 electives: £511 904; 20 non-electives: £334 960) and the upgrade to CRT-D cost £1 330 614 (44 electives: £1 046 364; 10 non-electives: £284 250), totalling £2 177 478 in implantation costs alone over a median of 3.2 years. If these 54 patients had a CRT-D at the initial implant, it would have cost £1 377 054 (34 electives: £808 554; 20 non-electives: £568 500). Therefore, this approach would have saved £800 424 in implantation costs alone. Conclusions This study indicates that upgrading from ICD to CRT-D is costly. Our findings suggest that implantation of CRT-D in patients with known left ventricular dysfunction may be more cost-effective.

Purpose: Clinical outcomes studies suggest that cardiac resynchronisation therapy with defibrillation (CRT-D) is superior to implantable cardioverter defibrillator (ICD) therapy alone in patients with left ventricular dysfunction. Methods: A retrospective analysis of all ICD and CRT-D implants from April 2006 to July 2012 from a single tertiary referral centre was undertaken. Cost data was obtained on an individual patient basis, derived from records of transactions between payers and providers. Results: A total of 921 patients (aged 63±14 yrs [mean ± SD]) underwent device implantation: 486 (53%) de novo CRT-D; 381 (41%) single/dual chamber ICD; and 54 (6%) upgrade from ICD to CRT-D. Amongst the latter, the median time to upgrade to CRT-D implantation was 3.2 yrs. From the time of assessment prior to ICD implantation to the assessment prior to CRT-D implantation, the left ventricular ejection fraction decreased from 30±9.4% to 22±8.7% (p<0.001), the QRS duration increased from 133±34.9ms to 158±29.3ms (p = 0.0003) and all patients had progressed to NYHA class III. In this upgrade group, the initial ICD implantation cost €1,016,236 (34 electives: €614,284; 20 non-electives: €401,952) and the upgrade to CRT-D cost €1,596,736 (44 electives: €1,255,636; 10 non-electives: €341,100), totalling €2,612,972 in implantation costs alone over a median of 3.2 yrs. If these 54 patients had a CRT-D at the initial implant, it would have cost €1,652,464 (34 electives: €970,264; 20 non-electives: €682,200). Therefore, this approach would have saved €960,508 in implantation costs alone. Conclusion: This study indicates that upgrading from ICD to CRT-D is costly. Our findings suggest that implantation of CRT-D in patients with known left ventricular dysfunction may be more cost-effective.

Background Myocardial strain imaging has the potential for clinical application in the detection of pre-clinical disease, stress induced myocardial dysfunction and dyssynchrony. Feature-tracking cardiovascular magnetic resonance (FT-CMR) uses routine CMR imaging (steady-state free-precession imaging) to calculate myocardial strain. Table 1 Intra-observer variability Intra-observer variability Inter-observer variability Inter-observer variability Variable CV (%)* ICC** CV (%)* ICC** Err 8.90 0.85 (0.66 to 0.94) 14.67 0.55 (0.11 to 0.81) Ecc 3.55 0.96 (0.90 to 0.99) 4.95 0.93 (0.81 to 0.97) ELL 7.68 0.88 (0.72 to 0.96) 5.48 0.98 (0.94 to 0.99) *, coefficient of variation; **, ICC (95% CI). Methods Healthy volunteers (n=20, age: 42±13 years, 11 (55%) male) underwent a standard protocol CMR. Endocardial and epicardial borders were manually drawn and automatically tracked through the cardiac cycle. Figure 1 Results As shown in the Table, circumferential strain (Ecc) was the most reproducible, followed by longitudinal strain (ELL) and radial strain (Err). FT-CMR analysis time was 3±1 mins. Conclusions FT-CMR is highly reproducible within operators, particularly with respect to Ecc. This, together with a short time required for analysis, enhances the potential of this imaging modality in clinical practice.

It has been shown that nitrite can be reduced to nitric oxide (NO) in intestine and a number of other tissues and released into the blood to form nitrosylhemoglobin (NO-Hb), existing in an equilibrium with S-nitrosohemoglobin. The latter has been suggested to be an NO transporter to distant organs. The aim of this study was to define the pathway of nitrite reduction to form NO in intestinal wall and to estimate whether this pathway has an effect on peripheral circulation. We have shown that in rat intestine at pH 7.0 70% of nitrite is converted to NO in mitochondria. At pH 6.0, nonenzymatic nitrite reduction becomes as efficient as the mitochondrial pathway. To prove whether the NO formed from nitrite in intestine can induce vasodilatation, sodium nitrite was instilled into intestinal lumen and the concentration of NO formed and diffused into the blood was followed by measuring of NO-Hb complex formation. We found that the concentration of NO-Hb gradually increases with the increase of nitrite concentration in intestinal lumen. However, it was not always accompanied by a decrease in systemic blood pressure. Blood pressure dropped down only after NO-Hb reached a threshold concentration of approximately 10 microM. These data show that NO-Hb cannot provide enough NO for vasodilatation if the concentration of NO bound to Hb is < 10 microM. The exact mechanism underlying vasodilatation observed when the concentration of NO-bound Hb was > 10 microM is, however, not clear yet and requires further studies.

Harada, N.; Szalay, L.; Umar, F.; Kober, C.; Jafarmadar, M.; Khadem, A.; Redl, H.; Bahrami, S. Author Information

The aim of this study was to compare rat tissues with respect to their reactive oxygen and nitrogen species (RONS) generating activities as a function of age. We quantified the RONS generation in vivo in young (6 months) and in old (30 months) male Sprague-Dawley rats using the recently developed spin trap 1-hydroxy-3-carboxy-pyrrolidine, applied intravenously. This spin trap reacts with superoxide radical and peroxynitrite yielding a stable spin adduct which is detectable by means of electron paramagnetic resonance (EPR) spectroscopy in frozen tissues. In old rats RONS generation was significantly increased compared to their young counterparts in the following order: blood < skeletal muscle < lung < heart, but did not change in intestine, brain, liver, and kidney. Experiments with isolated heart mitochondria showed a significant rate of RONS generation in succinate-supplemented mitochondria from old rats while no RONS were detected in mitochondria from young rats. This study identifies heart, lung, and skeletal muscle as the tissues with increased RONS formation as a function of age. (c) 2004 Elsevier B.V. All rights reserved.

D-lactate is produced by indigenous bacteria in the gastrointestinal tract. Mammals do not have the enzyme systems to metabolize D-lactate rapidly. The present study was designed to determine the kinetics of circulating D-lactate levels and to examine whether the severity of shock affects circulating D-lactate levels in rats subjected to hemorrhagic/traumatic shock. Anesthetized rats underwent midline laparotomy (duration 30 min) and were bled to 30-35 mmHg mean arterial pressure (MAP). After the onset of decompensation, MAP was either increased to 40-45 mmHg immediately by administration of Ringer's solution (moderate shock) or after 40% of shed blood volume had been re-infused as Ringer's solution (severe shock). MAP was then maintained at 40-45 mmHg for 40 min by further administration of Ringer's solution (inadequate resuscitation). Subsequently, adequate resuscitation was performed for 60 min with shed blood and additional Ringer's solution. Metabolic acidosis was significantly more pronounced in severe than in moderate hemorrhagic/traumatic shock. Plasma D-lactate levels were already significantly increased at the end of severe hemorrhagic/ traumatic shock and remained high during inadequate resuscitation. D-lactate levels were significantly higher after severe than after moderate shock. Endotoxin levels did not correlate with shock severity. Damage to the intestinal mucosa was more profound in severe shock than in moderate shock. Our data suggest that hemorrhagic/traumatic shock is associated with mucosal damage and increased plasma D-lactate levels. The severity of shock affects D-lactate concentrations in plasma. Plasma D-lactate may be a useful marker of intestinal injury after hemorrhagic/traumatic shock.