Cardiovascular magnetic resonance imaging characteristics in patients with methamphetamine-associated cardiomyopathy.

BACKGROUND: Methamphetamine-associated cardiomyopathy (MA-CMP) is an increasingly recognised aetiology of cardiomyopathy. Cardiovascular magnetic resonance (CMR) is a specialised cardiac imaging modality commonly used in assessment of cardiomyopathy. We aimed to identify specific CMR features associated with MA-CMP. METHODS: A retrospective cohort study of CMR scans was performed in a single centre between January 2015 and December 2020. Thirty patients with MA-CMP who had undergone CMR were identified. MA-CMP was defined as those with a history of significant methamphetamine use hospitalised with acute decompensated heart failure (other causes of cardiomyopathy excluded). A retrospective analysis of index admission CMRs was performed. All studies were performed on a 1.5 T CMR scanner. RESULTS: The mean age of MA-CMP patients was 43.7 ± 7.5 years, and 86.7% were male. The mean left ventricular (LV) volume obtained in this cohort was consistent with severe LV dilatation (LV end-diastolic volume (334 ± 99 ml); LV end-systolic volume: 269 ± 98 ml), whilst the right ventricular (RV) volume indicated moderate-to-severe dilatation (RV end-diastolic volume: 272 ± 91 ml; RV end-systolic volume: 173 ± 82 ml). Mean LV ejection fraction (20.9 ± 9.2%) indicated severe LV dysfunction, with moderate-to-severe RV dysfunction also detected (RV ejection fraction: 29.4 ± 13.4%). 22 patients (73.3%) had myocardial late gadolinium enhancement (LGE), of which 59.1% were located in the mid-wall, with all of these involving the interventricular septum. 22.7% displayed localised regions of sub-endocardial LGE in a variety of locations, and 18.2% had transmural regions of LGE that were located in the inferior and inferolateral segments. 6 patients (20%) had intracardiac thrombus (4 LV, 2 both LV and RV). CONCLUSION: MA-CMP was associated with severe biventricular dilatation and dysfunction, with a high prevalence of intraventricular thrombus. This cohort study highlights that MA-CMP patients have a high prevalence of CMR findings.

Methamphetamine-Associated Cardiomyopathy: Addressing the Clinical Challenges.

The growth in methamphetamine usage worldwide continues to present increasing societal and health care challenges. With the escalation of its usage in a variety of social demographics, the entity of methamphetamine-associated cardiomyopathy (MA-CMP) has emerged. This entity is increasingly responsible for an important proportion of heart failure burden in both admissions to hospital and in those individuals requiring chronic heart failure care. MA-CMP poses some unique challenges including its recognition, particularly in younger patients presenting with new-onset heart failure, its severity at presentation and complications as well as management options. The challenging nature of methamphetamine addiction and the necessity to achieve abstinence is a fundamental aspect of management of this condition. As methamphetamine use continues at high levels in Australia, the burden of MA-CMP will inevitably increase and, therefore, all clinicians responsible for heart failure management require an awareness of this disease entity and the specific clinical challenges of its care.

Progression of ultrasound plaque attenuation and low echogenicity associates with major adverse cardiovascular events.

AIMS: Intravascular ultrasound (IVUS) imaging can visualize vulnerable plaque features including attenuation (AP) and echolucency (ELP). While IVUS-derived vulnerable plaque features associate with microvascular obstruction during percutaneous coronary intervention, the relationship between these plaque features and clinical outcomes has not been established. This analysis aimed to evaluate the association of AP/ELP with cardiovascular events. METHODS AND RESULTS: Serial IVUS imaging was reviewed in 1497 patients, followed for 18-24 months, with coronary artery disease from two clinical trials. Attenuated plaque and ELP were identified to measure each characteristics (AP arc, ELP area, and lengths), which permitted calculation of an AP index (API) and ELP volume. Attenuated plaque/ELP progression was defined as patients with any increase of API or ELP volume on serial imaging. The major cardiovascular events (MACEs) were defined as death, myocardial infarction, stroke, and coronary revascularization. AP or ELP was identified in 282 patients (18.8%) at baseline and 160 (10.7%) patients demonstrated an increase in AP or ELP at follow-up. The incidence of MACE was higher in patients with baseline AP/ELP than those without (8.2% vs. 3.9%, P = 0.002). Patients with AP/ELP progression were more likely to be acute coronary syndrome (41.9 vs. 33.2%, P = 0.03) and have greater baseline percent atheroma volume (40.0% vs. 35.8%, P < 0.001) than those without. On multivariable analysis, AP/ELP progression was more strongly associated with MACE [baseline AP/ELP: hazard ratio (HR) 1.76, 95% confidence interval (CI) 1.05-2.97, AP/ELP progression: HR 2.19, 95% CI 1.24-3.86]. CONCLUSION: Attenuation/ELP progression was associated with a higher prevalence of cardiovascular events, supporting a potential role for the identification of high-risk vulnerable plaques in patients with coronary artery disease.

Postcardiac injury syndrome after cardiac implantable electronic device implantation.

BACKGROUND: Postcardiac injury syndrome (PCIS) is an inflammatory complication that derives from injury to the epicardium, myocardium, or endocardium. It occurs after trauma, myocardial infarction, percutaneous coronary intervention, cardiac surgery, intracardiac ablation, and implantation of cardiac implantable electronic device (CIED). In this study we assessed the incidence of PCIS after CIED implantation and its possible risk factors. MATERIAL AND METHODS: All patients who received CIED implantation at Heidelberg University Hospital between 2000 and 2014 were evaluated (n = 4989 patients). Clinical data including age, sex, underlying cardiac disease, type of implanted CIED, location of electrode implantation, clinical symptoms, time of symptom onset of PCIS, therapy, and outcome were extracted and analyzed. RESULTS: We identified 19 cases of PCIS in 4989 patients, yielding an incidence of 0.38%. The age of patients with PCIS ranged from 39 to 86 years. Dilated cardiomyopathy (DCM) as underlying cardiac disease and right atrial (RA) lead implantation had a significant association with occurrence of PCIS (p = 0.045 in DCM and p < 0.001 in RA lead implantation). Dyspnea, chest pain, dry cough, and fever were the most frequently reported symptoms in patients with PCIS. Pericardial and pleura effusion as well as elevated C­reactive protein (CRP), increased erythrocyte sedimentation rate (ESR), and leukocytosis were the most common findings. CONCLUSION: To the best of our knowledge, this is the largest cohort evaluating the incidence of PCIS after CIED implantation. The data show that PCIS is a rare complication after CIED implantation and occurs more frequently in patients with DCM and those with RA lead implantation. Although rare and mostly benign, PCIS can lead to potentially lethal complications and physicians must be aware of its symptoms.

Status of PCSK9 Monoclonal Antibodies in Australia.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAb) have progressed from showing marked low density lipoprotein cholesterol lowering in early phase trials through to reducing cardiovascular events in large clinical outcome trials. Recently in Australia, the indication for evolocumab has been expanded to include both heterozygous and homozygous familial hypercholesterolaemia under the Pharmaceutical Benefits Scheme (PBS). With prices remaining high currently their use in non-familial hypercholesterolaemia in Australia remains by private prescription only at this stage. This manuscript summarises the major outcomes trials of the PCSK9 mAbs and the secondary analyses that have assessed their benefits in high risk patient groups, and describes the consensus of authors on which patients would most likely benefit from PCSK9 mAb therapy.

Spin-Orbit Coupling and Magnetic Anisotropy in Iron-Based Superconductors.

We determine theoretically the effect of spin-orbit coupling on the magnetic excitation spectrum of itinerant multiorbital systems, with specific application to iron-based superconductors. Our microscopic model includes a realistic ten-band kinetic Hamiltonian, atomic spin-orbit coupling, and multiorbital Hubbard interactions. Our results highlight the remarkable variability of the resulting magnetic anisotropy despite constant spin-orbit coupling. At the same time, the magnetic anisotropy exhibits robust universal behavior upon changes in the band structure corresponding to different materials of iron-based superconductors. A natural explanation of the observed universality emerges when considering optimal nesting as a resonance phenomenon. Our theory is also of relevance to other itinerant systems with spin-orbit coupling and nesting tendencies in the band structure.

Spin Waves in Detwinned BaFe_{2}As_{2}.

Understanding magnetic interactions in the parent compounds of high-temperature superconductors forms the basis for determining their role for the mechanism of superconductivity. For parent compounds of iron pnictide superconductors such as AFe_{2}As_{2} (A=Ba, Ca, Sr), although spin excitations have been mapped out throughout the entire Brillouin zone, the respective measurements were carried out on twinned samples and did not allow for a conclusive determination of the spin dynamics. Here we use inelastic neutron scattering to completely map out spin excitations of ∼100% detwinned BaFe_{2}As_{2}. By comparing observed spectra with theoretical calculations, we conclude that the spin excitations can be well described by an itinerant model when taking into account moderate electronic correlation effects.

Dual Mechanism for Inhibition of Inwardly Rectifying Kir2.x Channels by Quinidine Involving Direct Pore Block and PIP2-interference.

Class IA antiarrhythmic drug quinidine was one of the first clinically used compounds to terminate atrial fibrillation and acts as multichannel inhibitor with well-documented inhibitory effects on several cardiac potassium channels. In the mammalian heart, heteromeric assembly of Kir2.1-2.3 channels underlies IK1 current. Although a low-affinity block of quinidine on Kir2.1 has already been described, a comparative analysis of effects on other Kir2.x channels has not been performed to date. Therefore, we analyzed the effects of quinidine on wild-type and mutant Kir2.x channels in the Xenopus oocyte expression system. Quinidine exerted differential inhibitory effects on Kir2.x channels with the highest affinity toward Kir2.3 subunits. Onset of block was slow and solely reversible in Kir2.2 subunits. Quinidine inhibited Kir2.x currents in a voltage-independent manner. By means of comparative Ala-scanning mutagenesis, we further found that residues E224, F254, D259, and E299 are essential for quinidine block in Kir2.1 subunits. Analogously, quinidine mediated Kir2.3 inhibition by binding corresponding residues E216, D247, D251, and E291. In contrast, Kir2.2 current block merely involved corresponding residue D260. Using channel mutants with altered (phosphatidylinositol 4,5-bisphosphate PIP2) affinities, we were able to demonstrate that high PIP2 affinities (i.e., Kir2.3 I214L) correlate with low quinidine sensitivity. Inversely, mutant channels interacting only weakly with PIP2 (i.e., Kir2.1 K182Q, and L221I) are prone to a higher inhibitory effect. Thus, we conclude that inhibition of Kir2.x channels by quinidine is mediated by joint modes of action involving direct cytoplasmic pore block and an impaired channel stabilization via interference with PIP2.

Targeting low-density lipoprotein cholesterol with PCSK9 inhibitors.

Over the past quarter century, clinical trials have consistently demonstrated that lowering levels of low-density lipoprotein cholesterol (LDL-C) with statins reduces the rate of major adverse cardiovascular events. However, the findings that many patients continue to experience events or harbour inappropriately high LDL-C levels despite intensive statin therapy and the clinical reality of statin intolerance suggests that additional therapeutic strategies are required in order to achieve more effective reductions in cardiovascular risk. The emergence of inhibitory monoclonal antibodies targeted against proprotein convertase subtilisin kexin type 9 (PCSK9) provides a novel approach to reducing LDL-C levels. The current experience of PCSK9 inhibitors and implications for clinical use and cost effectiveness will be reviewed.

ICESat-2 river surface slope (IRIS): A global reach-scale water surface slope dataset.

The global reach-scale "ICESat-2 River Surface Slope" (IRIS) dataset comprises average and extreme water surface slopes (WSS) derived from ICESat-2 observations between October 2018 and August 2022 as a supplement to 121,583 reaches from the "SWOT Mission River Database" (SWORD). To gain full advantage of ICESat-2's unique measurement geometry with six parallel lidar beams, the WSS is determined across pairs of beams or along individual beams, depending on the intersection angle of spacecraft orbit and river centerline. Combining both approaches maximizes spatial and temporal coverage. IRIS can be used to research river dynamics, estimate river discharge, and correct water level time series from satellite altimetry for shifting ground tracks. Additionally, by referencing SWORD as a common database, IRIS may be used in combination with observations from the recently launched SWOT mission.

Verapamil inhibits Kir2.3 channels by binding to the pore and interfering with PIP2 binding.

The inwardly rectifying potassium current of the cardiomyocyte (IK1) is the main determinant of the resting potential. Ion channels Kir2.1, Kir2.2, and Kir2.3 form tetramers and are the molecular correlate of macroscopic IK1 current. Verapamil is an antiarrhythmic drug used to suppress atrial and ventricular arrhythmias. Its primary mechanism of action is via blocking calcium channels. In addition, it has been demonstrated to block IK1 current and the Kir2.1 subunit. Its effect on other subunits that contribute to IK1 current has not been studied to date. We therefore analyzed the effect of verapamil on the Kir channels 2.1, 2.2, and 2.3 in the Xenopus oocyte expression system. Kir2.1, Kir2.2, and Kir2.3 channels were heterologously expressed in Xenopus oocytes. Respective currents were measured with the voltage clamp technique and the effect of verapamil on the current was measured. At a concentration of 300 µM, verapamil inhibited Kir2.1 channels by 41.36% ± 2.7 of the initial current, Kir2.2 channels by 16.51 ± 3.6%, and Kir2.3 by 69.98 ± 4.2%. As a verapamil effect on kir2.3 was a previously unknown finding, we analyzed this effect further. At wash in with 300 µM verapamil, the maximal effect was seen within 20 min of the infusion. After washing out with control solution, there was only a partial current recovery. The current reduction from verapamil was the same at - 120 mV (73.2 ± 3.7%), - 40 mV (85.5 ± 6.5%), and 0 mV (61.5 ± 10.6%) implying no voltage dependency of the block. Using site directed mutations in putative binding sites, we demonstrated a decrease of effect with pore mutant E291A and absence of verapamil effect for D251A. With mutant I214L, which shows a stronger affinity for PIP2 binding, we observed a normalized current reduction to 61.9 ± 0.06% of the control current, which was significantly less pronounced compared to wild type channels. Verapamil blocks Kir2.1, Kir2.2, and Kir2.3 subunits. In Kir2.3, blockade is dependent on sites E291 and D251 and interferes with activation of the channel via PIP2. Interference with these sites and with PIP2 binding has also been described for other Kir channels blocking drugs. As Kir2.3 is preferentially expressed in atrium, a selective Kir2.3 blocking agent would constitute an interesting antiarrhythmic concept.

Asia-Pacific Investigators and Asian Enrollment in Cardiometabolic Trials: Insights From Publications Between 2011 and 2020.

Background: A lack of geographic and racial diversity in clinical trial populations may arise from a disproportionate focus on the United States and Europe for trial leadership and conduct. Inadequate diversity may compromise the external validity to the Asia-Pacific (APAC) region, where 60% of global cardiometabolic disease exists. Objectives: This study aimed to assess the proportion and trends of Asian race participants and APAC authorship in cardiometabolic trials. Methods: We performed a systematic review of all cardiovascular, diabetes and obesity-related randomized controlled trials (phase ≥2, n = ≥100) published in these major medical journals: the New England Journal of Medicine, the Lancet, and the Journal of the American Medical Association between January 1, 2011, and December 31, 2020. Trial leadership was defined by first authorship, and any listed author was considered a trial collaborator. Temporal trends were evaluated using the Jonckheere-Terpstra proportion test and correlations using Pearson's correlation coefficient. Participant-to-prevalence ratios (PPR) were determined using Global Health Data Exchange registry data. Results: A total of 8.3% (218,613 of 2,619,710) participants identified as being of Asian race and 7.7% of total enrollment occurred in APAC. APAC lead authorship occurred in 52 of 656 (7.9%) trials and collaboration in 10.1% (1312 of 13,000 of authors), which correlated with Asian enrollment (r = 0.63 and r = 0.76, respectively). A marginal increase in the proportion of Asian race (Δ1.40% ± 6.95%/year, P = 0.003) and APAC regional (Δ1.46% ± 8.67%/year, P = 0.003) enrollment was observed; however, severe regional underrepresentation persisted (PPR <0.30). Conclusions: Despite a favorable trend over the past decade, Asian participants and authors from APAC remain significantly underrepresented in seminal cardiometabolic trials; barriers to trial conduct and leadership in this region must be addressed.

Inhibition of cardiac Kir2.1-2.3 channels by beta3 adrenoreceptor antagonist SR 59230A.

Kir2.x channels form the molecular basis of cardiac I(K1) current and play a major role in cardiac electrophysiology. However, there is a substantial lack of selective Kir2 antagonists. We found the ß(3)-adrenoceptor antagonist SR59230A to be an inhibitor of Kir2.x channels. Therefore, we characterized the effects of SR59230A on Kir2.x and other relevant cardiac potassium channels. Cloned channels were expressed in the Xenopus oocyte expression system and measured with the double-microelectrode voltage clamp technique. SR59230A inhibited homomeric Kir2.1 channels with an IC(50) of 33µM. Homomeric Kir2.2 and Kir2.3 channels and Kir2.x heteromers were also inhibited by SR59230A with similar potency. In contrast, no relevant inhibitory effects of SR59230A were found in cardiac Kv1.5, Kv4.3 and KvLQT1/minK channels. In hERG channels, SR59230A only induced a weak inhibition at a high concentration. These findings establish SR59230A as a novel inhibitor of Kir2.1-2.3 channels with a favorable profile with respect to additional effects on other cardiac repolarizing potassium channels.

Biological signalling supports biotechnology - Pulsed electric fields extract a cell-death inducing factor from Chlorella vulgaris.

Compared to mechanical extraction methods, pulsed electric field (PEF) treatment provides an energy-efficient and gentle alternative. However, the biological processes involved are poorly understood. The unicellular green microalga Chlorella vulgaris was used as model organism to investigate the effect of PEF treatment on biological cells. A viability assay using fluorescein diacetate measured by flow cytometry was established. The influence of developmental stage on viability could be shown in synchronised cultures when applying PEF treatment with very low specific energies where one part of cells undergoes cell death, and the other part stays viable after treatment. Reactive oxygen species generation after similar low-energy PEF treatment could be shown, indicating that PEFs could act as abiotic stress signal. Most importantly, a cell-death inducing factor could be extracted. A water-soluble extract derived from microalgae suspensions incubated for 24 h after PEF treatment caused the recipient microalgae to die, even though the recipient cells had not been subjected to PEF treatment directly. The working model assumes that low-energy PEF treatment induces programmed cell death in C.vulgaris while specifically releasing a cell-death inducing factor. Low-energy PEF treatment with subsequent incubation period could be a novel biotechnological strategy to extract soluble proteins and lipids in cascade process.

Polygenic Risk Scores for Atherosclerotic Cardiovascular Disease in the Asia-Pacific Region.

Approximately one-half of the phenotypic susceptibility to atherosclerotic cardiovascular disease (ASCVD) has a genetic basis. Although individual allelic variants generally impart a small effect on risk for ASCVD, an emerging body of data has shown that the aggregation and weighting of many of these genetic variations into "scores" can further discriminate an individual's risk beyond traditional risk factors alone. Consistent with the theory of population genetics, such polygenic risk scores (PRS) appear to be ethnicity specific because their elements comprise single-nucleotide variants that are always ethnicity specific. The currently available PRS are derived predominantly from European ancestry and thus predictably perform less well among non-European participants, a fact that has implications for their use in the Asia-Pacific region. This paper describes the current state of knowledge of PRS, the available data that support their use in this region, and highlights the needs moving forward to safely and effectively implement them in clinical care in the Asia-Pacific region.

Long-Term Impact of Arteriovenous Fistula Ligation on Cardiac Structure and Function in Kidney Transplant Recipients: A 5-Year Follow-Up Observational Cohort Study.

Background: The long-term effects of arteriovenous fistula (AVF) ligation on cardiovascular structure following kidney transplantation remain uncertain. A prospective randomized, controlled trial (RCT) examined the effect of AVF ligation at 6 months on cardiovascular magnetic resonance imaging (CMR)-derived parameters in 27 kidney transplant recipients compared with 27 controls. A mean decrease in left ventricular mass (LVM) of 22.1 g (95% CI, 15.0 to 29.1) was observed compared with an increase of 1.2 g (95% CI, -4.8 to 7.2) in the control group (P<0.001). We conducted a long-term follow-up observational cohort study in the treated cohort to determine the evolution of CMR-derived parameters compared with those documented at 6 months post-AVF ligation. Methods: We performed CMR at long-term follow-up in the AVF ligation observational cohort from our original RCT published in 2019. Results were compared with CMR at 6 months postintervention. The coprimary end point was the change in CMR-derived LVM and LVM index at long-term follow-up from imaging at 6 months postindex procedure. Results: At a median of 5.1 years (interquartile range, 4.7-5.5 years), 17 patients in the AVF ligation group were studied with repeat CMR with a median duration to follow-up imaging of 5.1 years (IQR, 4.7-5.5 years). Statistically significant further reductions in LVM (-17.6±23.0 g, P=0.006) and LVM index (-10.0±13.0 g/m2, P=0.006) were documented. Conclusions: The benefit of AVF ligation on LVM and LVM index regression appears to persist long term. This has the potential to lead to a significant reduction in cardiovascular mortality.

Tackling cardiometabolic risk in the Asia Pacific region.

With the global spread of abdominal obesity, cardiovascular disease continues to spread to all countries of the world. Given the large population, the challenges presented by cardiometabolic risk in the Asia Pacific region are considerable. In addition to the clinical consequences of cardiovascular disease, in terms of its morbidity and mortality, the diversity of the Asia Pacific region brings heterogeneity in approaches to prevention, diagnosis and treatment of cardiometabolic risk. In this manuscript, we will review the current state of knowledge of cardiometabolic risk in Asia Pacific and highlight the needs moving forward to tackle this public health challenge.

Statin intolerance: an updated, narrative review mainly focusing on muscle adverse effects.

INTRODUCTION: Statins have been established as the standard of care for dyslipidemia and preventing cardiovascular diseases while posing few safety concerns. However, misconceptions about statin intolerance lead to their underuse, indicating a need to improve the understanding of the safety of this treatment. AREAS COVERED: We searched PubMed and reviewed literatures related to statin intolerance published between February 2015 and February 2020. Important large-scale or landmark studies published before 2015 were also cited as key evidence. EXPERT OPINION: Optimal lowering of low-density lipoprotein cholesterol with statins substantially reduces the risk of cardiovascular events. Muscle adverse events (AEs) were the most frequently reported AEs by statin users in clinical practice, but they usually occurred at a similar rate with statins and placebo in randomized controlled trials and had a spurious causal relationship with statin treatment. We proposed a rigorous definition for identifying true statin intolerance and present the criteria for defining different forms of muscle AEs and an algorithm for their management. True statin intolerance is uncommon, and every effort should be made to exclude false statin intolerance and ensure optimal use of statins. For the management of statin intolerance, statin-based approaches should be prioritized over non-statin approaches.

Biophysical properties of zebrafish ether-à-go-go related gene potassium channels.

The zebrafish is increasingly recognized as an animal model for the analysis of hERG-related diseases. However, functional properties of the zebrafish orthologue of hERG have not been analyzed yet. We heterologously expressed cloned ERG channels in Xenopus oocytes and analyzed biophysical properties using the voltage clamp technique. zERG channels conduct rapidly activating and inactivating potassium currents. However, compared to hERG, the half-maximal activation voltage of zERG current is shifted towards more positive potentials and the half maximal steady-state inactivation voltage is shifted towards more negative potentials. zERG channel activation is delayed and channel deactivation is accelerated significantly. However, time course of zERG conducted current under action potential clamp is highly similar to the human orthologue. In summary, we show that ERG channels in zebrafish exhibit biophysical properties similar to the human orthologue. Considering the conserved channel function, the zebrafish represents a valuable model to investigate human ERG channel related diseases.

Unusual Primary Ocular Manifestation of Sarcoidosis.

A 23-year-old male patient presented with very mild visual disturbances, but a distinct prominence of the optic discs, more pronounced in the right than in the left eye. The ophthalmic symptoms initially seemed trivial, but a large-scale interdisciplinary workup later identified them as the presenting symptoms of sarcoidosis affecting lung and eyes. A standard steroid monotherapy successfully caused regression of the ophthalmic findings.