Natural compound plumbagin based inhibition of hIAPP revealed by Markov state models based on MD data along with experimental validations.

Human islet amyloid polypeptide (amylin or hIAPP) is a 37 residue hormone co-secreted with insulin from ß cells of the pancreas. In patients suffering from type-2 diabetes, amylin self-assembles into amyloid fibrils, ultimately leading to the death of the pancreatic cells. However, a research gap exists in preventing and treating such amyloidosis. Plumbagin, a natural compound, has previously been demonstrated to have inhibitory potential against insulin amyloidosis. Our investigation unveils collapsible regions within hIAPP that, upon collapse, facilitates hydrophobic and pi-pi interactions, ultimately leading to aggregation. Intriguingly plumbagin exhibits the ability to bind these specific collapsible regions, thereby impeding the aforementioned interactions that would otherwise drive hIAPP aggregation. We have used atomistic molecular dynamics approach to determine secondary structural changes. MSM shows metastable states forming native like hIAPP structure in presence of PGN. Our in silico results concur with in vitro results. The ThT assay revealed a striking 50% decrease in fluorescence intensity at a 1:1 ratio of hIAPP to Plumbagin. This finding suggests a significant inhibition of amyloid fibril formation by plumbagin, as ThT fluorescence directly correlates with the presence of these fibrils. Further TEM images revealed disappearance of hIAPP fibrils in plumbagin pre-treated hIAPP samples. Also, we have shown that plumbagin disrupts the intermolecular hydrogen bonding in hIAPP fibrils leading to an increase in the average beta strand spacing, thereby causing disaggregation of pre-formed fibrils demonstrating overall disruption of the aggregation machinery of hIAPP. Our work is the first to report a detailed atomistic simulation of 22 µs for hIAPP. Overall, our studies put plumbagin as a potential candidate for both preventive and therapeutic candidate for hIAPP amyloidosis.

Splenic switch-off in regadenoson 82Rb-PET myocardial perfusion imaging: assessment of clinical utility.

BACKGROUND: Splenic switch-off (SSO) is a phenomenon describing a decrease in splenic radiotracer uptake after vasodilatory stress. We aimed to assess the diagnostic utility of regadenoson-induced SSO. METHODS: We included consecutive patients who had clinically indicated Regadenoson Rb-82 PET-MPI for suspected CAD. This derivation cohort (no perfusion defects and myocardial flow reserves (MFR) ≥ 2) was used to calculate the splenic response ratio (SRR). The validation cohort was defined as patients who underwent both PET-MPI studies and invasive coronary angiography (ICA). RESULTS: The derivation cohort (n = 100, 57.4 ± 11.6 years, 77% female) showed a decrease in splenic uptake from rest to stress (79.9 ± 16.8 kBq⋅mL vs 69.1 ± 16.2 kBq⋅mL, P < .001). From the validation cohort (n = 315, 66.3 ± 10.4 years, 67% male), 28% (via SRR = 0.88) and 15% (visually) were classified as splenic non-responders. MFR was lower in non-responders (SRR; 1.55 ± 0.65 vs 1.76 ± 0.78, P = .02 and visually; 1.18 ± 0.33 vs 1.79 ± 0.77, P < .001). Based on ICA, non-responders were more likely to note obstructive epicardial disease with normal PET scans especially in patients with MFR < 1.5 (SRR; 61% vs 34% P = .05 and visually; 68% vs 33%, P = .01). CONCLUSION: Lack of splenic response based on visual or quantitative assessment of SSO may be used to identify an inadequate vasodilatory response.

Assessment of myocardial viability by cardiac MRI.

PURPOSE OF REVIEW: Left ventricular systolic dysfunction because of coronary artery disease is common, and ascertaining which patients will benefit from revascularization can be challenging. Viability testing is an accepted means by which to base this decision, with multiple noninvasive imaging modalities available for this purpose. This review aims to highlight the key role of cardiac magnetic resonance in myocardial viability assessment, with a focus on its unique strengths over other imaging modalities. RECENT FINDINGS: Transmural extent of hyperenhancement with late gadolinium imaging has been shown to be greater acutely in ST elevation myocardial infarction patients undergoing primary percutaneous coronary intervention and regress at follow-up studies. An explanation for this reported phenomenon and an argument against redefining CMR viability criteria in the acute setting will be offered. SUMMARY: Although not universally available, cardiac magnetic resonance is an exceptionally powerful and well tolerated imaging modality that should be considered when viability testing will influence patient management. Although observational outcomes data suggest a promising prognostic role for viability, randomized studies in this area are needed.

Association of left atrial volume index and all-cause mortality in patients referred for routine cardiovascular magnetic resonance: a multicenter study.

BACKGROUND: Routine cine cardiovascular magnetic resonance (CMR) allows for the measurement of left atrial (LA) volumes. Normal reference values for LA volumes have been published based on a group of European individuals without known cardiovascular disease (CVD) but not on one of similar United States (US) based volunteers. Furthermore, the association between grades of LA dilatation by CMR and outcomes has not been established. We aimed to assess the relationship between grades of LA dilatation measured on CMR based on US volunteers without known CVD and all-cause mortality in a large, multicenter cohort of patients referred for a clinically indicated CMR scan. METHOD: We identified 85 healthy US subjects to determine normal reference LA volumes using the biplane area-length method and indexed for body surface area (LAVi). Clinical CMR reports of patients with LA volume measures (n = 11,613) were obtained. Data analysis was performed on a cloud-based system for consecutive CMR exams performed at three geographically distinct US medical centers from August 2008 through August 2017. We identified 10,890 eligible cases. We categorized patients into 4 groups based on LAVi partitions derived from US normal reference values: Normal (21-52 ml/m2), Mild (52-62 ml/m2), Moderate (63-73 ml/m2) and Severe (> 73 ml/m2). Mortality data were ascertained for the patient group using electronic health records and social security death index. Cox proportional hazard risk models were used to derive hazard ratios for measuring association of LA enlargement and all-cause mortality. RESULTS: The distribution of LAVi from healthy subjects without known CVD was 36.3 ± 7.8 mL/m2. In clinical patients, enlarged LA was associated with older age, atrial fibrillation, hypertension, heart failure, inpatient status and biventricular dilatation. The median follow-up duration was 48.9 (IQR 32.1-71.2) months. On univariate analyses, mild [Hazard Ratio (HR) 1.35 (95% Confidence Interval [CI] 1.11 to 1.65], moderate [HR 1.51 (95% CI 1.22 to 1.88)] and severe LA enlargement [HR 2.14 (95% CI 1.81 to 2.53)] were significant predictors of death. After adjustment for significant covariates, moderate [HR 1.45 (95% CI 1.1 to 1.89)] and severe LA enlargement [HR 1.64 (95% CI 1.29 to 2.08)] remained independent predictors of death. CONCLUSION: LAVi determined on routine cine-CMR is independently associated with all-cause mortality in patients undergoing a clinically indicated CMR.

Optimizing Evaluation of Patients with Low-to-Intermediate-Risk Acute Chest Pain: A Randomized Study Comparing Stress Myocardial Perfusion Tomography Incorporating Stress-Only Imaging Versus Cardiac CT.

UNLABELLED: The purpose of this study was to determine whether stress myocardial perfusion (SPECT) optimized with stress-only (SO) imaging is comparable to cardiac CT angiography (CTA) for evaluating patients with acute chest pain (ACP). METHODS: This was a prospective randomized observational study in 598 ACP patients who underwent CTA versus SPECT. The primary endpoint was length of hospital stay, and secondary endpoints were test feasibility, time to diagnosis, diagnostic accuracy, radiation exposure, and overall cost. Median follow-up was 6.5 mo, with a 3.8% cardiac event rate defined as death or an acute coronary syndrome. RESULTS: Of 2,994 patients screened, 1,703 (56.9%) were not candidates for CTA because of prior cardiac disease (41%) or imaging contraindications (16%). Time to diagnosis (8.1 ± 8.5 vs. 9.4 ± 7.4 h) and length of hospital stay (19.7 ± 27.8 vs. 23.5 ± 34.4 h) were significantly shorter with CTA than with SPECT (P = 0.002). However, time to diagnosis (7.0 ± 6.2 vs. 6.8 ± 5.9 h, P = 0.20), length of stay (15.5 ± 17.2 vs. 16.7 ± 15.3 h, P = 0.36), and hospital costs ($4,242 ± $3,871 vs. $4,364 ± 1781, P = 0.86) were comparable with CTA versus SO SPECT, respectively. SO was also superior to conventional SPECT regarding all of the above metrics and significantly reduced radiation exposure (5.5 ± 4.4 vs. 12.5 ± 2.7 mSv, P < 0.0001). CONCLUSION: Stress SPECT when optimized with SO imaging is similar to CTA in time to diagnosis, length of hospital stay, and cost, with improved prognostic accuracy and less radiation exposure. Our results emphasize the importance of SO imaging, particularly in low-intermediate-risk emergency room patients who are a population likely to have a normal test result.

Additive prognostic value of coronary artery calcium score over coronary computed tomographic angiography stenosis assessment in symptomatic patients without known coronary artery disease.

The objective of this study was to examine the additive prognostic performance of coronary artery calcium score (CACS) over coronary computed tomography angiography (CCTA) stenosis assessment in symptomatic patients suspected for coronary artery disease (CAD) undergoing CCTA. A total of 805 symptomatic patients without known history of CAD who underwent coronary evaluation by multidetector cardiac CT were analyzed. Mean age of the cohort was 58 ± 13 years. A total of 44% (354 of 805) of the patients had a 0 CACS, 27% (215 of 805) had CACS 1 to 100, 14% (111 of 805) had CACS 101 to 400, and 15% (125 of 805) had CACS >400. CCTA showed normal coronary arteries in 43% (349 of 805) of patients, ≤50% stenosis in 42% (333 of 805), and >50% stenosis in 15% (123 of 805). Patients were followed for 2.3 ± 0.9 years. Major adverse cardiac event (MACE) was defined as cardiac death, nonfatal myocardial infarction, and late coronary revascularization. Overall incidence of MACE was 1.4% per year. Both CACS and CCTA stenosis were independently associated with increased MACE (p <0.05 for both). Addition of CACS into the model with clinical risk factors and CCTA stenosis significantly improved predictive performance for MACE from the model with clinical risk factors and CCTA stenosis only (global chi-square score 108 vs 70; p = 0.019). In conclusion; in symptomatic patients without known CAD, both CACS and CCTA stenosis were independently associated with increased cardiac events, and performing non-contrast-enhanced CACS evaluation in addition to contrast-enhanced CCTA improved predictive ability for future cardiac events compared to CCTA stenosis assessment alone.

Role of cardiac MRI in the assessment of nonischemic cardiomyopathies.

In this review, we will highlight the role of late gadolinium enhancement, along with other strengths available by cardiac MRI, in determining the underlying etiology of various nonischemic cardiomyopathies. Furthermore, we will also emphasize how late gadolinium enhancement may serve as a novel risk stratification tool to further impact patient care.

Stress cardiac magnetic resonance.

PURPOSE OF REVIEW: Coronary artery disease (CAD) is associated with significant morbidity and mortality. Several noninvasive imaging techniques such as stress echocardiography, stress nuclear studies, computed tomography coronary angiography, and, most recently, stress cardiovascular magnetic resonance (CMR) have enhanced the accuracy and efficiency of evaluation of patients. RECENT FINDINGS: The diagnostic capabilities of CMR have increased substantially over the past 20 years due to hardware and software advances. Today, CMR has a number of unique advantages over other imaging modalities - primarily because it provides a view of the entire heart without limitations from inadequate imaging windows or body habitus. Furthermore, along with stress imaging for inducible wall motion or perfusion abnormalities, CMR provides a comprehensive examination with concurrent evaluation of the ejection fraction, aorta, pericardium, and valves all without the inherent risks of radiation administration or contrast exposure. SUMMARY: The purpose of this article is to review the current state of stress CMR for both detection of significant disease and the prognostication of future cardiac events. Clinical data will demonstrate that stress CMR is accurate, with detection in a broad population of patients similar to or better than reported using other noninvasive stress imaging techniques. Moreover, patients with a normal adenosine stress CMR scan have an excellent prognosis on follow-up with no adverse cardiovascular outcomes. Thus, CMR perfusion stress testing has been deemed appropriate for the evaluation of chest pain syndromes in patients with intermediate probability of coronary artery disease (CAD) and for ascertaining the physiologic significance of indeterminate coronary artery lesions.