Migrating Localized ST-Segment Elevation With Ongoing Chest Pain.

A patient in their 60s presented with a 6-hour history of sudden-onset worsening chest pain associated with shortness of breath and diaphoresis. What is your diagnosis?

Intravascular Sono-Ablation for In-Stent Restenosis Relief: Transducer Development and the In-Vitro Demonstration.

OBJECTIVE: This study aimed to propose a new clinical modality for the relief of in-stent restenosis (ISR) using focused ultrasound (FUS) ablation. In the first research stage, a miniaturized FUS device was developed for the sonification of the remaining plaque after stenting, known as one of the causes of ISR. METHODS: This study presents a miniaturized (<2.8 mm) intravascular FUS transducer for ISR treatment. The performance of the transducer was predicted through a structural-acoustic simulation, followed by fabrication of the prototype device. Using the prototype FUS transducer, we demonstrated tissue ablation with bio-tissues over metallic stents, mimicking in-stent tissue ablation. Next, we conducted a safety test by detecting the existence of thermal damage to the arterial tissue upon sonication with a controlled dose. RESULTS: The prototype device successfully delivered sufficient acoustic intensity (>30 W/cm2) to a bio tissue (chicken breast) through a metallic stent. The ablation volume was approximately 3.9 × 7.8 × 2.6 mm3. Furthermore, 1.5 min sonication was sufficient to obtain an ablating depth of approximately 1.0 mm, not thermally damaging the underlying artery vessel. CONCLUSION: We demonstrated in-stent tissue sonoablation, suggesting it could be as a future ISR treatment modality. SIGNIFICANCE: Comprehensive test results provide a key understanding of FUS applications using metallic stents. Furthermore, the developed device can be used for sonoablation of the remaining plaque, providing a novel approach to the treatment of ISR.

A Paradoxical ST-Segment Elevation Distribution Rendering a Challenging Prediction of the Culprit Vessel in Acute Myocardial Infarction.

This case report describes a patient in their 50s with sudden-onset chest pain.

Photoplethysmographic imaging and analysis of pulsatile pressure wave in palmar artery at 10 wavelengths.

Significance: As a noncontact method, imaging photoplethysmography (iPPG) may provide a powerful tool to measure pulsatile pressure wave (PPW) in superficial arteries and extract biomarkers for monitoring of artery wall stiffness. Aim: We intend to develop a approach for extraction of the very weak cardiac component from iPPG data by identifying locations of strong PPW signals with optimized illumination wavelength and determining pulse wave velocity (PWV). Approach: Monochromatic in vivo iPPG datasets have been acquired from left hands to investigate various algorithms for retrieval of PPW signals, distribution maps and waveforms, and their dependence on arterial location and wavelength. Results: A robust algorithm of pixelated independent component analysis (pICA) has been developed and combined with spatiotemporal filtering to retrieve PPW signals. Spatial distributions of PPW signals have been mapped in 10 wavelength bands from 445 to 940 nm and waveforms were analyzed at multiple locations near the palmar artery tree. At the wavelength of 850 nm selected for timing analysis, we determined PWV values from 12 healthy volunteers in a range of 0.5 to 5.8 m/s across the hand region from wrist to midpalm and fingertip. Conclusions: These results demonstrate the potentials of the iPPG method based on pICA algorithm for translation into a monitoring tool to characterize wall stiffness of superficial artery by rapid and noncontact measurement of PWV and other biomarkers within 10 s.

Multimodality delineation of a fistulous ruptured sinus of Valsalva aneurysm: a teaching case report.

Background: Ruptured sinus of Valsalva (SOV) is a rare cardiac anomaly with poor prognosis if untreated. Early diagnosis with accurate delineation of its anatomy is critical for timely treatment and choice of surgical vs. percutaneous intervention. Here we report a case of fistulous rupture of SOV; the preoperative multimodality studies including echocardiography, cardiac magnetic resonance and cardiac catheterization provided teaching and learning points. Case summary: A 48-year-old man with history of heart murmur and hypertension presented with a 5-day history of shortness of breath and peripheral oedema. He was diagnosed with rapid atrial flutter. The transthoracic and transesophageal echocardiography showed severe biventricular systolic dysfunction with a left-to-right shunt from ruptured SOV. The colour Doppler by transthoracic and transesophageal echocardiography and cardiac magnetic resonance revealed a swaying shunt flow exiting in direction to the right atrium (RA) and basal right ventricle (RV) during systole and diastole with no myocardial scaring. The left and right heart catheterization showed elevated right-sided pressures, pulmonary capillary wedge pressure, and left ventricular end-diastolic pressure. There was no difference in O2 saturation between venae cavae and RA but a misleading step-up in O2 saturation between RA and RV. Owing to rupture anatomy with uncertainty, the patient underwent surgical intervention. The ruptured SOV tunnelled through the base of tricuspid annulus to the RA very close to the basal RV. Discussion: Even with multimodality studies it can still be challenging to delineate the anatomy of a ruptured SOV without uncertainty preoperatively.

Cholesterol Paradigm and Beyond in Atherosclerotic Cardiovascular Disease: Cholesterol, Sterol Regulatory Element-Binding Protein, Inflammation, and Vascular Cell Mobilization in Vasculopathy.

Hypercholesterolemia is a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD). How cholesterol and its carrier lipoproteins are involved in ASCVD is still under extensive investigation. Satins are thus far the best-proven class of cholesterol-lowering medications to improve the clinical outcomes of ASCVD. Statins specifically inhibit the rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA reductase of the mevalonate pathway for cholesterol biosynthesis. The widely accepted theory is that statins inhibit the hepatic cholesterol synthesis causing upregulation of hepatocyte low-density lipoprotein (LDL) receptor; receptor-mediated LDL uptake and metabolism in the liver results in reduction of circulating LDL cholesterol, which subsequently reduces vascular deposition and retention of cholesterol or LDL in atherogenesis. Nevertheless, cholesterol biosynthesis is ubiquitous, also in extrahepatic cells including those in vascular wall, under tight regulation by sterol regulatory element-binding protein (SREBP), the master gene transcription factor governing cholesterol biosynthesis. Studies have shown that SREBP can be upregulated in vascular wall subject to injury or stent implantation. SREBP can be activated by proinflammatory and mitogenic factors in vascular cells, leading to hyperactive mevalonate pathway, which promotes vascular cell mobilization, further proinflammatory and mitogenic factor release from vascular cells, and vascular inflammation. In this article, we review the cellular cholesterol homeostasis regulation by SREBP and SREBP-mediated vascular hyperactive cholesterol biosynthesis, we term vascular hypercholesterolism, in the pathogenesis of ASCVD and vasculopathy. SREBP functions as a platform bridging cholesterol, inflammation, and vascular cell mobilization in ASCVD pathogenesis. Targeting vascular hypercholesterolism could open a new avenue in fighting against ASCVD.

Spatio-temporal hybrid neural networks reduce erroneous human "judgement calls" in the diagnosis of Takotsubo syndrome.

BACKGROUND: We investigate whether deep learning (DL) neural networks can reduce erroneous human "judgment calls" on bedside echocardiograms and help distinguish Takotsubo syndrome (TTS) from anterior wall ST segment elevation myocardial infarction (STEMI). METHODS: We developed a single-channel (DCNN[2D SCI]), a multi-channel (DCNN[2D MCI]), and a 3-dimensional (DCNN[2D+t]) deep convolution neural network, and a recurrent neural network (RNN) based on 17,280 still-frame images and 540 videos from 2-dimensional echocardiograms in 10 years (1 January 2008 to 1 January 2018) retrospective cohort in University of Iowa (UI) and eight other medical centers. Echocardiograms from 450 UI patients were randomly divided into training and testing sets for internal training, testing, and model construction. Echocardiograms of 90 patients from the other medical centers were used for external validation to evaluate the model generalizability. A total of 49 board-certified human readers performed human-side classification on the same echocardiography dataset to compare the diagnostic performance and help data visualization. FINDINGS: The DCNN (2D SCI), DCNN (2D MCI), DCNN(2D+t), and RNN models established based on UI dataset for TTS versus STEMI prediction showed mean diagnostic accuracy 73%, 75%, 80%, and 75% respectively, and mean diagnostic accuracy of 74%, 74%, 77%, and 73%, respectively, on the external validation. DCNN(2D+t) (area under the curve [AUC] 0·787 vs. 0·699, P = 0·015) and RNN models (AUC 0·774 vs. 0·699, P = 0·033) outperformed human readers in differentiating TTS and STEMI by reducing human erroneous judgement calls on TTS. INTERPRETATION: Spatio-temporal hybrid DL neural networks reduce erroneous human "judgement calls" in distinguishing TTS from anterior wall STEMI based on bedside echocardiographic videos. FUNDING: University of Iowa Obermann Center for Advanced Studies Interdisciplinary Research Grant, and Institute for Clinical and Translational Science Grant. National Institutes of Health Award (1R01EB025018-01).

Targeting the Cholesterol Paradigm in the Risk Reduction for Atherosclerotic Cardiovascular Disease: Does the Mechanism of Action of Pharmacotherapy Matter for Clinical Outcomes?

Hypercholesterolemia is a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD). Low-density lipoprotein cholesterol (LDL-C) has been labeled as "bad" cholesterol and high-density lipoprotein cholesterol (HDL-C) as "good" cholesterol. The prevailing hypothesis is that lowering blood cholesterol levels, especially LDL-C, reduces vascular deposition and retention of cholesterol or apolipoprotein B (apoB)-containing lipoproteins which are atherogenic. We review herein the clinical trial data on different pharmacological approaches to lowering blood cholesterol and propose that the mechanism of action of cholesterol lowering, as well as the amplitude of cholesterol reduction, are critically important in leading to improved clinical outcomes in ASCVD. The effects of bile acid sequestrants, fibrates, niacin, cholesteryl ester transfer protein (CETP) inhibitors, apolipoprotein A-I and HDL mimetics, apoB regulators, acyl coenzyme A: cholesterol acyltransferase (ACAT) inhibitors, cholesterol absorption inhibitors, statins, and proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, among other strategies are reviewed. Clinical evidence supports that different classes of cholesterol lowering or lipoprotein regulating approaches yielded variable effects on ASCVD outcomes, especially in cardiovascular and all-cause mortality. Statins are the most widely used cholesterol lowering agents and have the best proven cardiovascular event and survival benefits. Manipulating cholesterol levels by specific targeting of apoproteins or lipoproteins has not yielded clinical benefit. Understanding why lowering LDL-C by different approaches varies in clinical outcomes of ASCVD, especially in survival benefit, may shed further light on our evolving understanding of how cholesterol and its carrier lipoproteins are involved in ASCVD and aid in developing effective pharmacological strategies to improve the clinical outcomes of ASCVD.

A case report of an STEMI mimicker in a patient presenting with haemoptysis and chest pain with metastatic myocardial infiltration and left ventricular mural thrombi.

BACKGROUND: ST-elevation myocardial infarction (STEMI) requires timely coronary reperfusion but localizing ST-segment elevation (STE) can develop in clinical settings other than STEMI. CASE SUMMARY: We report a case of a 66-year-old man, with a history of diabetes mellitus and arthritis presenting with haemoptysis and chest pain. The electrocardiogram (ECG) at presentation showed marked localizing STE but emergent cardiac catheterization showed no significant coronary artery obstruction and the serial serum cardiac troponin levels were within normal limits. The patient was found to have squamous cell carcinoma with a right upper lobe cavitated lung mass and cardiac infiltrative metastasis as shown by computed tomography, echocardiography, cardiac magnetic resonance, and 18F-fluorodeoxyglucose-positron emission tomography-computed tomography (FDG-PET-CT) imaging. Mobile left ventricular mural thrombi were also noted on echocardiography. DISCUSSION: Metastatic myocardial infiltration can cause STE mimicking STEMI on ECG. The STE is persistent and may reflect an ongoing injury current between the infiltrated and normal myocardium. The STE is localizing, which may have value in evaluating the extent and region of metastatic myocardial damage. Myocardial metastasis can be complicated by ventricular mural thrombosis and due to lack of population data, there is no firm guidance on choice of anticoagulation.

A Systematic Approach to Evaluate Patients Presenting With ST-Segment Elevation in Lead aVR: A Case Series.

ST-segment elevation (STE) in the lead aVR indicates global ischemia of the myocardium and is often associated with obstructive coronary artery disease (CAD). We report a serial of cases presenting with STE in aVR and diffuse ST depressions in more than six other leads as a common feature, but of different etiologies, i.e., severe anemia due to gastrointestinal bleeding; drug over-dose-induced vasospasm and tachycardia, and severe CAD involving distal left main and ostial right coronary arteries, which required specific management approaches. We categorize the possible causes of STE in aVR with or without diffuse ST depression ECG according to whether anticoagulation/antithrombotic agents are indicated, contra-indicated, and propose a systematic approach in evaluating and managing these patients.

Effects of Restoration of Blood Flow on the Development of Aortic Atherosclerosis in ApoE-/- Mice With Unilateral Renal Artery Stenosis.

BACKGROUND: Chronic unilateral renal artery stenosis (RAS) causes accelerated atherosclerosis in apolipoprotein E-deficient (ApoE(-/-)) mice, but effects of restoration of renal blood flow on aortic atherosclerosis are unknown. METHODS AND RESULTS: Male ApoE(-/-) mice underwent sham surgery (n=16) or had partial ligation of the right renal artery (n=41) with the ligature being removed 4 days later (D4LR; n=6), 8 days later (D8LR; n=11), or left in place for 90 days (chronic RAS; n=24). Ligature removal at 4 or 8 days resulted in improved renal blood flow, decreased plasma angiotensin II levels, a return of systolic blood pressure to baseline, and increased plasma levels of neutrophil gelatinase associated lipocalin. Chronic RAS resulted in increased lipid staining in the aortic arch (33.2% [24.4, 47.5] vs 11.6% [6.1, 14.2]; P<0.05) and descending thoracic aorta (10.2% [6.4, 25.9] vs 4.9% [2.8, 7.8]; P<0.05), compared to sham surgery. There was an increased amount of aortic arch lipid staining in the D8LR group (22.7% [22.1, 32.7]), compared to sham-surgery, but less than observed with chronic RAS. Lipid staining in the aortic arch was not increased in the D4LR group, and lipid staining in the descending aorta was not increased in either the D8LR or D4LR groups. There was less macrophage expression in infrarenal aortic atheroma in the D4LR and D8LR groups compared to the chronic RAS group. CONCLUSIONS: Restoration of renal blood flow at either 4 or 8 days after unilateral RAS had a beneficial effect on systolic blood pressure, aortic lipid deposition, and atheroma inflammation.

Critical role of prohibitin in endothelial cell apoptosis caused by glycated low-density lipoproteins and protective effects of grape seed procyanidin B2.

Elevated level of glycated low-density lipoproteins (glyLDL) is believed to contribute to endothelial dysfunction, which is involved in the pathogenesis and acceleration of diabetic vascular diseases. Grape seed procyanidin B2 (GSPB2) has been reported to possess protective effects against endothelial dysfunction. However, the underlying mechanism remains unclear. Prohibitin (PHB) is a multifunctional protein implicated in cellular survival and apoptosis. In this study, we showed that glyLDL treatment decreased protein level of PHB, reduced viability, and increased apoptosis in human umbilical vein endothelial cells (HUVEC). PHB overexpression or GSPB2 significantly attenuated apoptosis induced by glyLDL. Moreover, PHB siRNA increased HUVEC apoptosis, along with defective mitochondria and increased levels of cytosol cytochrome c concentration, caspase-3 activity, Bax/Bcl-2 ratio, and phosphorylated Akt, whereas PHB overexpression or GSPB2 restored these changes. Our study identified PHB as an important player responsible for HUVEC apoptosis induced by glyLDL. GSPB2 protected against HUVEC apoptosis at least in part through upregulating PHB. Targeting PHB could be significant in fighting against diabetic vascular complications.

PIMT prevents the apoptosis of endothelial cells in response to glycated low density lipoproteins and protective effects of grape seed procyanidin B2.

BACKGROUND: The development of diabetic angiopathy is associated with profound vascular endothelial cells (VEC) dysfunction and apoptosis. Glycated low density lipoproteins (gly-LDL) continuously produced in the setting of diabetic patients play an important role in causing VEC dysfunction and apoptosis. However, the underlying molecular mechanism remains largely elusive. Protein L-isoaspartyl methyltransferase (PIMT) is a widely expressed protein repair enzyme by multiple cell types of arterial wall including VEC. Our previous proteomic studies showed that the expression of PIMT was significantly decreased in the aorta of diabetic rats as compared with control rats and treatment with grape seed procyanidin extracts significantly increased the PIMT expression in diabetic rats. We hypothesized that PIMT plays a critical role in gly-LDL induced VEC apoptosis; grape seed procyanidin B2 (GSPB2) protect against gly-LDL induced VEC apoptosis through PIMT regulation. METHODS AND RESULTS: HUVEC transfected negative control and PIMT siRNA were treated with or without GSPB2 (10 µmol/L) for 48 h. Moreover, HUVEC of PIMT overexpression were stimulated by gly-LDL (50 µg/ml) in the presence or absence of GSPB2 (10 µmol/L) for 48 h. Our results showed that gly-LDL downregulated PIMT expression and PIMT overexpression or GSPB2 significantly attenuated gly-LDL induced VEC apoptosis. PIMT siRNA increased VEC apoptosis with up-regulation of p53, cytochrome c release, caspase-9 and caspase-3 activation. Mechanistically, overexpression of PIMT or GSPB2 increased the phosphorylation of ERK1/2 and GSK3ß in the gly-LDL induced VEC. CONCLUSION: In summary, our study identified PIMT as a key player responsible for gly-LDL induced VEC apoptosis and GSPB2 protect against gly-LDL induced VEC apoptosis by PIMT up-regulation. Targeting PIMT including use of GSPB2 could be turned into clinical application in the fighting against diabetic vascular complications.

Proteomic analysis of kidney and protective effects of grape seed procyanidin B2 in db/db mice indicate MFG-E8 as a key molecule in the development of diabetic nephropathy.

Diabetic nephropathy, as a severe microvascular complication of diabetic mellitus, has become the leading cause of end-stage renal diseases. However, no effective therapeutic strategy has been developed to prevent renal damage progression to end stage renal disease. Hence, the present study evaluated the protective effects of grape seed procyanidin B2 (GSPB2) and explored its molecular targets underlying diabetic nephropathy by a comprehensive quantitative proteomic analysis in db/db mice. Here, we found that oral administration of GSPB2 significantly attenuated the renal dysfunction and pathological changes in db/db mice. Proteome analysis by isobaric tags for relative and absolute quantification (iTRAQ) identified 53 down-regulated and 60 up-regulated proteins after treatment with GSPB2 in db/db mice. Western blot analysis confirmed that milk fat globule EGF-8 (MFG-E8) was significantly up-regulated in diabetic kidney. MFG-E8 silencing by transfection of MFG-E8 shRNA improved renal histological lesions by inhibiting phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2), Akt and glycogen synthase kinase-3beta (GSK-3ß) in kidneys of db/db mice. In contrast, over-expression of MFG-E8 by injection of recombinant MFG-E8 resulted in the opposite effects. GSPB2 treatment significantly decreased protein levels of MFG-E8, phospho-ERK1/2, phospho-Akt, and phospho-GSK-3ß in the kidneys of db/db mice. These findings yield insights into the pathogenesis of diabetic nephropathy, revealing MFG-E8 as a new therapeutic target and indicating GSPB2 as a prospective therapy by down-regulation of MFG-E8, along with ERK1/2, Akt and GSK-3ß signaling pathway.