Intra- and inter-reader reproducibility in quantitative coronary plaque analysis on coronary computed tomography angiography.

PURPOSE: Coronary artery plaque burden, low attenuation non-calcified plaque (LAP), and pericoronary adipose tissue (PCAT) on coronary CT angiography (CCTA), have been linked to future cardiac events. The purpose of this study was to evaluate intra- and inter reader reproducibility in the quantification of coronary plaque burden and its characteristics using an artificial intelligence-enhanced semi-automated software. MATERIALS AND METHODS: A total of 10 women and 6 men, aged 52 (IQR 49-58) underwent CCTA using a Siemens Somatom Force, Somatom Definition AS and Somatom Definition Flash scanners. Two expert readers utilized dedicated semi-automatic software (vascuCAP, Elucid Bioimaging, Wenham, MA) to assess calcified plaque, low attenuation plaque and PCAT. Readers were blinded to all clinical information and repeated their analysis at 6 weeks in random order to minimize recall bias. Data analysis was performed on the right and left coronary arteries. Intra- and inter-reader reproducibility was compared using Pearson correlation coefficient, while absolute values between analyses and readers were compared with paired non-parametric tests. This is a sub-study of the Specialized Center of Research Excellence (SCORE) clinical trial (5U54AG062334). RESULTS: A total of 64 vessels from 16 patients were analyzed. Intra-reader Pearson correlation coefficients for calcified plaque volume, LAP volume and PCAT volumes were 0.96, 0.99 and 0.92 for reader 1 and 0.94, 0.94 and 0.95 for reader 2, respectively, (all p < 0.0001). Inter-reader Pearson correlation coefficients for calcified plaque volume, LAP and PCAT volumes were 0.92, 0.96 and 0.78, and 0.99, 0.99 and 0.93 on the second analyses, all had a p value <0.0001. There was no significant bias on the corresponding Bland-Altman analyses. CONCLUSION: Volume measurement of coronary plaque burden and PCAT volume can be performed with high intra- and inter-reader agreement.

Updates in the management of cancer therapy-related hypertension.

PURPOSE OF REVIEW: To provide a comprehensive review of hypertension among patients with cancer. Several cancer therapies cause hypertension which has resulted in a growing and vulnerable population of patients with difficult to control hypertension which has significant downstream effects. RECENT FINDINGS: Hypertension affects up to 50% of cancer patients and higher comorbidity when compared to the general population. Many anticancer therapies can cause hypertension through their treatment effect. Antihypertensive treatment is crucial given cardiovascular mortality is a leading cause of death among cancer patients. It is already known that hypertension is poorly controlled in the general population, and there are additional challenges in management among patients with cancer. Patients with cancer suffer from multimorbidity, are on multiple medications creating concern for drug interactions, and often have blood pressure lability, which can worsen clinical inertia among patients and their providers. It is crucial to effectively treat hypertension in cancer patients to mitigate downstream adverse cardiovascular events. SUMMARY: In recent years, there have been significant changes in management guidelines of hypertension and simultaneously as influx of new cancer therapeutics. We provide an update on hypertension treatment among patients with cancer on different chemotherapeutic agents.

Clinical considerations and pathophysiological associations among obesity, weight loss, heart failure, and hypertension.

PURPOSE OF REVIEW: To describe the relationship between three pandemics: hypertension, obesity, and heart failure. From pathophysiology to treatment, understanding how these disease entities are linked can lead to breakthroughs in their prevention and treatment. The relevance of this review lies in its discussion of novel pharmacological and surgical treatment strategies for obesity and hypertension, and their role in the prevention and treatment of heart failure. RECENT FINDINGS: Novel medications such as GLP-1 agonists have demonstrated sustained weight loss in patients with obesity, and concurrent improvements in their cardiometabolic profile, and possibly also reductions in hypertension-related comorbidities including heart failure. Surgical therapies including laparoscopic bariatric surgery represent an important treatment strategy in obese patients, and recent studies describe their use even in patients with advanced heart failure, including those with ventricular assist devices. SUMMARY: These developments have deep implications on our efforts to understand, mitigate, and ultimately prevent the three pandemics, and offer promising improvements to quality of life, survival, and the cost burden of these diseases.

Multimodality cardiovascular imaging in hypertension.

PURPOSE OF THE REVIEW: Hypertension accounts for the largest proportion of cardiovascular (CV) mortality worldwide and its prevalence continues to rise. While prominent CV societies have offered strong recommendations on the management of hypertension in adults, the role of noninvasive CV imaging in the evaluation of hypertensive patients remains incompletely defined. RECENT FINDINGS: Noninvasive imaging is a rapidly expanding field with a growing number of sophisticated and readily applicable modalities to assess how cardiac structure and function changes after periods of sustained, elevated blood pressure. Echocardiography remains the initial modality to screen these patients while developments in nuclear, computed tomography and cardiac magnetic resonance complement and expand investigations for alternative diagnoses that may complement or conflict with the diagnosis of left ventricular hypertrophy. SUMMARY: In this review article, we summarize the application of echocardiography, nuclear imaging, cardiac computed tomography, and cardiac magnetic resonance imaging in the evaluation and management of hypertensive heart disease.

Diagnostic Tools for Cardiac Amyloidosis: A Pragmatic Comparison of Pathology, Imaging and Laboratories.

Cardiac amyloidosis (CA) is a complex disease considered to be the most common underdiagnosed form of restrictive cardiomyopathy. Accumulation of misfolded proteins called amyloid fibrils in the extracellular space results in clinical deterioration and late diagnosis is associated with morbidity and mortality. Both types of this disease, light chain CA and transthyretin-related CA share many cardiac and extracardiac features that compromise multiple organs such as kidneys, musculoskeletal system, autonomic nervous system, and gastrointestinal tract. Early diagnosis and detection of CA are imperative. Clinicians should maintain a high degree of suspicion among patients with unexplained diastolic heart failure to implement different disease-altering therapies at the early stages of the disease. In this article, we provided a comprehensive review of multiple invasive and non-invasive cardiac imaging modalities with their respective degrees of sensitivities and specificity.

Intra- and Postprocedural Multimodality Imaging in Atrial Fibrillation.

Multi-modality imaging plays critical roles during and after procedures associated with atrial fibrillation. Transesophageal echocardiography is an invaluable tool for left atrial appendage occlusion during the procedure and at follow-up. Both cardiac computed tomography and cardiac magnetic resonance contribute to postprocedural evaluation of pulmonary vein isolation ablation. The present review is the second of a 2-part series where we discuss the roles of cardiac imaging in the evaluation and management of patients with atrial fibrillation, focusing on intraprocedural and postprocedural assessment, including the clinical evidence and outcomes data supporting this future applications.

Preprocedural Multimodality Imaging in Atrial Fibrillation.

Atrial fibrillation (AF) is the most common arrhythmia worldwide and is associated with increased risk of heart failure, stroke, and death. In current medical practice, multimodality imaging is routinely used in the management of AF. Twenty-one years ago, the ACUTE trial (Assessment of Cardioversion Using Transesophageal Echocardiography) results were published, and the management of AF changed forever by incorporating transesophageal echocardiography guided cardioversion of patients in AF for the first time. Current applications of multimodality imaging in AF in 2022 include the use of transesophageal echocardiography and computed tomography before cardioversion to exclude left atrial thrombus and in left atrial appendage occlusion device implantation. Transesophageal echocardiography, cardiac computed tomography, and cardiac magnetic resonance are clinically used for AF ablation planning. The decision to use a particular imaging modality in AF is based on patient's characteristics, guideline recommendation, institutional preferences, expertise, and cost. In this first of 2-part review series, we discuss the preprocedural role of echocardiography, computed tomography, and cardiac magnetic resonance in the AF, with regard to their clinical applications, relevant outcomes data and unmet needs, and highlights future directions in this rapidly evolving field.

Factors influencing outcomes of older children with medulloblastoma over 15 years in Peru, a resource-limited setting.

BACKGROUND: Medulloblastoma is the most common malignant brain tumor in children. While survival has improved in high-income countries (HIC), the outcomes for patients in low-to-middle-income countries (LMIC) are unclear. Therefore, we sought to determine the survival of children with medulloblastoma at the Instituto Nacional de Enfermedades Neoplasicas (INEN) between 1997 and 2013 in Peru. METHODS: Between 1997 and 2013, data from 103 children older than 3 years with medulloblastoma were analyzed. Fourteen patients were excluded. The patients were split into two distinct cohorts, 1997-2008 and 2009-2013, corresponding with chemotherapy regimen changes. Event-free (EFS) and overall survival (OS) were calculated using the Kaplan-Meier method, whereas prognostic factors were determined by univariate analysis (log-rank test). RESULTS: Eighty-nine patients were included; median age was 8.1 years (range: 3-13.9 years). The 5-year OS was 62% (95% CI: 53%-74%), while EFS was 57% (95% CI: 48%-69%). The variables adversely affecting survival were anaplastic histology (compared to desmoplastic; OS: HR = 3.4, p = .03), metastasis (OS: HR = 3.5, p = .01; EFS: HR = 4.3, p = .004), delay in radiation therapy of 31-60 days (compared to ≤30 days; EFS: HR = 2.1, p = .04), and treatment 2009-2013 cohort (OS: HR = 2.2, p = .02; EFS: HR = 2.0, p = .03). CONCLUSIONS: Outcomes for medulloblastoma at INEN were low compared with HIC. Anaplastic subtype, metastasis at diagnosis, delay in radiation therapy, and treatment in the period 2009-2013 negatively affected the outcomes in our study. Multidisciplinary teamwork, timely delivery of treatment, and partnerships with loco-regional groups and colleagues in HIC is likely beneficial.

Primary central nervous system sarcoma with DICER1 mutation-treatment results of a novel molecular entity in pediatric Peruvian patients.

BACKGROUND: A high frequency of primary central nervous system (CNS) sarcomas was observed in Peru. This article describes the clinical characteristics, biological characteristics, and outcome of 70 pediatric patients. METHODS: Data from 70 pediatric patients with primary CNS sarcomas diagnosed between January 2005 and June 2018 were analyzed. DNA methylation profiling from 28 tumors and gene panel sequencing from 27 tumors were available. RESULTS: The median age of the patients was 6 years (range, 2-17.5 years), and 66 of 70 patients had supratentorial tumors. DNA methylation profiling classified 28 of 28 tumors as primary CNS sarcoma, DICER1 mutant. DICER1 mutations were found in 26 of 27 cases, TP53 mutations were found in 22 of 27 cases, and RAS-pathway gene mutations (NF1, KRAS, and NRAS) were found in 19 of 27 tumors, all of which were somatic (germline control available in 19 cases). The estimated incidence in Peru was 0.19 cases per 100,000 children (<18 years old) per year, which is significantly higher than the estimated incidence in Germany (0.007 cases per 100,000 children [<18 years] per year; P < .001). Patients with nonmetastatic disease (n = 46) that were treated with a combination therapy had a 2-year progression-free survival (PFS) rate of 58% (95% CI, 44%-76%) and a 2-year overall survival rate of 71% (95% CI, 57%-87%). PFS was the highest in patients treated with chemotherapy with ifosfamide, carboplatin, and etoposide (ICE) after upfront surgery followed by radiotherapy and ICE (2-year PFS, 79% [59%-100%], n = 18). CONCLUSIONS: Primary CNS sarcoma with DICER1 mutation has an aggressive clinical course. A combination of surgery, chemotherapy, and radiotherapy seems beneficial. An underlying cancer predisposition syndrome explaining the increased incidence in Peruvian patients has not been identified so far. LAY SUMMARY: A high incidence of primary pediatric central nervous system sarcomas in the Peruvian population is described. Using sequencing technologies and DNA methylation profiling, it is confirmed that these tumors molecularly belong to the recently proposed entity "primary central nervous system sarcomas, DICER1 mutant." Unexpectedly, DICER1 mutations as well as all other defining tumor mutations (TP53 mutations and RAS-pathway mutations) were not inherited in all 19 patients where analyzation was possible. These tumors have an aggressive clinical course. Multimodal combination therapy based on surgery, ifosfamide, carboplatin, and etoposide chemotherapy, and local radiotherapy leads to superior outcomes.

Speckle-Tracking Echocardiography in Cardio-Oncology and Beyond.

Speckle-tracking echocardiography has enabled clinicians to detect changes in myocardial function with more sensitivity than that afforded by traditional diastolic and systolic functional measurements, including left ventricular ejection fraction. Speckle-tracking echocardiography enables evaluation of myocardial strain in terms of strain (percent change in length of a myocardial segment relative to its length at baseline) and strain rate (strain per unit of time). Both measurements have potential for use in diagnosing and monitoring the cardiovascular side effects of cancer therapy. Regional and global strain measurements can independently predict outcomes not only in patients who experience cardiovascular complications of cancer and cancer therapy, but also in patients with a variety of other clinical conditions. This review and case series examine the clinical applications and overall usefulness of speckle-tracking echocardiography in cardio-oncology and, more broadly, in clinical cardiology.

Network Analysis of Outcomes in Patients Undergoing Transcatheter Aortic Valve Replacement for Stenotic Bicuspid Aortic Valves According to Valve Type.

BACKGROUND: It is currently unknown if outcomes after transcatheter aortic valve replacement (TAVR) differ according to the prosthetic valve deployed in patients with bicuspid aortic valves (BAV). OBJECTIVES: This study evaluated valve-specific outcomes post-TAVR in patients with BAV. METHODS: Literature search was performed using the Cochrane databases, PubMed, ClinicalTrials, SCOPUS and EMBASE databases from inception until July 2018. We computed risk ratios and their 95% confidence intervals for all outcomes of interest. For each outcome, the data were pooled using a multivariate random-effects meta-analysis including multiple treatment as well as direct and indirect comparisons. RESULTS: Ten studies enrolling a total of 1547 BAV patients undergoing TAVR using 6 different prosthetic valve types were analyzed. There were no significant differences in 30-day all-cause mortality, life-threatening bleeding and device success among the diverse prosthetic valve types implanted. However, 2nd generation balloon-expandable valves had consistently lower risk of moderate-to-severe prosthetic valve regurgitation. CONCLUSION: In patients with BAV, there were no significant differences in 30-day all-cause mortality after TAVR among the various prosthetic valve types.

Outcomes following percutaneous coronary intervention in patients with cancer.

BACKGROUND: Randomized clinical trials demonstrated the benefits of percutaneous coronary interventions (PCI) in diverse clinical settings. Patients with cancer were not routinely included in these studies. METHODS/RESULTS: Literature search of PubMed, Cochrane, Medline, SCOPUS, EMBASE, and ClinicalTrials was conducted to identify studies that assessed one-year all-cause, cardiovascular and non-cardiovascular mortality in patients with historical or active cancer. Using the random effects model, we computed risk ratios (RRs) and standardized mean differences and their 95% confidence intervals for the dichotomous and continuous measures and outcomes, respectively. Of 171 articles evaluated in total, 5 eligible studies were included in this meta-analysis. In total, 33,175 patients receiving PCI were analyzed, of whom 3323 patients had cancer and 29,852 no cancer history. Patients in the cancer group had greater all-cause mortality [RR 2.22 (1.51-3.26; p<0.001)], including cardiovascular mortality [RR 1.34 (1.1-1.65; p=0.005)] and non-cardiovascular mortality [RR 3.42 (1.74-6.74; p≤0.001], at one-year compared to non-cancer patients. Patients in the cancer group had greater one-month all-cause mortality [RR 2.01 (1.24-3.27; p=0.005)] and greater non-cardiovascular mortality [RR 6.87 (3.10-15.21; p≤0.001)], but no difference in one-month cardiovascular mortality compared to non-cancer patients. Meta-regression analyses showed that the difference in one-year all-cause and cardiovascular mortality between both groups was not attributable to differences in baseline characteristics, index PCI characteristics, or medications prescribed at discharge. CONCLUSIONS: Patients with cancer undergoing PCI have worse mid-term outcomes compared to non-cancer patients. Cancer patients should be managed by a multi-specialist team, in an effort to close the mortality gap.

Mitochondrial Protein Poldip2 (Polymerase Delta Interacting Protein 2) Controls Vascular Smooth Muscle Differentiated Phenotype by O-Linked GlcNAc (N-Acetylglucosamine) Transferase-Dependent Inhibition of a Ubiquitin Proteasome System.

RATIONALE: The mitochondrial Poldip2 (protein polymerase interacting protein 2) is required for the activity of the tricarboxylic acid cycle. As a consequence, Poldip2 deficiency induces metabolic reprograming with repressed mitochondrial respiration and increased glycolytic activity. Though homozygous deletion of Poldip2 is lethal, heterozygous mice are viable and show protection against aneurysm and injury-induced neointimal hyperplasia, diseases linked to loss of vascular smooth muscle differentiation. Thus, we hypothesize that the metabolic reprograming induced by Poldip2 deficiency controls VSMC differentiation. OBJECTIVE: To determine the role of Poldip2-mediated metabolic reprograming in phenotypic modulation of VSMC. METHODS AND RESULTS: We show that Poldip2 deficiency in vascular smooth muscle in vitro and in vivo induces the expression of the SRF (serum response factor), myocardin, and MRTFA (myocardin-related transcription factor A) and dramatically represses KLF4 (Krüppel-like factor 4). Consequently, Poldip2-deficient VSMC and mouse aorta express high levels of contractile proteins and, more significantly, these cells do not dedifferentiate nor acquire macrophage-like characteristics when exposed to cholesterol or PDGF (platelet-derived growth factor). Regarding the mechanism, we found that Poldip2 deficiency upregulates the hexosamine biosynthetic pathway and OGT (O-linked N-acetylglucosamine transferase)-mediated protein O-GlcNAcylation. Increased protein glycosylation causes the inhibition of a nuclear ubiquitin proteasome system responsible for SRF stabilization and KLF4 repression and is required for the establishment of the differentiated phenotype in Poldip2-deficient cells. CONCLUSIONS: Our data show that Poldip2 deficiency induces a highly differentiated phenotype in VSMCs through a mechanism that involves regulation of metabolism and proteostasis. Additionally, our study positions mitochondria-initiated signaling as key element of the VSMC differentiation programs that can be targeted to modulate VSMC phenotype during vascular diseases.

One-Year Mortality in Patients Undergoing Transcatheter Aortic Valve Replacement for Stenotic Bicuspid versus Tricuspid Aortic Valves: A Meta-Analysis and Meta-Regression.

OBJECTIVE: To assess 1-year mortality after transcatheter aortic valve replacement (TAVR) in patients with bicuspid aortic stenosis (AS). BACKGROUND: Clinical trials have proven the beneficial effect of TAVR on mortality in patients with tricuspid AS. Individuals with bicuspid AS were excluded from these trials. METHODS: A meta-analysis using literature search from the Cochrane, PubMed, ClinicalTrials, SCOPUS, and EMBASE databases was conducted to determine the effect of TAVR on 1-year mortality in patients with bicuspid AS. Short-term outcomes that could potentially impact one-year mortality were analyzed. RESULTS: After evaluating 380 potential articles, 5 observational studies were selected. A total of 3890 patients treated with TAVR were included: 721 had bicuspid and 3,169 had tricuspid AS. No statistically significant difference between the baseline characteristics of the two groups of patients was seen outside of mean aortic gradient. Our primary endpoint of one-year all-cause mortality revealed 85 deaths in 719 patients (11.82%) with bicuspid AS compared to 467 deaths in 3100 patients (15.06%) with tricuspid AS, with no difference between both groups [relative risk (RR) 1.03; 95% CI 0.70-1.51]. Patients with bicuspid AS were associated with a decrease in device success (RR 0.62; 95% CI 0.45-0.84) and an increase in moderate-to-severe prosthetic valve regurgitation (RR 1.55; 95% CI 1.07-2.22) after TAVR compared to patients with tricuspid AS. The effect of meta-regression coefficients on one-year all-cause mortality was not statistically significant for any patient baseline characteristics. CONCLUSION: When comparing TAVR procedure in tricuspid AS versus bicuspid AS, there was no difference noted in one-year all-cause mortality.

Cellular Mechanisms of Aortic Aneurysm Formation.

Aortic aneurysms are a common vascular disease in Western populations that can involve virtually any portion of the aorta. Abdominal aortic aneurysms are much more common than thoracic aortic aneurysms and combined they account for >25 000 deaths in the United States annually. Although thoracic and abdominal aortic aneurysms share some common characteristics, including the gross anatomic appearance, alterations in extracellular matrix, and loss of smooth muscle cells, they are distinct diseases. In recent years, advances in genetic analysis, robust molecular tools, and increased availability of animal models have greatly enhanced our knowledge of the pathophysiology of aortic aneurysms. This review examines the various proposed cellular mechanisms responsible for aortic aneurysm formation and identifies opportunities for future studies.

Early Evidence of Cardiotoxicity and Tumor Response in Patients with Sarcomas after High Cumulative Dose Doxorubicin Given as a Continuous Infusion.

BACKGROUND: Despite the dose-dependent response rate of sarcomas to doxorubicin, clinicians limit its cumulative dose due to cardiotoxicity. This study evaluates early evidence of cardiotoxicity in patients treated with high-dose doxorubicin given as a continuous infusion. METHODS: Data was collected on patients who received 90 mg/m2 doxorubicin as a continuous infusion and 10 gm/m2 ifosfamide for up to 6 cycles as part of a phase II study. Cardiotoxicity was assessed with serial echocardiograms or multigated acquisition scans and serum brain natriuretic peptide and troponin levels. Tumor responses were determined by serial radiographic imaging per RECIST. RESULT: Out of the 48 patients enrolled, no patient developed heart failure symptoms; however, 4 out of the 38 (10%) patients with serial left ventricular ejection fraction assessments developed subclinical cardiotoxicity (asymptomatic drop in LVEF ≥ 10%). Twenty-three patients received all six 72-hour cycles of doxorubicin with a mean cumulative dose of 540 mg/m2. Among these patients, 4% (n = 1) developed subclinical cardiotoxicity. In the advanced disease group (n = 39), patients with a complete or partial response received a higher mean cumulative dose than those with stable disease (p < 0.033). CONCLUSIONS: Doxorubicin cardiotoxicity can be limited by administering doxorubicin as a continuous infusion, allowing higher cumulative dosing to maximize efficacy.