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.

Utility of positron emission tomography myocardial perfusion imaging for identifying ischemia and guiding treatment in patients with anomalous coronary arteries.

BACKGROUND: The assessment of anomalous coronary arteries (AAOCA) remains controversial without an optimal stress modality for ischemia. We evaluated the value of PET-CT myocardial perfusion imaging in these patients and subsequent management. METHODS AND RESULTS: AAOCA patients (n = 82) undergoing PET-CT from 2015 to 2021 were retrospectively chart reviewed. Multivariable analyses performed to assess relevant clinical and imaging factors associated with ischemia on PET and AAOCA surgery. Key characteristics include mean age 45 ± 20 years, 30 (37%) female, 45 (55%) with chest pain, 19 (23%) anomalous left main coronary artery, 58 (71%) anomalous right coronary artery, 26 (32%) with objective ischemia on PET-CT, and 37 (45%) who underwent AAOCA surgery. Adverse outcomes over mean follow-up of 2.2 ± 1.8 years included one death and two myocardial infarctions. Anomalous left main was independently associated with ischemia on PET-CT, odds ratio (95% confidence intervals) 4.15 (1.31-13.1), P = .006. Chest pain and ischemia on PET-CT were independently associated with and provided incremental prognostic value for surgery, odds ratio 9.73 (2.78-34.0), P < .001 and 6.79 (1.99-23.2), P = .002, respectively. CONCLUSION: Ischemia on PET-CT occurred in a third of our cohort, identifying patients who may benefit from surgery. Larger studies are needed to evaluate the interplay between AAOCA, ischemia by PET and surgery.

Paradigm Shift in Diagnosis and Targeted Therapy in Recurrent Pericarditis.

PURPOSE OF THE REVIEW: We review the pathophysiology, diagnosis, and contemporary treatment for recurrent pericarditis, with focus on interleukin-1 (IL-1) inhibitors. RECENT FINDINGS: Recurrent pericarditis occurs in about 15-30% of patients who have acute pericarditis. With increased understanding of the autoinflammatory pathophysiology of recurrent pericarditis, IL-1 inhibitors including anakinra, canakinumab, and rilonacept have been applied to this condition with great promise. In particular, the RHAPSODY trial found rilonacept significantly improves pain and inflammation, while also reducing recurrence with few adverse events. The next IL-1 inhibitor on the block for pericarditis, goflikicept, is also discussed. Understanding the role of the inflammasome via the autoinflammatory pathway in pericarditis has led to incorporation of IL-1 inhibitors in the treatment of recurrent pericarditis, with proven efficacy and safety and randomized trials. This will lead to increase uptake of this agent which demonstrated lower rates of recurrence and faster time to resolution.

Validating patient prioritization in the 2018 Revised United Network for Organ Sharing Heart Allocation System: A single-center experience.

The 2018 Revised United Network for Organ Sharing Heart Allocation System (HAS) was proposed to reclassify status 1A candidates into groups of decreasing acuity; however, it does not take into account factors such as body mass index (BMI) and blood group which influence waitlist (WL) outcomes. We sought to validate patient prioritization in the new HAS at our center. We retrospectively evaluated patients listed for heart transplantation (n = 214) at Emory University Hospital from 2011 to 2017. Patients were reclassified into the 6-tier HAS. Multistate modeling and competing risk analysis were used to compare outcomes of transplantation and WL death/deterioration between new tiers. Additionally, a stratified sensitivity analysis by BMI and blood group was performed. Compared with tier 4 patients, there was progressively increasing hazard of WL death/deterioration in tier 3 (HR: 2.52, 95% CI: 1.37-4.63, P = .003) and tier 2 (HR: 5.03, 95% CI: 1.99-12.70, P < .001), without a difference in transplantation outcome. When stratified by BMI and blood group, this hierarchical association was not valid in patients with BMI ≥30 kg/m2 and non-O blood groups in our cohort. Therefore, the 2018 HAS accurately prioritizes the sickest patients in our cohort. Factors such as BMI and blood group influence this relationship and iterate that the system can be further refined.

Functional relevance of the histone gammaH2Ax in the response to DNA damaging agents.

The phosphorylation of H2Ax on its S139 site, γH2Ax, is important during DNA double-strand repair and is considered necessary for assembly of repair complexes, but its functional role after other kinds of DNA damage is less clear. We have measured the survival of isogenic mouse cell lines with the H2Ax gene knocked out, and replaced with wild-type or mutant (S139A) H2Ax genes, exposed to a range of agents with varied mechanisms of DNA damage. Knockout and mutant cells were sensitive to γ-rays, etoposide, temozolamide, and endogenously generated reactive oxygen species, each of which can include double-strand breaks among their spectra of DNA lesions. The absence or mutation of H2Ax had no influence on sensitivity to cisplatin or mitomycin C. Although UV light induced the highest levels of γH2Ax, mutation of S139 had no influence on UV sensitivity or the UV DNA damage response. Complete loss of H2Ax reduced the survival of cells exposed to UV light and reduced pChk1 induction, suggesting that sites other than S139 may impact the ATR-pChk1 pathway. The relative intensity of γH2Ax measured in Western blots in wild-type cells did not correlate with the functional importance of γH2Ax. The use of γH2Ax as a general biomarker of DNA damage is therefore potentially misleading because it is not an unambiguous indicator of double-strand breaks, and a significant fraction of DNA repair, especially involving nucleotide excision or crosslink repair, can occur without functional involvement of γH2Ax.

An evaluation of mavacamten for the treatment of symptomatic obstructive hypertrophic cardiomyopathy in adults.

INTRODUCTION: Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disorder leading to hypertrophy of the left ventricle excluding other etiologies. Patients can experience exertional chest pain, dyspnea, syncope or even sudden cardiac death (SCD). Traditional medical management consists of beta blockers (BB), nondihydropyridine calcium channel blockers and disopyramide. Mavacamten, a novel cardiac myosin inhibitor, has recently been shown to improve both quantitative and qualitative measures of obstructive HCM allowing some patients to defer septal reduction therapy. AREAS COVERED: This review delves into the pharmacotherapy of mavacamten, the evidence behind this first-in-class drug for HCM, guidance for clinical usage, and possible future uses for cardiac myosin inhibitors. EXPERT OPINION: Mavacamten should be incorporated into the standard armamentarium of medications used to treat obstructive HCM. PIONEER-HCM, EXPLORER-HCM and VALOR-HCM demonstrated improvements in peak LVOT gradient both at rest and post-exercise, cardiac biomarkers, New York Heart Association (NYHA) functional class and Kansas City Cardiomyopathy Questionnaire (KCCQ) scores. Unlike other medications utilized for treatment, mavacamten can delay or even obviate the need for septal reduction therapy.

Review of Mavacamten for Obstructive Hypertrophic Cardiomyopathy and Future Directions.

Hypertrophic cardiomyopathy (HCM) is a condition with abnormal hypertrophy of the left ventricle in the absence of common causes. The most common form involves the basal septum and can lead to obstruction of the left ventricular outflow tract. Patients can experience exertional symptoms such as chest pain, dyspnea and syncope. Traditional treatment has included beta blockers and nondihydropyridine calcium channel blockers with second-line therapy being disopyramide. Recently, mavacamten, a cardiac myosin inhibitor, has demonstrated improvement in quantitative measures of obstruction and symptom relief to such a degree that patients were able to defer invasive management of the disease. This review focuses on the pharmacology of mavacamten, its clinical trial data and guidance on how to incorporate this drug into clinical practice. Furthermore, it discusses emerging therapies currently being investigated for HCM.

Contemporary Review of Transcatheter Mitral Valve Interventions for Mitral Regurgitation.

Mitral regurgitation (MR) is the most common form of valvular heart disease in the United States, and there are established guidelines for indications for requiring mitral valve surgeries. However, there is an unmet clinical need for a subset of high-risk MR patients, especially those with advanced age, heart failure and/or secondary MR. Following the successes of transcatheter aortic valve replacements, significant advances have occurred over the last decade in transcatheter mitral valve interventions in order to manage these patients in both clinical practice and trials. The three main types of these interventions include a transcatheter edge-to-edge repair, percutaneous mitral annuloplasty (both direct and indirect) and transcatheter mitral valve replacement (including when applied to a prior prosthetic valve, annuloplasty ring and mitral annuloplasty ring). This review aims to discuss the contemporary techniques, evidence, indications, multimodality imaging evaluations and outcomes of the various transcatheter mitral valve interventions.

Multimodality imaging of hypertrophic cardiomyopathy.

The diagnosis and management of hypertrophic cardiomyopathy (HCM) requires multimodality imaging. Transthoracic echocardiogram (TTE) remains the first-line imaging modality to diagnose HCM identifying morphology and obstruction, which includes left ventricular outflow obstruction, midcavitary obstruction and systolic anterior motion. Cardiac magnetic resonance imaging (CMR) can adjudicate equivocal cases, rule out alternative diagnoses and evaluate for risk factors of sudden cardiac death. Imaging with TTE or transesophageal echocardiogram can also guide alcohol septal ablation or surgical myectomy respectively. Furthermore, TTE can guide medical management of these patients by following peak gradients. Thus, multimodality imaging in HCM is crucial throughout the course of these patients' care.

Mental Stress-Induced Change in Plasma Stromal Cell-Derived Factor-1 and Adverse Cardiovascular Outcomes: A Cohort Study.

Background: Acute psychological stress can provoke mental stress-induced myocardial ischemia (MSIMI) in coronary artery disease (CAD). Stromal cell-derived factor 1 (SDF1) is released in response to hypoxia, and higher levels of SDF1 are associated with adverse outcomes. We examined whether an increase in SDF1 level in response to mental stress predicts adverse outcomes in CAD patients. Methods: A total of 554 patients with stable CAD (mean age 63 years; 76% male; 26% Black) underwent standardized mental stress testing. Plasma SDF1 levels were measured at rest and 90 minutes after mental stress, and MSIMI was evaluated by 99mTc-sestamibi perfusion imaging. Participants were followed for 5 years for the primary endpoint of composite of death and myocardial infarction (MI) and the secondary endpoint of composite of death, MI, and heart failure hospitalization. Cox hazard models were used to assess the association between SDF1 change and incident adverse events. Results: Mean (standard deviation) SDF1 change with mental stress was +56.0 (230) pg/mL. During follow-up, a rise of 1 standard deviation in SDF1 with mental stress was associated with a 32% higher risk for the primary endpoint of death and MI (95% confidence interval, 6%-64%), independent of the resting SDF1 level, demographic and clinical risk factors, and presence of ischemia. A rise of 1 standard deviation in SDF1 was associated with a 33% (95% confidence interval, 11%-59%) increase in the risk for the secondary endpoint, independent of the resting SDF1 level, demographic, and clinical risk factors and presence of ischemia. Conclusions: An increase in SDF1 level in response to mental stress is associated with a higher risk of adverse events in stable CAD, independent of MSIMI.

Contexte: Un stress psychologique aigu peut provoquer une ischémie myocardique induite par le stress mental chez les patients atteints d'une coronaropathie. Le facteur dérivé des cellules stromales de type 1 (SDF1) est libéré en réponse à une hypoxie, et des taux accrus de SDF1 sont associés à des résultats défavorables. Nous avons examiné si une élévation des taux de SDF1 en réponse à un stress mental permettait de prévoir la survenue de résultats défavorables chez des patients atteints d'une coronaropathie. Méthodologie: Au total, 554 patients présentant une coronaropathie stable (âge moyen de 63 ans; 76 % d'hommes; 26 % de patients de race noire) ont subi une évaluation standardisée du stress mental. Les taux plasmatiques de SDF1 ont été mesurés au repos et 90 minutes après un stress mental, et l'ischémie myocardique induite par le stress mental a été évaluée par imagerie avec injection de Tc-99m sestamibi. Les participants ont fait l'objet d'un suivi pendant cinq ans afin de surveiller la survenue des événements constituant le paramètre d'évaluation principal composé (décès et infarctus du myocarde [IM]) et le paramètre d'évaluation secondaire composé (décès, IM et hospitalisation en raison d'une insuffisance cardiaque). Des modèles de Cox ont été utilisés pour évaluer le lien entre la modification des taux de SDF1 et les événements indésirables susceptibles de survenir. Résultats: La variation moyenne du taux de SDF1 (écart-type) associée au stress mental a été de +56,0 (230) pg/ml. Pendant le suivi, une augmentation de 1 écart-type du taux de SDF1 en raison du stress mental a été associée à un risque 32 % plus élevé de survenue de l'un des événements constituant le paramètre d'évaluation principal (décès et IM) [intervalle de confiance [IC] à 95 % : 6 % à 64 %], indépendamment du taux de SDF1 au repos, des caractéristiques démographiques, des facteurs de risque clinique et de la présence d'une ischémie. Une augmentation de 1 écart-type du taux de SDF1 a été associée à un risque 33 % plus élevé (IC à 95 % : 11 % à 59 %) de survenue de l'un des événements constituant le paramètre d'évaluation secondaire, indépendamment du taux de SDF1 au repos, des caractéristiques démographiques, des facteurs de risque clinique et de la présence d'une ischémie. Conclusions: Une augmentation du taux de SDF1 en réponse à un stress mental est associée à une augmentation du risque d'événements indésirables chez les patients atteints d'une coronaropathie stable, indépendamment de la présence d'une ischémie myocardique induite par le stress mental.

Defective DNA repair and cell cycle arrest in cells expressing Merkel cell polyomavirus T antigen.

The pathways by which Merkel cell polyomavirus (MCV) infection contributes to the formation of Merkel cell carcinomas are important for understanding the pathogenesis of these cancers. We hypothesized that MCV T antigen suppresses normal responses to ultraviolet radiation (UVR)-induced DNA damage. An MCV-infected cell line (MKL-1) exhibited UVR hypersensitivity, impaired repair of DNA lesions and cell cycle arrest after UVR, as well as reduced levels of the DNA damage recognition protein, XPC. When ectopically expressed in uninfected UISO cells, mutant but not wild-type T antigen resulted in loss of repair of UVR-induced cyclobutane pyrimidine dimers and reductions in XPC, p53 and p21 levels, whereas both wild-type and mutant T antigen inhibited cell cycle arrest after UVR. Similarly, only mutant T antigen in normal fibroblasts inhibited DNA repair and XPC expression, while both mutant and wild-type T antigens produced cell cycle dysregulation. Wild-type T antigen expression produced large T, 57 kT and small T antigens while mutant T antigen was only detectable as a truncated large T antigen protein. Expression of wild-type large T antigen but not small T antigen inhibited the G1 checkpoint in UISO cells, but neither wild-type large T nor small T antigens affected DNA repair, suggesting that large T antigen generates cell cycle defects, and when mutated may also impair DNA repair. These results indicate that T antigen expression by MCV can inhibit key responses to UVR-induced DNA damage and suggest that progressive MCV-mediated abrogation of genomic stability may be involved in Merkel cell carcinogenesis.

Dissecting Into the 2021 Chest Pain Guidelines.

Although acute coronary syndromes remain crucial diagnoses of chest pain that cannot be missed, there are several other potentially fatal diagnoses that can manifest similarly. This case report applies the 2021 chest pain guidelines emphasizing the importance of considering alternative nonischemic but still serious presentations under the umbrella of chest pain. (Level of Difficulty: Advanced.).

Triaging Down the 2021 Chest Pain Guidelines.

We applied the 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR chest pain guidelines to a case of a 76-year-old woman with no known coronary disease presenting to the emergency department with acute chest pain and an intermediate probability of acute coronary syndrome. Her workup per the guidelines involved rapid electrocardiogram, high-sensitivity troponins, nuclear stress testing, and eventually coronary invasive angiography. (Level of Difficulty: Advanced.).

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.

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.

Mechanistic Insights into Tricuspid Regurgitation Secondary to Pulmonary Arterial Hypertension.

The simultaneous presence of pulmonary arterial hypertension (PAH) and secondary tricuspid regurgitation (STR) portends particularly poor outcomes. However, not all patients with PAH develop significant STR, and the mechanisms and clinical implications underlying this phenomenon remain unclear. We sought to describe the functional, anatomic, hemodynamic, and clinical characteristics of patients with PAH with and without STR. Patients diagnosed with PAH between 2007 and 2013 were included. STR, defined by absent primary tricuspid valve disease on transthoracic echocardiogram, was considered significant if ≥ moderate in severity. The characteristics of right-sided chambers and tricuspid valve annuli and leaflets were compared between patients with significant versus nonsignificant STR using a transthoracic echocardiogram, cardiac computed tomography, and right-sided cardiac catheterization. These features were then correlated with the composite outcome of all-cause mortality and PAH hospitalization. Of 88 included patients, 52 had significant STR. No baseline clinical differences, including atrial fibrillation, were observed. Patients with significant STR had worse right ventricular dysfunction (tricuspid annular planar systolic excursion = 1.5 vs 2.1 cm; p = 0.02) and increased right ventricular sphericity (sphericity index = 1.8 vs 2; p = 0.004), with similar annular dimensions/shape, lengths/angles of the mural and septal leaflets, and tenting height. After a median of 54 months, right atrial mean pressure was independently associated with the composite outcome on multivariable analysis (hazard ratio = 1.07, p = 0.02). In conclusion, anatomic and functional alterations in the right ventricle rather than the tricuspid valve are implicated in developing significant STR in PAH. Multimodality imaging provides mechanistic insight, and hemodynamic assessment may offer prognostic guidance in this population.

A methodology to explore ventilatory chemosensitivity and opioid-induced respiratory depression risk.

Reported incidence of postoperative opioid-induced respiratory depression (OIRD) ranges from 0.5-41% and is not reliably predicted by traditional risk factors. This study tests a new methodology to investigate ventilatory chemosensitivity as a new potential risk factor and explore OIRD distribution across sleep and wakefulness. Preoperative patient ventilatory chemosensitivity was quantified by hypercapnic ventilatory responses with (HCVRREMI, effect site concentration 0.7 or 2.0 ng/mL) and without (HCVRBL) remifentanil during hyperoxia and hypoxia. Postoperative opioid consumption was recorded during hospital stays. OIRD frequency was the primary outcome of the study, detected as incidences of respiratory rate < 60% of baseline, minute ventilation < 60% of predicted value, pulse oximetry [Formula: see text] < 90% (breathing room air) or 92% (supplemental O2), transcutaneous Pco2 > 50 mmHg, and central and obstructive apnea/hypopnea. Sleep stages were recorded until the first postoperative morning to determine the OIRD sleep distribution as the secondary outcome. The methodology was feasible in implementation and posed no obstacles to standard care. In the nine patients studied (2 females, mean age 65 ± 7.5 yr), remifentanil depressed HCVR to a highly variable degree. High OIRD frequency was generally observed with lower HCVRREMI. OIRD predominantly occurred during light sleep. This study supports ventilatory chemosensitivity as an important predictor of OIRD, lending a new perspective to classify risk for OIRD and detailing a methodology in which to pursue this investigation for future studies.NEW & NOTEWORTHY Our new and noteworthy methodology allows for exploration of preoperative ventilatory chemosensitivity, measured as the hypercapnic ventilatory response (HCVR), as a risk factor for postoperative opioid-induced respiratory depression (OIRD). This feasible and reliable methodology produced preliminary data that showed highly variable depression of HCVR by remifentanil, predominance of OIRD during light sleep, and potentially negative correlation between OIRD frequency generally and HCVR measurements when measured in the presence of remifentanil. Although the results are preliminary in nature, this novel methodology may guide future studies that can one day lead to effective clinical screening tools.