Treatment of RAF1-Related Obstructive Hypertrophic Cardiomyopathy by MEK Inhibition Using Trametinib.

RASopathies cause nonsarcomeric hypertrophic cardiomyopathy via dysregulated signaling through RAS and upregulated mitogen-activated protein kinase activity. We provide the first report of the successful treatment of an adult with RAF1-associated hypertrophic cardiomyopathy using trametinib, a MEK inhibitor.

Ventricular-arterial decoupling is associated with in-hospital adverse events in normotensive pulmonary embolism.

During acute pulmonary embolism (PE) a compensatory increase in right ventricular (RV) contractility is required to match increased afterload to maintain right ventricular-pulmonary arterial (RV-PA) coupling. The aim of this study was to assess the prognostic utility of RV-PA decoupling in acute PE. We assessed the association between measures of transthoracic echocardiography (TTE)-derived RV-PA coupling including tricuspid annular plane systolic excursion (TAPSE)/right ventricular systolic pressure (RVSP) and right ventricular fractional area change (FAC)/RVSP as well as stroke volume index (SVI)/RVSP (a measure of pulmonary artery capacitance) with adverse PE-related events (in-hospital PE-related mortality or cardiopulmonary decompensation) using logistic regression analysis. In 820 normotensive patients TTE-derived markers of RV-PA coupling were associated with PE-related adverse events. For each 0.1 mm/mmHg decrease in TAPSE/RVSP the odds of an adverse event increased by 2.5-fold [adjusted OR (aOR) 2.49, 95% confidence interval (CI) 1.46-4.24, p = 0.001], for every 0.1%/mmHg decrease in FAC/RVSP the odds of an adverse event increased by 1.4-fold (aOR 1.42, CI 1.09-1.86, p = 0.010), and for every 0.1 mL/mmHg m2 decrease in SVI/RVSP the odds of an event increased by 2.75-fold (aOR 2.78, CI 1.72-4.50, p < 0.001). In multivariable analysis, TAPSE/RVSP and SVI/RVSP were independent of other risk stratification methods including computed tomography-derived right ventricular dysfunction (RVD), the Bova score, and subjective assessment of TTE-derived RVD. In patients with normotensive acute PE, TTE-derived measures of RV-PA coupling are associated with adverse in-hospital PE-related events and provide incremental value in the risk assessment beyond computed tomography-derived RVD, the Bova score, or subjective TTE-derived RVD.

Prognostic value of echocardiography-derived right ventricular dysfunction in haemodynamically stable pulmonary embolism: a systematic review and meta-analysis.

BACKGROUND: We sought to determine the prognostic value of transthoracic echocardiography (TTE)-derived right ventricular dysfunction (RVD) in haemodynamically stable and intermediate-risk patients with acute pulmonary embolism (PE), evaluate continuous RVD parameters, and assess the literature quality. METHODS: We searched MEDLINE, Embase and the Cochrane Central Register of Controlled Trials for studies assessing TTE-derived RVD in haemodynamically stable PE that reported in-hospital adverse events within 30 days. We determined pooled odds ratios (ORs) using a random-effects model, created funnel plots, evaluated the Newcastle-Ottawa scale and performed Grading of Recommendations, Assessment, Development and Evaluation. RESULTS: Based on 55 studies (17 090 patients, 37.8% RVD), RVD was associated with combined adverse events (AEs) (OR 3.29, 95% confidence interval (CI) 2.59-4.18), mortality (OR 2.00, CI 1.66-2.40) and PE-related mortality (OR 4.01, CI 2.79-5.78). In intermediate-risk patients, RVD was associated with AEs (OR 1.99, CI 1.17-3.37) and PE-related mortality (OR 6.16, CI 1.33-28.40), but not mortality (OR 1.63, CI 0.76-3.48). Continuous RVD parameters provide a greater spectrum of risk compared to categorical RVD. We identified publication bias, poor methodological quality in 34/55 studies and overall low certainty of evidence. CONCLUSIONS: RVD is frequent in PE and associated with adverse outcomes. However, data quality and publication bias are limitations of existing evidence.

Upfront riociguat and ambrisentan combination therapy for newly diagnosed pulmonary arterial hypertension: A prospective open-label trial.

BACKGROUND: Initial combination therapy with an endothelin receptor antagonist (ERA) and riociguat in pulmonary arterial hypertension (PAH) has limited supporting data. METHODS: We performed a prospective, single-arm, open-label trial of riociguat, and ambrisentan for incident PAH patients in functional class III. The primary endpoint was pulmonary vascular resistance (PVR) at 4-months. RESULTS: Twenty patients (59 ± 13 years old, 85% female) enrolled and 1 died before their 4-month follow-up. Fifteen patients completed a 4-month and 13 completed the 12-month follow-up. At 4-months PVR decreased 54% with an absolute change of -5.8 Wood units (95% CI -4.0; -7.5, p < 0.001). Other hemodynamic variables and risk scores also improved. Six patients discontinued riociguat and 8 discontinued ambrisentan, with 5 (25%) discontinuing both. CONCLUSIONS: These results do not support the routine use of riociguat plus ambrisentan in initial regimens. Future studies are needed to compare this strategy with phosphodiesterase-5 inhibitors and an ERA with respect to tolerability and long-term outcomes.

The State of the Heart Biopsy: A Clinical Review.

Endomyocardial biopsy (EMB) is an invaluable and underused diagnostic tool for myocardial disease. The primary indications are surveillance of cardiac allograft rejection and the diagnosis of inflammatory and infiltrative cardiomyopathies. EMB is typically performed by sampling the right ventricular septum via the right internal jugular vein using fluoroscopic guidance. The diagnostic yield of EMB is improved by sampling both ventricles and with the use of guidance from imaging or electroanatomic mapping. The risk of major cardiac complications is operator dependent and < 1% in experienced centres. EMB is the gold standard and most common form of cardiac allograft rejection surveillance, whereas advanced cardiac imaging and donor-specific antibody quantification provide complementary information. Gene expression profiling is an alternative surveillance strategy to EMB for low-risk patients. EMB is recommended for myocarditis and can guide therapy for giant-cell myocarditis, necrotizing eosinophilic myocarditis, sarcoidosis, and immune checkpoint inhibitor myocarditis. There is growing interest in using EMB to guide therapy for viral myocarditis, although the uptake of this approach is limited to specialized centres. EMB has been replaced as a first-line test for infiltrative cardiomyopathy by nonbiopsy diagnostic techniques, but is still useful to clarify the diagnosis or disease subtype. The miniaturization of bioptomes and advances in laboratory techniques such as microarrays promises to improve the safety and yield of EMB. We review the contemporary use of EMB for cardiac allograft rejection, inflammatory cardiomyopathy, and infiltrative cardiomyopathy.

La biopsie endomyocardique est un outil diagnostique sous-utilisé et très utile en cas de maladie myocardique. Ses principales indications sont la surveillance du rejet d'une allogreffe cardiaque et le diagnostic des cardiomyopathies restrictives (infiltrantes) et inflammatoires. La biopsie endomyocardique est généralement réalisée en prélevant un échantillon du septum ventriculaire droit par la veine jugulaire interne droite, sous guidage fluoroscopique. Le succès diagnostique de la biopsie endomyocardique est amélioré en prélevant un échantillon des deux ventricules et en utilisant le guidage par imagerie ou cartographie électroanatomique. Le risque de complications cardiaques majeures varie en fonction de la personne qui effectue l'intervention, et est de moins de 1 % dans les centres où cette intervention est courante. La biopsie endomyocardique est la norme de référence et la forme la plus courante de surveillance du rejet d'une allogreffe cardiaque, tandis que les techniques avancées d'imagerie cardiaque et la quantification des anticorps spécifiques au donneur fournissent de l'information complémentaire. Le profil d'expression génétique est une stratégie de surveillance qui peut être utilisée plutôt que la biopsie endomyocardique chez les patients à faible risque. La biopsie endomyocardique est recommandée pour la myocardite et peut guider le traitement dans les cas de myocardite à cellules géantes, de myocardite nécrosante éosinophilique, de sarcoïdose et de myocardite induite par les inhibiteurs du point de contrôle immunitaire. La biopsie endomyocardique est de plus en plus utilisée pour guider le traitement de la myocardite virale, même si l'adoption de cette approche n'est observée que dans les centres spécialisés. En première intention, la biopsie endomyocardique a été remplacée par des techniques diagnostiques n'ayant pas recours à la biopsie dans les cas de cardiomyopathie restrictive, mais demeure néanmoins utile pour préciser le diagnostic ou le sous-type de maladie. La miniaturisation des bioptomes et les progrès en matière de techniques de laboratoire, comme les microréseaux, devraient améliorer l'innocuité et l'efficacité de la biopsie endomyocardique. Nous avons passé en revue l'utilisation faite à l'heure actuelle de la biopsie endomyocardique en ce qui concerne le rejet de l'allogreffe cardiaque, la cardiomyopathie inflammatoire et la cardiomyopathie restrictive.

The effect of antiplatelet therapy on survival and cardiac allograft vasculopathy following heart transplantation: A systematic review and meta-analysis.

Cardiac allograft vasculopathy (CAV) is mediated by endothelial inflammation, platelet activation and thrombosis. Antiplatelet therapy may prevent the development of CAV. This systematic review and meta-analysis summarizes and appraises the evidence on the effect of antiplatelet therapy after heart transplantation (HT). CENTRAL(Ovid), MEDLINE(Ovid), Embase(Ovid) were searched from inception until April 30, 2020. Outcomes included CAV, all-cause mortality, and CAV-related mortality. Data were pooled using random-effects models. Seven observational studies including 2023 patients, mean age 52 years, 22% female, 47% with ischemic cardiomyopathy followed over a mean 7.1 years proved eligible. All studies compared acetylsalicylic acid (ASA) to no treatment and were at serious risk of bias. Data from 1911 patients in 6 studies were pooled in the meta-analyses. The evidence is very uncertain about the effect of ASA on all-cause or CAV-related mortality. ASA may reduce the development of CAV (RR 0.75, 95% CI: 0.44-1.29) based on very low certainty evidence. Two studies that conducted propensity-weighted analyses showed further reduction in CAV with ASA (HR 0.31, 95% CI: 0.13-0.74). In conclusion, there is limited evidence that ASA may reduce the development of CAV. Definitive resolution of the impact of antiplatelet therapy on CAV and mortality will require randomized clinical trials.

The Effect of Age on Outcomes After Destination-Therapy Left Ventricular Assist Device Implantation: An Analysis of the IMACS Registry.

BACKGROUND: As patients with advanced heart failure are living longer, defining the impact of left ventricular assist devices (LVADs) on outcomes in an aging population is of great importance. We describe overall survival, rates of adverse events (AEs), and post-AE survival in patients age ≥ 70 years vs age 50-69 years after destination-therapy (DT) LVAD implantation. METHODS: A retrospective analysis was conducted with the use of the International Society for Heart and Lung Transplantation Mechanically Assisted Circulatory Support (IMACS) registry. All adults age ≥ 50 years with a continuous-flow DT LVAD from 2013 to 2017 were included. The primary outcome was all-cause mortality. The secondary outcomes were the incidence of and survival after gastrointestinal (GI) bleeding, infection, stroke, pump thrombosis, pump exchange, and right-side heart failure. Mortality and AEs were assessed with the use of competing risk models. RESULTS: At total of 5,572 patients were included: 3,700 aged 50-69 and 1,872 aged ≥ 70. All-cause mortality by 42 months was 55.8% in patients aged ≥ 70 and 44.8% in patients aged 50-69 (P = 0.001). Patients aged ≥ 70 had a 37.8% higher risk of death after DT LVAD implantation (hazard ratio 1.378, 95% CI 1.251-1.517). Patients aged ≥ 70 had higher risk of GI bleeding but lower risk of right-side heart failure. There was no difference between age groups for risk of infection or stroke. Experiencing any AE was associated with an increased risk of death that did not vary with age. CONCLUSIONS: Patients aged ≥ 70 years have reduced survival after DT LVAD, in part because of increased GI bleeding, while the incidence of other AEs is similar to that of patients aged 50-69 years. Careful patient selection beyond age alone may allow for optimal outcomes after DT LVAD implantation.

Pericardial waffle for effusive-constrictive pericarditis.

We present the case of a 55-year-old female marathon runner who presented with progressive exercise intolerance and was diagnosed with effusive-constrictive pericarditis. Stereotypical findings of this challenging diagnosis are shown by transthoracic echocardiographic and right heart catheterization. We treated the patient with a parietal pericardiectomy and pericardial waffle procedure to relieve a thick and constrictive epicardium.

Lung Ultrasound for Cardiologists in the Time of COVID-19.

Lung ultrasound (LUS) is a point-of-care ultrasound technique used for its portability, widespread availability, and ability to provide real-time diagnostic information and procedural guidance. LUS outperforms lung auscultation and chest X-ray, and it is an alternative to chest computed tomography in selected cases. Cardiologists may enhance their physical and echocardiographic examination with the addition of LUS. We present a practical guide to LUS, including device selection, scanning, findings, and interpretation. We outline a 3-point scanning protocol using 2-dimensional and M-mode imaging to evaluate the pleural line, pleural space, and parenchyma. We describe LUS findings and interpretation for common causes of respiratory failure. We provide guidance specific of COVID-19, which at the time of writing is a global pandemic. In this context, LUS emerges as a particularly useful tool for the diagnosis and management of patients with cardiopulmonary disease.

Left Ventricular Assist Device With a Left Atrial Inflow Cannula for Hypertrophic Cardiomyopathy.

Patients with restrictive or hypertrophic cardiomyopathy (HCM) are often ineligible for a left ventricular assist device (LVAD) due to the risk of suction events with a small left ventricular cavity size and left ventricular inflow cannula. We describe an alternative LVAD configuration using a left atrial inflow cannula as a bridge to transplantation in an adult with HCM. (Level of Difficulty: Advanced.).

Medical Management of Left Ventricular Assist Device Patients: A Practical Guide for the Nonexpert Clinician.

Left ventricular assist devices (LVADs) provide short- or long-term circulatory support to improve survival and reduce morbidity in selected patients with advanced heart failure. LVADs are being used increasingly and now have expanded indications. Health care providers across specialties will therefore not only encounter LVAD patients but play an integral role in their care. To accomplish that, they need to understand the elements of LVAD function, physiology and clinical use. This article provides a concise overview of the medical management of LVAD patients for nonexpert clinicians. Our presentation includes the basics of LVAD physiology, design, and operation, patient selection and assessment, medical management, adverse event identification and management, multidisciplinary care, and management of special circumstances, such as noncardiac surgery, cardiac arrest, and end-of-life care. The clinical examination of LVAD patients is unique in terms of blood pressure and heart rate assessment, LVAD "hum" auscultation, driveline and insertion site inspection, and device parameter recording. Important potential device-related adverse events include stroke, gastrointestinal bleeding, hematologic disorders, device infection, LVAD dysfunction, arrhythmias, and heart failure. Special considerations include the approach to the unconscious or pulseless patient, noncardiac surgery, and palliative care. An understanding of the principles presented in this paper will enable the nonexpert clinician to be effective in collaborating with an LVAD center in the assessment, medical management, and follow-up of LVAD patients. Future opportunities and challenges include the improvement of device designs, greater application of minimally invasive surgical implantation techniques, and management of health economics in cost-constrained systems like those of Canada and many other jurisdictions.

Impact of Donor Origin on Survival After Orthotopic Heart Transplantation.

Heart transplantation is the definitive management for select patients with end-stage heart failure. Owing to an ongoing organ donor shortage, organs are sometimes allocated from distant locales. These organs may be perceived as less desirable because of donor risk factors and ischemic times. We compared survival after heart transplantation by donors originating from British Columbia (BC), other Canadian provinces, and the United States. This retrospective cohort analysis included all patients transplanted in BC between December 1, 1988, and October 21, 2014, and excluded those with missing data or retransplantation. Among 382 patients, 297 (77.7%) recipients and 238 (62.3%) donors were male. The median recipient age was 54.6 years (interquartile range, 46.0-61.0 years) and the median donor age was 33 years (interquartile range, 22-46 years). Overall 10-year survival was 62.1% (95% confidence interval, 56.3-67.4). There was no difference in 10-year survival when comparing donors from BC, other Canadian provinces, and the United States despite significantly lower median ischemic times in donors from BC. Donor location was not predictive of mortality after controlling for recipient age, donor age, and cold ischemic time. Donor origin did not impact 10-year survival after heart transplantation despite increased ischemic time, suggesting that distant donors result in similar outcomes in BC.

Pheochromocytoma-Induced Takotsubo Syndrome Treated With Extracorporeal Membrane Oxygenation: Beware of the Apical Sparing Pattern.

A 45-year-old female presents with suspected acute myocardial infarction with cardiogenic shock requiring mechanical circulatory support. Pheochromocytoma-induced atypical Takotsubo syndrome is diagnosed. Clinicians should suspect high catecholamine states as a cause of the basal subtype of atypical Takotsubo syndrome. (Level of Difficulty: Beginner.).