Abstract Background Normative changes in right ventricular (RV) structure and function have not been characterized in the context of treatment-associated functional recovery (RVFnRec). The aim of this study is to assess the clinical relevance of a proposed RVFnRec definition. Methods We evaluated 63 incident patients with PAH by right heart catheterization and cardiac MRI (CMR) at diagnosis and CMR and invasive cardiopulmonary exercise (CPET) following treatment (∼11 months). Sex, age, race/ethnicity matched healthy control subjects (n=62) with one-time CMR and non-invasive CPET were recruited from the PVDOMICS project. We examined therapeutic CMR changes relative to the evidence-based peak oxygen consumption (VO2 peak )>15mL/kg/min to define RVFnRec by receiver operating curve analysis. Afterload was measured in the as mean pulmonary artery pressure, resistance, compliance, and elastance. Results A drop in RV end-diastolic volume of -15 mL best defined RVFnRec (AUC 0.87, P=0.0001) and neared upper 95% CI RVEDV of controls. 22/63 (35%) of subjects met this cutoff which was reinforced by freedom from clinical worsening, RVFnRec 1/21 (5%) versus no RVFnRec 17/42, 40%, (log rank P=0.006). A therapy-associated increase of 0.8 mL/mmHg in compliance had the best predictive value of RVFnRec (AUC 0.76, CI 0.64-0.88, P=0.001). RVFnRec subjects had greater increases in stroke volume, and cardiac output at exercise. Conclusions RVFnRec defined by RVEDV therapeutic decrease of -15mL predicts exercise capacity, freedom from clinical worsening, and nears normalization. A therapeutic improvement of compliance is superior to other measures of afterload in predicting RVFnRec. RVFnRec is also associated with increased RV output reserve at exercise. Clinical Perspective What is new? Right ventricular functional recovery (RVFnRec) represents a novel endpoint of therapeutic success in PAH. We define RVFnRec as treatment associated normative RV changes related to function (peak oxygen consumption). Normative RV imaging changes are compared to a well phenotyped age, sex, and race/ethnicity matched healthy control cohort from the PVDOMICS project. Previous studies have focused on RV ejection fraction improvements. However, we show that changes in RVEDV are perhaps more important in that improvements in LV function also occur. Lastly, RVFnRec is best predicted by improvements in pulmonary artery compliance versus pulmonary vascular resistance, a more often cited metric of RV afterload. What are the clinical implications? RVFnRec represents a potential non-invasive assessment of clinical improvement and therapeutic response. Clinicians with access to cardiac MRI can obtain a limited scan (i.e., ventricular volumes) before and after treatment. Future study should examine echocardiographic correlates of RVFnRec.
Case Presentation: A 40-year-old male presented with decompensated heart failure and severe pulmonary hypertension (echo-predicted right ventricular systolic pressure 60 mmHg). Right heart catheterization revealed high output heart failure (cardiac index 7.3 L/min/m 2 ), left to right shunt (Qp:Qs 3.6:1), pulmonary hypertension (mean 38 mmHg), and normal pulmonary resistance (1.53 Wood units). Transesophageal echocardiogram revealed a large non-coronary sinus of Valsalva aneurysm with communication to the right atrium (Figure 1a and b). Percutaneous transcatheter closure of the aneurysm was deferred due to large size (3.3 x 4.3 cm), proximity to the right coronary artery, and risk of aneurysm rupture with catheter manipulation (Figure 1c). The patient underwent surgical aneurysm resection and aortic root replacement and recovered well. Discussion: Sinus of Valsalva aneurysms (SVAs) are rare pathologies characterized by expansion of the aortic root wall between the sinotubular junction and the aortic valve annulus and are often associated with connective tissue disorders. SVAs are often diagnosed incidentally on imaging but can present with symptoms if they rupture into nearby cardiac structures, such as an aorto-atrial fistula with left to right shunting, high output heart failure and hemodynamic compromise, as in this case. While transthoracic echocardiogram is the diagnostic modality of choice for most SVAs, multimodality imaging, catheterization, and advanced imaging may also be needed. Surgical repair remains the gold standard of therapy, however treatment with transcatheter device placement has also been successfully performed.
Abstract: Atrial fibrillation is the most common arrhythmia in the elderly. It is responsible for significant morbidity and mortality from cardioembolic complications like stroke. As a result, atrial fibrillation patients are risk-stratified using the CHADS 2 or CHA 2 DS 2 -VASc scoring systems. Those at intermediate-to-high risk have traditionally been treated with therapeutic anticoagulation with warfarin for stroke prevention. Although effective, warfarin use is fraught with multiple concerns, such as a narrow therapeutic window, drug–drug and drug–food interactions, and excessive bleeding. Novel oral anticoagulant agents have recently become available as viable alternatives for warfarin therapy. Direct thrombin inhibitor dabigatran and factor Xa inhibitors like rivaroxaban and apixaban have already been approved by the US Food and Drug Administration (FDA) for stroke prevention in patients with nonvalvular atrial fibrillation. Edoxaban is the latest oral direct factor Xa inhibitor studied in the largest novel oral anticoagulant trial so far: ENGAGE AF-TIMI 48. Treatment with a 30 mg or 60 mg daily dose of edoxaban was found to be noninferior to dose-adjusted warfarin in reducing the rate of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, with a lower incidence of bleeding complications and cardiovascular deaths. Edoxaban was recently reviewed by an FDA advisory committee and recommended as a stroke-prophylaxis agent. Once approved, it promises to provide another useful alternative to warfarin therapy. Keywords: atrial fibrillation, stroke prevention, novel oral anticoagulants, factor Xa inhibitors, edoxaban
43-year old female presented to the emergency department with substernal chest pain. She had similar symptoms years ago without obstructive CAD on coronary angiogram and was diagnosed with myocarditis. Presenting ECG revealed new anterolateral T wave inversions (Fig 1), and high-sensitivity troponins peaked at 322 ng/L consistent with NSTEMI. TTE was significant for global hypokinesis of the left ventricle with a reduced ejection fraction of 35 to 40%. Invasive coronary angiogram showed no obstructive CAD or spontaneous coronary artery dissection however there was reduced flow in the mid to distal LAD raising suspicion for endothelial and microvascular dysfunction. Contrast-enhanced cardiac MRI showed myocardial edema in the anterior and anteroseptal walls with elevated myocardial T1 and T2 values, and early enhancement post gadolinium administration showed an acute LAD territorial infarct (Fig 2). Findings were consistent with myocardial infarction with non-obstructive coronary artery disease (MINOCA). She was started on carvedilol for empiric treatment of coronary artery spasm and microvascular dysfunction, along with aspirin and atorvastatin. Losartan was added for heart failure management. Outpatient invasive coronary reactivity testing showed severe epicardial (70% vasoconstriction) and microvascular (80% decrease in coronary blood flow) endothelial dysfunction in response to acetylcholine (Fig 3 and Fig 4) as underlying etiology of recent MINOCA. CFR was normal. L-arginine (NO precursor) was added to the medical regimen. Patient has not had recurrence of chest pain or ACS at 1 year follow-up and LVEF normalized on repeat echocardiogram. This case shows the importance of cardiac MRI in confirming the diagnosis of MINOCA in patients with no obstructive CAD, and the crucial role of coronary reactivity testing in diagnosing and treating severe coronary endothelial dysfunction, which is aligned with the AHA/ACC MINOCA consensus document.
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Fibrosis is a key pathological process in many chronic inflammatory disease states.We hypothesized that tissue inhibitor metalloproteinase-1 and matrix metalloproteinase-9 (TIMP-1 and MMP-9), biomarkers of fibrosis, would predict all-cause mortality and we assessed the incremental value of these biomarkers when adjusting for clinical and other biomarkers.The cohort included 5511 community-dwelling participants in the AGES-Reykjavik Study. The baseline Cox proportional hazards regression model was based on the Framingham Risk Score variables; we added TIMP-1, MMP-9, serum high-sensitivity C-reactive protein (hsCRP), and estimated glomerular filtration rate (eGFR). The primary outcome was all-cause 10-year mortality. Cause of death was categorized as cardiovascular death (CVD), cancer death, and other causes.Participants averaged 76 years and 43% were male. Ten-year mortality was 41% (2263 deaths). Of these, 915 (16.6%) died of cardiovascular disease (CVD), 543 (9.9%) with cancer, and 805 (14.6%) from other causes. For 10-year mortality, age was the strongest predictor (log likelihood χ2 = 798.7, P < 0.0001), followed by TIMP-1 (χ2 = 125.2, P < 0.0001), female gender, current smoker, diabetes mellitus, total cholesterol, eGFR (χ2 16.7, P < 0.0001), body mass index, and hsCRP (χ2 11.3, P = 0.0008) in that order. TIMP-1 and hsCRP had the highest continuous net reclassification improvement over the baseline model for 5-year survival [net reclassification index (NRI) 0.28 and 0.19, respectively, both P < 0.0001] and for 10-year survival (NRI 0.19 and 0.11, respectively, both statistically significant).TIMP-1 is the strongest predictor of all-cause mortality after age. The metabolic pathways regulating extracellular matrix homeostasis and fibrogenic processes appear pathologically relevant and are prognostically important.
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