Inhaled nitric oxide to treat intermediate risk pulmonary embolism: A multicenter randomized controlled trial.

OBJECTIVE: To test the hypothesis that adjunctive inhaled NO would improve RV function and viability in acute PE. METHODS: This was a randomized, placebo-controlled, double blind trial conducted at four academic hospitals. Eligible patients had acute PE without systemic arterial hypotension but had RV dysfunction and a treatment plan of standard anticoagulation. Subjects received either oxygen plus 50 parts per million nitrogen (placebo) or oxygen plus 50 ppm NO for 24 h. The primary composite endpoint required a normal RV on echocardiography and a plasma troponin T concentration <14 pg/mL. The secondary endpoint required a blood brain natriuretic peptide concentration <90 pg/mL and a Borg dyspnea score ≤ 2. The sample size of N = 76 tested if 30% more patients treated with NO would achieve the primary endpoint with 80% power and alpha = 5%. RESULTS: We randomized 78 patients and after two withdrawals, 38 were treated per protocol in each group. Patients were well matched for baseline conditions. At 24 h, 5/38 (13%) of patients treated with placebo and 9/38 (24%) of patients treated with NO reached the primary endpoint (P = 0.375). The secondary endpoint was reached in 34% with placebo and 13% of the NO (P = 0.11). In a pre-planned post-hoc analysis, we examined how many patients with RV hypokinesis or dilation at enrollment resolved these abnormalities; 29% more patients treated with NO resolved both abnormalities at 24 h (P = 0.010, Cochrane's Q test). CONCLUSIONS: In patients with severe submassive PE, inhaled nitric oxide failed to increase the proportion of patients with a normal troponin and echocardiogram but increased the probability of eliminating RV hypokinesis and dilation on echocardiography. CLINICAL TRIAL REGISTRATION: NCT01939301.

Randomized trial of inhaled nitric oxide to treat acute pulmonary embolism: The iNOPE trial.

BACKGROUND: The study hypothesis is that administration of inhaled nitric oxide (NO) plus oxygen to subjects with submassive pulmonary embolism (PE) will improve right ventricular (RV) systolic function and reduce RV strain and necrosis, while improving patient dyspnea, more than treatment with oxygen alone. METHODS: This article describes the rationale and protocol for a registered (NCT01939301), nearly completed phase II, 3-center, randomized, double-blind, controlled trial. Eligible patients have pulmonary imaging-proven acute PE. Subjects must be normotensive, and have RV dysfunction on echocardiography or elevated troponin or brain natriuretic peptide and no fibrinolytics. Subjects receive NO plus oxygen or placebo for 24 hours (±3 hours) with blood sampling before and after treatment, and mandatory echocardiography and high-sensitivity troponin posttreatment to assess the composite primary end point. The sample size of N=78 was predicated on 30% more NO-treated patients having a normal high-sensitivity troponin (<14 pg/mL) and a normal RV on echocardiography at 24 hours with α=.05 and ß=.20. Safety was ensured by continuous spectrophotometric monitoring of percentage of methemoglobinemia and a predefined protocol to respond to emergent changes in condition. Blinding was ensured by identical tanks, software, and physical shielding of the device display and query of the clinical care team to assess blinding efficacy. RESULTS: We have enrolled 78 patients over a 31-month period. No patient has been withdrawn as a result of a safety concern, and no patient has had a serious adverse event related to NO. CONCLUSIONS: We present methods and a protocol for the first double-blinded, randomized trial of inhaled NO to treat PE.

Independent evaluation of a simple clinical prediction rule to identify right ventricular dysfunction in patients with shortness of breath.

BACKGROUND: Many patients have unexplained persistent dyspnea after negative computed tomographic pulmonary angiography (CTPA). We hypothesized that many of these patients have isolated right ventricular (RV) dysfunction from treatable causes. We previously derived a clinical decision rule (CDR) for predicting RV dysfunction consisting of persistent dyspnea and normal CTPA, finding that 53% of CDR-positive patients had isolated RV dysfunction. Our goal is to validate this previously derived CDR by measuring the prevalence of RV dysfunction and outcomes in dyspneic emergency department patients. METHODS: A secondary analysis of a prospective observational multicenter study that enrolled patients presenting with suspected PE was performed. We included patients with persistent dyspnea, a nonsignificant CTPA, and formal echo performed. Right ventricular dysfunction was defined as RV hypokinesis and/or dilation with or without moderate to severe tricuspid regurgitation. RESULTS: A total of 7940 patients were enrolled. Two thousand six hundred sixteen patients were analyzed after excluding patients without persistent dyspnea and those with a significant finding on CTPA. One hundred ninety eight patients had echocardiography performed as standard care. Of those, 19% (95% confidence interval [CI], 14%-25%) and 33% (95% CI, 25%-42%) exhibited RV dysfunction and isolated RV dysfunction, respectively. Patients with isolated RV dysfunction or overload were more likely than those without RV dysfunction to have a return visit to the emergency department within 45 days for the same complaint (39% vs 18%; 95% CI of the difference, 4%-38%). CONCLUSION: This simple clinical prediction rule predicted a 33% prevalence of isolated RV dysfunction or overload. Patients with isolated RV dysfunction had higher recidivism rates and a trend toward worse outcomes.

Frequency, time course, and possible causes of right ventricular systolic dysfunction after cardiac transplantation: a single center experience.

BACKGROUND: The frequency and causes of right ventricular (RV) systolic dysfunction early after cardiac transplantation are not well defined. METHODS: We investigated the prevalence and causes of RV dysfunction in 27 heart transplant recipients, as measured by lateral tricuspid annular plane excursion (TAPSE) and fractional area change (FAC) at a mean of 15 ± 11 days after transplant. Tissue Doppler imaging was used to assess systolic time velocity integral (TVI) of the RV basal free wall. A subset of 22 patients had follow-up TAPSE measurement at 406 ± 121 days. RESULTS: RV systolic dysfunction, defined as TAPSE > 2 standard deviation (SD) below values in a control group, was present in 100% (27/27) of patients (P < 0.05). FAC was also significantly lower in patients compared with controls (P < 0.0001). TVI confirmed the presence of RV dysfunction in all 16 patients with both TAPSE and TVI (P < 0.05). Ischemic time (P = 0.017) and posttransplant tricuspid regurgitation (P = 0.024) were independent predictors of early RV dysfunction (r = 0.753). On follow-up, RV function improved in 15 of 22 patients but all patients remained with TAPSE > 2 SD below controls. CONCLUSION: This study showed that 100% of patients had reduced RV function early after transplant. Two thirds of patients had partial recovery of RV function during the first year. In all patients, however, RV function remained significantly lower than in controls.

A practical approach to using strain echocardiography to evaluate the left ventricle.

Left ventricular (LV) evaluation is the most important use of echocardiography. Speckle tracking strain echocardiography (SE) provides a quantitative regional and global LV assessment, is an independent supplement to wall motion analysis and has been validated over the past 10 years. Despite these facts, SE is not being used routinely, especially in the United States. SE can generate longitudinal, radial, and circumferential strain measurements and LV twist. Although intriguing and potentially useful, these measurements also are confusing, complicated, time consuming, and frequently displayed as difficult-to-interpret wave forms. A pragmatic approach to SE simplifies the suggested method for strain calculation to reduce the time required and enhance reproducibility. With this modification the strain calculations take only 2-4 min. The yield is >80% in all patients. Reproducibility is at least as good as ejection fraction. Longitudinal strain is the most sensitive and reproducible of the various strain measurements, so it is the only strain we record. For simplicity, systolic strain is displayed as a positive number. Lastly, we primarily use a bullseye presentation for peak systolic strain. Many clinical examples are illustrated. However, as with all tests, SE is not perfect; there are limitations and potential false positives, but a practical approach to SE eventually should help make it a part of all echocardiographic examinations.

Recurrent Parotid Adenocarcinoma Presenting as Diffuse Myocardial Metastatic Disease.

A 64-year-old man who had undergone treatment for left parotid adenocarcinoma presented with progressive exertional shortness of breath. Evaluation revealed metastatic invasion of the myocardium as a rare presentation of recurrent parotid adenocarcinoma. This case highlights the importance of using multimodal imaging methods in diagnostic evaluation and a collaborative multidisciplinary approach in managing patient care.

Common genetic polymorphisms of adenosine A2A receptor do not influence response to regadenoson.

AIM: Hemodynamic response to regadenoson varies greatly, and underlying mechanisms for variability are poorly understood. We hypothesized that five common variants of adenosine A2A receptor (ADORA2A) are associated with altered response to regadenoson. METHODS: Consecutive subjects (n = 357) undergoing resting regadenoson nuclear stress imaging were enrolled. Genotyping was performed using Taqman-based assays for rs5751862, rs2298383, rs3761422, rs2267076 and rs5751876. RESULTS: There was no significant difference in heart rate or blood pressure between different genotypes following regadenoson administration. There was also no significant difference in myocardial ischemia detected by nuclear perfusion imaging as defined by summed difference score, or in self-reported side effects among the genotypes tested. CONCLUSION: The common A2A variants studied are not associated with variability in hemodynamic response to regadenoson or variability in detection of ischemia with nuclear perfusion stress imaging.

Genome-Wide Association Study for Anthracycline-Induced Congestive Heart Failure.

PURPOSE: Anthracycline-induced congestive heart failure (CHF) is a rare but serious toxicity associated with this commonly employed anticancer therapy. The ability to predict which patients might be at increased risk prior to exposure would be valuable to optimally counsel risk-to-benefit ratio for each patient. Herein, we present a genome-wide approach for biomarker discovery with two validation cohorts to predict CHF from adult patients planning to receive anthracycline. EXPERIMENTAL DESIGN: We performed a genome-wide association study in 3,431 patients from the randomized phase III adjuvant breast cancer trial E5103 to identify single nucleotide polymorphism (SNP) genotypes associated with an increased risk of anthracycline-induced CHF. We further attempted candidate validation in two independent phase III adjuvant trials, E1199 and BEATRICE. RESULTS: When evaluating for cardiologist-adjudicated CHF, 11 SNPs had a P value <10-5, of which nine independent chromosomal regions were associated with increased risk. Validation of the top two SNPs in E1199 revealed one SNP rs28714259 that demonstrated a borderline increased CHF risk (P = 0.04, OR = 1.9). rs28714259 was subsequently tested in BEATRICE and was significantly associated with a decreased left ventricular ejection fraction (P = 0.018, OR = 4.2). CONCLUSIONS: rs28714259 represents a validated SNP that is associated with anthracycline-induced CHF in three independent, phase III adjuvant breast cancer clinical trials. Clin Cancer Res; 23(1); 43-51. ©2016 AACR.

Effect of Body Mass Index on Left Ventricular Mass in Career Male Firefighters.

Left ventricular (LV) mass is a strong predictor of cardiovascular disease (CVD) events; increased LV mass is common among US firefighters and plays a major role in firefighter sudden cardiac death. We aim to identify significant predictors of LV mass among firefighters. Cross-sectional study of 400 career male firefighters selected by an enriched randomization strategy. Weighted analyses were performed based on the total number of risk factors per subject with inverse probability weighting. LV mass was assessed by echocardiography (ECHO) and cardiac magnetic resonance, and normalized (indexed) for height. CVD risk parameters included vital signs at rest, body mass index (BMI)-defined obesity, obstructive sleep apnea risk, low cardiorespiratory fitness, and physical activity. Linear regression models were performed. In multivariate analyses, BMI was the only consistent significant independent predictor of LV mass indexes (all, p <0.001). A 1-unit decrease in BMI was associated with 1-unit (g/m1.7) reduction of LV mass/height1.7 after adjustment for age, obstructive sleep apnea risk, and cardiorespiratory fitness. In conclusion, after height-indexing ECHO-measured and cardiac magnetic resonance-measured LV mass, BMI was found to be a major driver of LV mass among firefighters. Our findings taken together with previous research suggest that reducing obesity will improve CVD risk profiles and decrease on-duty CVD and sudden cardiac death events in the fire service. Our results may also support targeted noninvasive screening for LV hypertrophy with ECHO among obese firefighters.

Caffeine Consumption and Heart Rate and Blood Pressure Response to Regadenoson.

BACKGROUND: Current guidelines recommend that caffeinated products should be avoided for at least 12 hours prior to regadenoson administration. We intended to examine the effect of caffeine consumption and of timing of last dose on hemodynamic effects after regadenoson administration for cardiac stress testing. METHODS: 332 subjects undergoing regadenoson stress testing were enrolled. Baseline characteristics, habits of coffee/caffeine exposure, baseline vital signs and change in heart rate, blood pressure, percent of maximal predicted heart rate, and percent change in heart rate were prospectively collected. RESULTS: Non-coffee drinkers (group 1) (73 subjects) and subjects who last drank coffee >24 hours (group 3) (139 subjects) prior to regadenoson did not demonstrate any difference in systolic blood pressure, heart rate change, maximal predicted heart rate and percent change in heart rate. Systolic blood pressure change (15.2±17.1 vs. 7.2±10.2 mmHg, p = 0.001), heart rate change (32.2±14 vs. 27.3±9.6 bpm, p = 0.038) and maximal predicted heart rate (65.5±15.6 vs. 60.7±8.6%, p = 0.038) were significantly higher in non-coffee drinkers (group 1) compared to those who drank coffee 12-24 hours prior (group 2) (108 subjects). Subjects who drank coffee >24 hours prior (group 3) exhibited higher systolic blood pressure change (13±15.8 vs. 7±10.2, p = 0.007), and heart rate change (32.1±15.3 vs. 27.3±9.6, p = 0.017) as compared to those who drank coffee 12-24 hours prior to testing (group 2). CONCLUSIONS: Caffeine exposure 12-24 hours prior to regadenoson administration attenuates the vasoactive effects of regadenoson, as evidenced by a blunted rise in heart rate and systolic blood pressure. These results suggest that caffeine exposure within 24 hours may reduce the effects of regadenoson administered for vasodilatory cardiac stress testing.

Derivation of a screening tool to identify patients with right ventricular dysfunction or tricuspid regurgitation after negative computerized tomographic pulmonary angiography of the chest.

Many dyspneic patients who undergo computerized tomographic pulmonary angiography (CTPA) for presumed acute pulmonary embolism (PE) have no identified cause for their dyspnea yet have persistent symptoms, leading to more CTPA scanning. Right ventricular (RV) dysfunction or overload can signal treatable causes of dyspnea. We report the rate of isolated RV dysfunction or overload after negative CTPA and derive a clinical decision rule (CDR). We performed secondary analysis of a multicenter study of diagnostic accuracy for PE. Inclusion required persistent dyspnea and no PE. Echocardiography was ordered at clinician discretion. A characterization of isolated RV dysfunction or overload required normal left ventricular function and RV hypokinesis, or estimated RV systolic pressure of at least 40 mmHg. The CDR was derived from bivariate analysis of 97 candidate variables, followed by multivariate logistic regression. Of 647 patients, 431 had no PE and persistent dyspnea, and 184 (43%) of these 431 had echocardiography ordered. Of these, 64 patients (35% [95% confidence interval (CI): 28%-42%]) had isolated RV dysfunction or overload, and these patients were significantly more likely to have a repeat CTPA within 90 days (P = .02, [Formula: see text] test). From univariate analysis, 4 variables predicted isolated RV dysfunction: complete right bundle branch block, normal CTPA scan, active malignancy, and CTPA with infiltrate, the last negatively. Logistic regression found only normal CTPA scanning significant. The final rule (persistent dyspnea + normal CTPA scan) had a positive predictive value of 53% (95% CI: 37%-69%). We conclude that a simple CDR consisting of persistent dyspnea plus a normal CTPA scan predicts a high probability of isolated RV dysfunction or overload on echocardiography.

AMPD1 polymorphism and response to regadenoson.

AIMS:  AMPD1 c.34C > T (rs17602729) polymorphism results in AMPD1 deficiency. We examined the association of AMPD1 deficiency and variability of hemodynamic response to regadenoson. SUBJECTS & METHODS: Genotyping for c.34C>T was performed in 267 patients undergoing regadenoson cardiac stress testing. RESULTS: Carriers of c.34C >T variant exhibited higher relative changes in systolic blood pressure (SBP) compared with wild-type subjects ([%] SBP change to peak: 12 ± 25 vs 5 ± 13%; p = 0.01) ([%] SBP change to nadir: -3 ± 15 vs -7 ± 11%; p = 0.04). Change in heart rate was similar between groups, but side effects were more common in carriers of the variant (+LR = 4.2; p = 0.04). CONCLUSION: AMPD1 deficiency may be involved in the modulation of regadenoson's systemic effects.

Prevalence and Prognostic Value of Right Ventricular Systolic Dysfunction in Patients With Constrictive Pericarditis Who Underwent Pericardiectomy.

Impaired right ventricular systolic function (RVSF) may complicate the treatment of constrictive pericarditis (CP) by pericardiectomy, which is a procedure that remains with significant morbidity and mortality. We evaluated RVSF in patients with CP who underwent pericardiectomy to determine the prognostic value of RVSF. RVSF was assessed by measuring Tricuspid Annular Plane Systolic Excursion (TAPSE) in 35 patients (mean age 52 ± 15.4 years) who underwent pericardiectomy. Thirty-one patients (88.6%) had reduced RVSF (TAPSE ≤1.8 cm). Eight patients (23%) had postoperative events (heart failure 3 and hospital mortality 5). Logistic regression showed that concomitant coronary artery bypass grafting (CABG) (p = 0.052), left ventricular ejection fraction (p = 0.059), left atrial diameter (p = 0.028), and TAPSE (p = 0.016) were borderline or significant univariate predictors of events. TAPSE (p = 0.018, odds ratio = 0.605 [0.40 to 0.92]) and CABG (p = 0.033, odds ratio = 20 [1.26 to 315]) were independent predictors of events on multivariate analysis. Stepwise analysis showed that TAPSE provided incremental prognostic value (p = 0.029, chi-square increase 11.6 to 16.3) to the combination of CABG, ejection fraction, and left atrial diameter. Receiver-operating characteristic curve analysis showed an area under the curve of 0.815 for TAPSE. TAPSE of 1.38 cm had a sensitivity of 88% and specificity of 67% for identifying patients with events. TAPSE was also inversely related to the length of hospital stay after pericardiectomy (p = 0.02, R = -0.424). Hence, our study showed that RVSF is frequently reduced in patients with CP who underwent pericardiectomy. In conclusion, TAPSE is an independent predictor of events and provides incremental prognostic value to other clinical and echocardiographic variables.

Noninvasive imaging techniques of constrictive pericarditis.

Constrictive pericarditis (CP) is the result of scarring and loss of elasticity of the pericardial sac, resulting in external impedance of cardiac filling. It can occur after virtually any pericardial disease process. Patients typically present with signs and symptoms of right heart failure and/or low cardiac output. An important pathophysiological hallmark of CP is exaggerated ventricular interdependence and impaired diastolic filling. Echocardiography is the initial imaging modality for diagnosis of CP. Unfortunately, no echocardiographic sign or combination of signs is pathognomonic for CP. CT scan and cardiac MRI are other imaging techniques that can provide incremental diagnostic information. CT scan can easily detect pericardial thickening and calcification, while cardiac MRI provides a comprehensive evaluation of the pericardium, myocardium and cardiac physiology. Occasionally, a multimodality approach needs to be considered for the conclusive diagnosis of CP.

Current noninvasive imaging techniques for detection of coronary artery disease.

The development and widespread use of noninvasive imaging techniques have contributed to the improvement in evaluation of patients with known or suspected coronary artery disease. Stress echocardiography and single-photon computed tomography are well-established noninvasive techniques with a proven track record for the diagnosis of coronary atherosclerosis. These modalities are generally widely available and provide a relatively high sensitivity and specificity along with an incremental value over clinical risk factors for detection of coronary artery disease. PET has a high diagnostic performance but continues to have limited clinical use because of the high expense of the dedicated equipment and difficulties in obtaining adequate radionuclides. Cardiac MRI and multislice computed tomography constitute the most recent addition to the cardiac imaging armamentarium. Cardiac MRI offers a comprehensive cardiac evaluation, which includes wall-motion analysis, myocardial tissue morphology, rest and stress first-pass myocardial perfusion, as well as ventricular systolic function. Cardiac computed tomography allows coronary calcium scanning along with noninvasive anatomic assessment of the coronary tree. It can be combined with functional imaging to provide a complete evaluation of the presence and physiological significance of the atherosclerotic coronary disease. No single imaging modality has been proven to be superior overall. Available tests all have advantages and drawbacks, and none can be considered suitable for all patients. The choice of the imaging method should be tailored to each person based on the clinical judgment of the a priori risk of cardiac event, clinical history and local expertise.

Prediction of ischemic events by anatomic M-mode strain rate stress echocardiography.

OBJECTIVE: We assessed the prognostic value of anatomic M-mode strain rate stress echocardiography (SRSE) in patients with known or suspected coronary artery disease. Previous studies showing that M-mode SRSE may be an accurate method for detection of coronary artery disease suggest that this technique may be useful for risk stratification. METHODS: M-mode SRSE, using a color-coded display of strain rate (SR), was performed in 358 patients (48, dobutamine; 68, bicycle; 242, treadmill). SR was graded by visual assessment of the color-coded display in 12 apical segments. Abnormal rest SR was defined as SR more positive than -1/s (green-yellow). Ischemia was defined by the development of post-systolic shortening or lack of improvement of SR to more negative than -2/s (brown hue) with stress. Patients were followed for cardiac events. RESULTS: Twelve patients with early intervention for an abnormal two-dimensional stress echocardiogram or stress electrocardiogram were excluded. Follow-up (mean 10.7 months) was completed in 98% (338/346) of the remaining patients. Events occurred in 1.7% (4/230) of patients with normal SRSE compared with 10% (11/108) with abnormal SRSE (P = .002). The annualized hard event (infarction, death) rate in those with normal SRSE was 0.5% versus 7.2% in those with abnormal SRSE (P = .001). Smoking (P = .048, relative risk 2.91), nitrate use (P = .001, relative risk 7.81), and the severity of the abnormality on SRSE (P = .009, relative risk 1.75) independently predicted events. Wall motion assessment was not predictive. Patients with normal SRSE had better event-free survival compared with those with abnormal SRSE (P < .001). CONCLUSION: SRSE is an independent predictor of outcome. A normal SRSE predicts a low risk of infarction or death in short-term follow-up.