Impact of Baseline Heart Failure on Acute Pulmonary Embolism Risk Stratification and Clinical Outcomes.

Among patients with acute pulmonary embolism (PE), abnormal cardiac biomarkers and elevated right ventricular to left ventricular (RV/LV) diameter ratio are associated with increased morbidity and mortality. However, subjects with baseline heart failure (HF) have abnormalities in cardiac chamber dimensions and biomarkers. We sought to describe risk stratification variables in a cohort with acute PE and categorized HF status as no HF, HF with reduced ejection fraction (HFrEF), or HF with preserved ejection fraction (HFpEF). In total, 182 subjects were identified for this study, of whom 142 were categorized as having no HF, 16 as having HFrEF, and 24 as having HFpEF. The median age was 65 years [interquartile range 51 to 75 years], and 43% were male. Subjects with HFrEF had significantly greater LV diameters and significantly lower RV/LV diameter ratio (no HF 0.94, HFrEF 0.65, HFpEF 0.89, p = 0.002). Subjects with HFrEF also had significantly higher B-type natriuretic peptide levels (no HF 112 pg/mL, HFrEF 835 pg/mL, HFpEF 241 pg/mL, p <0.001) and higher 90-day mortality rates. Among subjects with acute PE, those with baseline HFrEF had significantly greater LV diameter and lower RV/LV diameter ratio than those of patients with HFpEF or no HF. In addition, subjects with HFrEF had significantly higher B-type natriuretic peptide levels and worse survival at 90 days. In conclusion, these results indicate that PE risk stratification using current guidelines, especially reliance on RV/LV ratio, is inaccurate among subjects with baseline HFrEF.

Predictors of reduced cardiac index in patients with acute submassive pulmonary embolism.

OBJECTIVES: Determine the baseline clinical, laboratory, and echocardiographic values that predict reduced cardiac index (CI) among subjects with acute submassive pulmonary embolism (PE). BACKGROUND: Submassive PE represents a large portion of acute PE population and there is controversy regarding optimal treatment strategies for these patients. There is significant heterogeneity within the submassive PE population and further refinement of risk stratification may aid clinical decision-making. METHODS: We identified subjects with normotensive acute PE who underwent echocardiogram and right heart catheterization (RHC) prior to catheter-directed thrombolysis (CDT). We sought to determine the predictors of reduced CI, defined as CI < 2.2 L min-1 m-2 . RESULTS: Thirty-two subjects met the inclusion criteria and 41% had reduced CI. Baseline variables did not distinguish subjects with reduced versus normal CI. Brain natriuretic peptide (BNP) was significantly different between the reduced versus normal CI groups (BNP 440 vs. 160 pg/ml, p = .004, respectively). Univariate logistic regression identified BNP, right ventricular (RV):left ventricular (LV) diameter ratio, tricuspid annular plane systolic excursion (TAPSE), and right ventricular systolic pressure as predictors of reduced CI. In a multivariate logistic regression model, only TAPSE was an independent predictor of reduced CI. ROC curve analysis identified the following optimal cut points for prediction of reduced CI: BNP > 216 pg/ml, RV:LV ratio > 1.41, or TAPSE <1.6 cm. CONCLUSIONS: Almost half of subjects with acute submassive PE have reduced CI, despite normal systemic blood pressure. Optimal cut points for BNP, RV:LV ratio, and TAPSE were identified to predict reduced CI among patients with acute PE. These findings may aid in clinical decision-making and risk stratification of patients with acute submassive PE.

Prognostic Value of Computed Tomography Versus Echocardiography Derived Right to Left Ventricular Diameter Ratio in Acute Pulmonary Embolism.

BACKGROUND: Computed Tomography (CT) Pulmonary Angiography is the most commonly used diagnostic study for acute pulmonary embolism (PE). Echocardiogram (ECHO) is also used for risk stratification in acute PE, however the diagnostic performance of CT versus ECHO for risk stratification remains unclear. METHODS: CT and ECHO right ventricle (RV) and left ventricle (LV) diameters were measured in a retrospective cohort of patients with acute PE. RV:LV diameter ratios were calculated and correlation between CT and ECHO RV:LV ratio was assessed. Sensitivity and specificity for the composite adverse events endpoint of mortality, respiratory failure requiring intubation, cardiac arrest, or shock requiring vasopressors within 30 days of admission were assessed for CT or ECHO derived RV:LV ratio alone and in combination with biomarkers (troponin or B-type natriuretic peptide). RESULTS: A total of 74 subjects met the inclusion criteria and had a mean age of 62±18 years. The proportion of patients with RV:LV >1 was similar when comparing CT (37.8%) versus ECHO (33.8%) (P = 0.61). A statistically significant correlation was found between CT derived and ECHO derived RV:LV diameter ratio (r = 0.832, P < 0.001). The sensitivity and specificity to predict 30-day composite adverse events for CT versus ECHO derived RV:LV diameter ratio >1 together with positive biomarker status was similar with sensitivity and specificity of 87% and 41% versus 87% and 42%, respectively. CONCLUSIONS: In patients with acute PE, CT and ECHO RV:LV diameter ratio correlate well and identify similar proportion of PE patients at risk for early adverse events. These findings may streamline risk stratification of patients with acute PE.

Early Rapid Decline in Kidney Function in Medically Managed Patients With Atherosclerotic Renal Artery Stenosis.

Background Early rapid declines of kidney function may occur in patients with atherosclerotic renal artery stenosis with institution of medical therapy. The causes and consequences are not well understood. Methods and Results Patients enrolled in the medical therapy-only arm of the CORAL (Cardiovascular Outcomes With Renal Artery Lesions) study were assessed for a rapid decline (RD) in estimated glomerular filtration rate (eGFR), defined as a ≥30% decrease from baseline to either 3 months, 6 months, or both. In the medical therapy-only cohort, eGFR was available in 359 subjects at all time points, the subjects were followed for a median of 4.72 years, and 66 of 359 (18%) subjects experienced an early RD. Baseline log cystatin C (odds ratio, 1.78 [1.11-2.85]; P=0.02), age (odds ratio, 1.04 [1.00-1.07]; P<0.05), and Chronic Kidney Disease Epidemiology Collaboration creatinine eGFR (odds ratio, 1.86 [1.15-3.0]; P=0.01) were associated with an early RD. Despite continued medical therapy only, the RD group had an improvement in eGFR at 1 year (6.9%; P=0.04). The RD and nondecline groups were not significantly different for clinical events and all-cause mortality (P=0.78 and P=0.76, respectively). Similarly, renal replacement therapy occurred in 1 of 66 (1.5%) of the RD patients and in 6 of 294 (2%) of the nondecline patients. The regression to the mean of improvement in eGFR at 1 year in the RD group was estimated at 5.8±7.1%. Conclusions Early rapid declines in kidney function may occur in patients with renal artery stenosis when medical therapy is initiated, and their clinical outcomes are comparable to those without such a decline, when medical therapy only is continued.

Circulating Lactonase Activity but Not Protein Level of PON-1 Predicts Adverse Outcomes in Subjects with Chronic Kidney Disease.

The burden of cardiovascular disease and death in chronic kidney disease (CKD) outpaces that of the other diseases and is not adequately described by traditional risk factors alone. Diminished activity of paraoxonase (PON)-1 is associated with increased oxidant stress, a common feature underlying the pathogenesis of CKD. We aimed to assess the prognostic value of circulating PON-1 protein and PON lactonase activity on adverse clinical outcomes across various stages and etiologies of CKD. Circulating PON-1 protein levels and PON lactonase activity were measured simultaneously in patients with CKD as well as a cohort of apparently healthy non-CKD subjects. Both circulating PON-1 protein levels and PON lactonase activity were significantly lower in CKD patients compared to the non-CKD subjects. Similarly, across all stages of CKD, circulating PON-1 protein and PON lactonase activity were significantly lower in patients with CKD compared to the non-CKD controls. Circulating PON lactonase activity, but not protein levels, predicted future adverse clinical outcomes, even after adjustment for traditional risk factors. The combination of lower circulating protein levels and higher activity within the CKD subjects were associated with the best survival outcomes. These findings demonstrate that diminished circulating PON lactonase activity, but not protein levels, predicts higher risk of future adverse clinical outcomes in patients with CKD.

MicroRNA profiling in kidney disease: Plasma versus plasma-derived exosomes.

Liquid biopsies have advanced rapidly in recent years for use in diagnostic and prognostic applications. One important aspect of this advancement is the growth in our understanding of microRNA (miRNA) biology. The measurement of miRNAs packaged within exosomes, which are constantly released into the blood stream, may reflect pathological changes within the body. The current study performed miRNA profiling using plasma and plasma-derived exosome samples from two animal models of kidney disease, the 5/6th partial nephrectomy (PNx) and two-kidney-one-clip (2K1C) models. The RT-qPCR-based profiling results revealed that the overall miRNA expression level was much higher in plasma than in plasma-derived exosomes. With 200µl of either plasma or exosomes derived from the same volume of plasma, 629 out of 665 total miRNAs analyzed were detectable in plasma samples from sham-operated rats, while only 403 were detectable in exosomes with a cutoff value set at 35cycles. Moreover, the average miRNA expression level in plasma was about 16-fold higher than that in exosomes. We also found a select subset of miRNAs that were enriched within exosomes. The number of detectable miRNAs from plasma-derived exosomes was increased in rats subjected to PNx or 2K1C surgery compared to sham-operated animals. Importantly, we found that the changes of individual miRNAs measured in plasma had very poor concordance with that measured in plasma-derived exosomes in both animal models, suggesting that miRNAs in plasma and plasma-derived exosomes are differentially regulated in these disease conditions. Interestingly, PNx and 2K1C surgeries induced similar changes in miRNA expression, implying that common pathways were activated in these two disease models. Pathway analyses using DIANA-miRPath v3.0 showed that significantly changed exosomal miRNAs were associated with extracellular matrix (ECM) receptor interaction and mucin type-O-glycan synthesis pathways, which are related with tissue fibrosis and kidney injury, respectively. In conclusion, our results demonstrated that due to the differential changes in miRNAs, the measurement of exosomal miRNAs cannot be replaced by the measurement of miRNAs in plasma, or vice versa. We also showed that a set of miRNAs related with kidney injury and organ fibrosis were dysregulated in plasma-derived exosomes from animal models of kidney disease.

Cigarette smoking and cardio-renal events in patients with atherosclerotic renal artery stenosis.

Cigarette smoking causes cardiovascular disease and is associated with poor kidney function in individuals with diabetes mellitus and primary kidney diseases. However, the association of smoking on patients with atherosclerotic renal artery stenosis has not been studied. The current study utilized data from the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL, NCT00081731) clinical trial to evaluate the effects of smoking on the risk of cardio-renal events and kidney function in this population. Baseline data showed that smokers (n = 277 out of 931) were significantly younger at enrollment than non-smokers (63.3±9.1 years vs 72.4±7.8 years; p<0.001). In addition, patients who smoke were also more likely to have bilateral renal artery stenoses and peripheral vascular disease (PVD). Longitudinal analysis showed that smokers experienced composite endpoint events (defined as first occurrence of: stroke; cardiovascular or renal death; myocardial infarction; hospitalization for congestive heart failure; permanent renal replacement; and progressive renal insufficiency defined as 30% reduction of GFR from baseline sustained for ≥ 60 days) at a substantially younger age compared to non-smokers (67.1±9.0 versus 76.1±7.9, p<0.001). Using linear regression and generalized linear modeling analysis controlled by age, sex, and ethnicity, smokers had significantly higher cystatin C levels (1.3±0.7 vs 1.2±0.9, p<0.01) whereas creatinine and estimated glomerular filtration rate (eGFR) were not different from non-smokers. From these data we conclude that smoking has a significant association with deleterious cardio-renal outcomes in patients with renovascular hypertension.

An alternative empirical likelihood method in missing response problems and causal inference.

Missing responses are common problems in medical, social, and economic studies. When responses are missing at random, a complete case data analysis may result in biases. A popular debias method is inverse probability weighting proposed by Horvitz and Thompson. To improve efficiency, Robins et al. proposed an augmented inverse probability weighting method. The augmented inverse probability weighting estimator has a double-robustness property and achieves the semiparametric efficiency lower bound when the regression model and propensity score model are both correctly specified. In this paper, we introduce an empirical likelihood-based estimator as an alternative to Qin and Zhang (2007). Our proposed estimator is also doubly robust and locally efficient. Simulation results show that the proposed estimator has better performance when the propensity score is correctly modeled. Moreover, the proposed method can be applied in the estimation of average treatment effect in observational causal inferences. Finally, we apply our method to an observational study of smoking, using data from the Cardiovascular Outcomes in Renal Atherosclerotic Lesions clinical trial. Copyright © 2016 John Wiley & Sons, Ltd.

Regional and physician specialty-associated variations in the medical management of atherosclerotic renal-artery stenosis.

For people enrolled in Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL), we sought to examine whether variation exists in the baseline medical therapy of different geographic regions and if any variations in prescribing patterns were associated with physician specialty. Patients were grouped by location within the United States (US) and outside the US (OUS), which includes Canada, South America, Europe, South Africa, New Zealand, and Australia. When comparing US to OUS, participants in the US took fewer anti-hypertensive medications (1.9 ± 1.5 vs. 2.4 ± 1.4; P < .001) and were less likely to be treated with an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (46% vs. 62%; P < .001), calcium channel antagonist (37% vs. 58%; P < .001), and statin (64% vs. 75%; P < .05). In CORAL, the identification of variations in baseline medical therapy suggests that substantial opportunities exist to improve the medical management of patients with atherosclerotic renal-artery stenosis.

Use of renin-angiotensin inhibitors in people with renal artery stenosis.

BACKGROUND AND OBJECTIVES: People with atherosclerotic renal artery stenosis may benefit from renin-angiotensin inhibitors, angiotensin-converting enzyme inhibitors, and angiotensin-receptor blockers, but little is known about the factors associated with their use. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Cardiovascular Outcomes in Renal Atherosclerotic Lesions study (ClinicalTrials.gov identified: NCT00081731) is a prospective, international, multicenter clinical trial that randomly assigned participants with atherosclerotic renal artery stenosis who received optimal medical therapy to stenting versus no stenting from May 2005 through January 2010. At baseline, medication information was available from 853 of 931 randomly assigned participants. Kidney function was measured by serum creatinine-based eGFR at a core laboratory. RESULTS: Before randomization, renin-angiotensin inhibitors were used in 419 (49%) of the 853 participants. Renin-angiotensin inhibitor use was lower in those with CKD (eGFR<60 ml/min per 1.73 m(2)) (58% versus 68%; P=0.004) and higher in individuals with diabetes (41% versus 27%; P<0.001). Presence of bilateral renal artery stenosis or congestive heart failure was not associated with renin-angiotensin inhibitor use. Although therapy with renin-angiotensin inhibitors varied by study site, differences in rates of use were not related to the characteristics of the site participants. Participants receiving a renin-angiotensin inhibitor had lower systolic BP (mean ± SD, 148 ± 23 versus 152 ± 23 mmHg; P=0.003) and more often had BP at goal (30% versus 22%; P=0.01). CONCLUSIONS: Kidney function and diabetes were associated with renin-angiotensin inhibitor use. However, these or other clinical characteristics did not explain variability among study sites. Patients with renal artery stenosis who received renin-angiotensin inhibitor treatment had lower BP and were more likely to be at treatment goal.

Randomized comparison of rapid ambulation using radial, 4 French femoral access, or femoral access with AngioSeal closure.

Radial access and closure devices are associated with improved quality of life (QOL) after cardiac catheterization. Whether this is related to the access site or time to ambulation is unknown. Seventy-five patients undergoing cardiac catheterization were randomized to femoral 6 Fr with AngioSeal closure (F+C), femoral 4 Fr without closure, and radial (R) access. All patients were ambulated at 1 hr. QOL was measured utilizing visual analogue scales and Short Form-36 at baseline, 1 day, and 1 week. Time to ambulation and discharge were equivalent, as was postprocedure QOL. However, angiographic quality was lower in the 4 Fr group (P < 0.0001) and catheterization costs were higher in the F+C group (P < 0.0001). Ambulation 1 hr after catheterization can be accomplished utilizing radial, femoral 6 Fr with closure device, or femoral 4 Fr access with equivalent outcomes and QOL. However, this is achieved at a higher cost with a closure device, or lesser angiographic quality with 4 Fr catheters.

Renal insufficiency as a predictor of adverse events and mortality after renal artery stent placement.

BACKGROUND: Renal artery stenosis (RAS) is associated with substantial morbidity and mortality. This relationship is strongest in the presence of renal insufficiency (RI). The goal of this study is to assess the relationship between RI, mortality, and adverse events in the setting of renovascular disease. METHODS: Two hundred sixty-one patients with significant RAS treated with endovascular stenting were followed up prospectively for 21 +/- 18 months (range, 0 to 85 months). Blood pressure (BP), renal function, medication use, and comorbidities were assessed. Death was verified through the Social Security Death Master Index File, and cause of death was derived from death certificates. Medical records of 230 subjects subsequently were reviewed to identify adverse cardiovascular and renal events. RESULTS: Overall, 37% of patients experienced at least 1 adverse event postprocedure. Myocardial infarction (MI) and congestive heart failure (CHF) events increased with degree of baseline RI. Seventy-three deaths (28%) occurred postprocedure (range, 13 to 2,457 days). Baseline characteristics associated with mortality included advanced age, decreased use of beta-blockers, increased use of diuretics, increased serum creatinine (Cr) level, decreased Cr clearance (CrCl), bilateral stenoses or stenosis of a solitary kidney, history of CHF, and history of MI. Follow-up characteristics associated with mortality included lower systolic and diastolic BP, increased serum Cr level, and decreased CrCl. RI at baseline and follow-up remained associated with mortality after adjusting for other clinically and statistically significant variables. Patients in whom renal function improved after stenting appeared to show improved survival over those without improved renal function (45% versus 0% cumulative survival, P < 0.05). CONCLUSION: In patients with RAS undergoing stent therapy, baseline RI is associated with an increased incidence of adverse events, as well as decreased survival, independent of other baseline clinical factors. Importantly, improvement in renal function appears to be associated with increased survival.