Impact of Paravalvular Leak on Outcomes After Transcatheter Aortic Valve Implantation: Meta-Analysis of Kaplan-Meier-derived Individual Patient Data.

Background: Paravalvular leak (PVL) after transcatheter aortic valve implantation (TAVI) is frequent and the impact of mild PVL on outcomes remains uncertain. Our study aimed to evaluate the impact of PVL on TAVI outcomes. Methods: To analyze late outcomes of patients after TAVI according to the presence and severity of PVL, PubMed/MEDLINE, EMBASE and Google Scholar were searched for studies that reported rates of all-cause mortality/survival and/or rehospitalization and/or cardiovascular mortality accompanied by at least one Kaplan-Meier curve for any of these outcomes. We adopted a 2-stage approach to reconstruct individual patient data based on the published Kaplan-Meier graphs. Results: Thirty-eight studies with Kaplan-Meier curves met our eligibility criteria including over 25,000 patients. Patients with any degree of PVL after TAVI had a significantly higher risk of overall mortality (hazard ratio (HR), 1.52; 95% confidence interval (CI), 1.43-1.61; p < 0.001), rehospitalization (HR, 1.81; 95% CI, 1.54-2.12; p < 0.001), and cardiovascular mortality (HR, 1.52; 95% CI, 1.33-1.75; p < 0.001) over time. These findings remained consistent when we stratified the results for the methods of assessment of PVL (i.e., echocardiography vs. angiography) and PVL severity. Both moderate/severe PVL and mild PVL were associated with increased risk of overall mortality (p < 0.001), rehospitalization (p < 0.001), and cardiovascular mortality (p < 0.001) during follow-up. Conclusions: Patients with PVL, even if mild, experience higher risk of all-cause mortality, rehospitalization, and cardiovascular mortality following TAVI. These findings provide support to the implementation of procedural strategies to prevent any degree of PVL at the time of TAVI.

Correlation of right atrial enlargement on ECG to right atrial volume by echocardiography in patients with pulmonary hypertension.

Previous attempts to validate ECG criteria for right atrial (RA) enlargement (RAE) have been limited by sample sizes and lack of accepted standards for measuring RA size. New guidelines have recommended that RA volume (RAV) be used to determine RA size. Since these guidelines were released, no studies have been published that correlate RAE by ECG to RAV using the new standards. We aimed to validate previously proposed ECG criteria for RAE, commonly called P pulmonale, and to establish whether a correlation exists between P wave amplitudes and RAV as determined by echocardiogram in patients from the pulmonary hypertension (PHT) clinic. We identified patients from the PHT clinic that had an echocardiogram and ECG done at most 30days apart. We defined increased P wave amplitude as ≥2mm in lead II and ≥1mm in lead V1. The RA was determined to be enlarged if the RAV index (RAVI) was ≥39mL/m2 for men and ≥33mL/m2 for women. Patients were stratified into four groups: those with P II≥2mm, those with P V1≥1mm, those that met both criteria, and those that met neither. Right atrial volumes were then compared. Sixty-three patients were included in the study (7 men, 56 women). Three men and 36 women had an ECG that met criteria for P pulmonale. Five men and 28 women had an enlarged RA on echocardiogram. Sixty-nine percent of ECGs that met criteria for RAE were associated with increased RAV by echocardiogram. The specificity of each of the ECG criteria for P pulmonale at detecting RAE was 100% for men. The criterion with the highest specificity among women was P II≥2mm AND P V1≥1mm (94%). The least specific criterion for women was P II≥2mm (70%). The sensitivity of each criterion was much lower. The most sensitive criteria for men and women were P V1≥1mm (66.6%) and P II≥2mm (48%), respectively. The correlation of P wave amplitude in leads II and V1 and RAVI was not statistically significant for any of the ECG criteria for P pulmonale. In patients from the PHT clinic, the specificity of P pulmonale for detecting RAE is high, but the sensitivity is relatively low. These results suggest that in PHT, P pulmonale can be used to confirm that the RA is enlarged, but it is not a reliable test for diagnosing RAE.

Outcomes of hemodynamic support with Impella in very high-risk patients undergoing balloon aortic valvuloplasty: Results from the Global cVAD Registry.

BACKGROUND: Reports on the role of hemodynamic support devices in patients with severe aortic stenosis (AS) and left ventricular (LV) dysfunction undergoing balloon aortic valvuloplasty (BAV) are limited. METHODS: Patients were identified from the cVAD registry, an ongoing multicenter voluntary registry at selected sites in North America that have used Impella in >10 patients. RESULTS: A total of 116 patients with AS who underwent BAV with Impella support were identified. Mean age was 80.41±9.03years and most patients were male. Mean STS score was 18.77%±18.32, LVEF was 27.14%±16.07, and 42% underwent concomitant PCI. In most cases Impella was placed electively prior to BAV, whereas 26.7% were placed as an emergency. The two groups had similar baseline characteristics except for higher prevalence of CAD and lower LVEF in the elective group, and higher STS score in the emergency group. Elective strategy was associated higher 1-year survival compared to emergency placement (56% vs. 29.2%, p=0.003). One-year survival was higher when BAV was used as a bridge to definitive therapy as opposed to palliative treatment (90% vs. 28%, p<0.001). On multivariate analysis, STS score and aim of BAV (bridge to definitive therapy vs. palliative indication) were independent predictors of mortality. CONCLUSION: In this large cohort of patients with AS and severe LV dysfunction undergoing BAV, our results demonstrates feasibility and promising long-term outcomes using elective Impella support with the intention to bridge to a definitive therapy.

Systemic effects of controlled exposure to diesel exhaust: a meta-analysis from randomized controlled trials.

INTRODUCTION: Ambient air pollution is associated with adverse cardiovascular events. This meta-analysis aimed to investigate the short-term association between air pollution and cardiovascular effects on healthy volunteers. METHODS: We searched databases to identify randomized trials with controlled human exposures to either of two models for studying ambient particulate matter: diesel-exhaust or concentrated ambient particles. Estimates of size effect were performed using standardized mean difference (SMD). Heterogeneity was assessed with I2 statistics. Outcomes were vascular function estimated by forearm blood flow (FBF), blood pressure, heart rate, and blood analysis. RESULTS: Database searches yielded 17 articles (n = 342) with sufficient information for meta-analyses. High levels of heterogeneity for the some outcomes were analyzed using random-effects model. The pooled effect estimate showed that short-term exposure to air pollution impaired FBF response from 2.7 to 2.5 mL/100 mL tissue/min (SMD 0.404; p = .006). There was an increase in 5000 platelet/mm3 following pollution exposure (SMD 0.390; p = .050) but no significant differences for other outcomes. CONCLUSION: Controlled human exposures to air pollution are associated with the surrogates of vascular dysfunction and increase in platelet count, which might be related to adverse cardiovascular events. Given the worldwide prevalence of exposure to air pollution, these findings are relevant for public health. KEY MESSAGES Controlled exposure to air pollution impairs vasomotor response, which is a surrogate for adverse cardiovascular events. This is the first meta-analysis from randomized clinical trials showing short-term association between air pollution and cardiovascular effects on healthy volunteers. Given the worldwide prevalence of exposure to air pollution, this finding is important for public health.

Evaluation of clinical and laboratory data for early diagnosis of heparin-induced thrombocytopenia.

PURPOSE: Results of a study to determine the utility of combining laboratory values and clinical probability scores to improve the detection of heparin-induced thrombocytopenia (HIT) are reported. METHODS: In a retrospective, single-site, chart review-based investigation, 156 cases in which patients with suspected HIT had positive results on a widely used diagnostic test (the anti-heparin/platelet factor 4, or anti-PF4, assay) were identified; in all cases, the blood specimens had been sent to a reference laboratory for confirmation of HIT via serotonin release assay (SRA). After investigator scoring of the clinical probability of HIT in each case by the 4T's method, a multiple logistic regression model was used to evaluate the combined effect of 4T's scores and anti-PF4 assay values in predicting SRA results. RESULTS: 4T's scores indicating an intermediate or high probability of HIT combined with high anti-PF4 test values (i.e., optical density [OD] value of ≥1.4) were strongly predictive of a positive SRA result, as were high-probability 4T's scores alone. Low-probability 4T's scores alone or in combination with anti-PF4 OD values of <1.4 were highly correlated with negative SRA results. Controlling for potential confounding factors, logistic regression analysis indicated that the 4T's score was a better predictor of SRA results than the anti-PF4 test value. CONCLUSION: The combination of anti-PF4 OD values and 4T's scores accurately predicted SRA results, suggesting that the SRA may not be necessary to confirm HIT in patients with a relatively low 4T's score and a low anti-PF4 OD value.

Pleiotropic effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors in pulmonary diseases: a comprehensive review.

The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) are used extensively in the treatment of hyperlipidemia. They have also demonstrated a secondary benefit in a variety of other disease processes, actions which are known as pleiotropic effects. Review of the current pulmonary literature suggests a potential advantage of statin usage in a variety of pulmonary conditions. Our paper serves as a focused discussion on the pleiotropic effects of statins in the most common pulmonary disorders.

Chagas cardiomyopathy is associated with higher incidence of stroke: a meta-analysis of observational studies.

BACKGROUND: Chagas disease (CD) has been associated with an elevated risk of stroke, but current data are conflicting and prospective controlled studies are lacking. We performed a systematic review and meta-analysis examining the association between stroke and CD. METHODS: Pubmed, Embase, Cochrane Central, Latin American database, and unpublished data were searched with the use of the following terms: ("Chagas" OR "American trypanosomiasis") AND ("dilated" OR "ischemic" OR "idiopathic" OR "nonChagasic" OR "stroke" OR "cerebrovascular"). We included studies that reported prevalence or incidence of stroke in a CD group compared with a non-CD control group. Odds ratios (ORs) and their 95% confidence intervals (CIs) were computed with the use of a random-effects model. RESULTS: A total of 8 studies and 4,158 patients were included, of whom 1,528 (36.7%) had CD. Risk of stroke was elevated in the group of patients with CD (OR 2.10, 95% CI 1.17-3.78). Similar results were observed in a subanalysis of cardiomyopathy patients (OR 1.74, 95% CI 1.02-3.00) and in sensitivity analysis with removal of each individual study. Furthermore, exclusion of studies at higher risk for bias also yielded consistent results (OR 1.70, 95% CI 1.06-2.71). Subanalysis restricted to studies that included patients with the indeterminate form found no significant difference in the stroke prevalence between CD and non-CD patients (OR 3.10, 95% CI 0.89-10.77). CONCLUSIONS: CD is significantly associated with cerebrovascular events, particularly among patients with cardiomyopathy. These findings underline the need for prospective controlled studies in patients with Chagas cardiomyopathy to ascertain the prognostic significance of cerebrovascular events and to evaluate the role of therapeutic anticoagulation in primary prevention.

Interleukin-4 modulates the inflammatory response in ifosfamide-induced hemorrhagic cystitis.

We investigated whether interleukin-4 (IL-4) is present and capable of reducing inflammatory changes seen in ifosfamide-induced hemorrhagic cystitis. Male Swiss mice were treated with saline or ifosfamide alone or ifosfamide with the classical protocol with mesna and analyzed by changes in bladder wet weight (BWW), macroscopic and microscopic parameters, exudate, and hemoglobin quantification. In other groups, IL-4 was administered intraperitoneally 1 h before ifosfamide. In other experimental groups, C57BL/6 WT (wild type) and C57BL/6 WT IL-4 (-/-) knockout animals were treated with ifosfamide and analyzed for changes in BWW. Quantification of bladder IL-4 protein by ELISA in control, ifosfamide-, and mesna-treated groups was performed. Immunohistochemistry to tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß) as well as protein identification by Western blot assay for inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) was carried out on ifosfamide- and IL-4-treated animals. In other experimental groups, antiserum against IL-4 was given 30 min before ifosfamide. In IL-4-treated animals, the severity of hemorrhagic cystitis was significantly milder than in animals treated with ifosfamide only, an effect that was reverted with serum anti-IL-4. Moreover, knockout animals for IL-4 (-/-) exhibit a worse degree of inflammation when compared to C57BL/6 wild type. Exogenous IL-4 also attenuated TNF-α, IL-1ß, iNOS, and COX-2 expressions in ifosfamide-treated bladders. IL-4, an anti-inflammatory cytokine, attenuates the inflammation seen in ifosfamide-induced hemorrhagic cystitis.

Routine serial echocardiography in systolic heart failure: is it time for the heart failure guidelines to change?

The authors sought to obtain objective evidence for impacting the American College of Cardiology Heart Failure Guidelines for the routine use of serial echocardiography by assessing the reliability of the use of clinician-assessed patient symptoms and New York Heart Association (NYHA) functional classification compared with ejection fraction (EF) measured by echocardiography. A prospective study in 256 patients with systolic heart failure (HF) enrolled into an HF disease management program with EF ≤40% and at least 2 annual echocardiograms were included. Only 86 of 256 (33.5%) patients were correctly classified by NYHA class as showing improvement, no change, or deterioration as compared with echocardiographic assessments. Patients whose NYHA class showed no change between echocardiograms had the lowest survival rate. Quantification in patient's status with NYHA classification is not always a reliable assessment to evaluate prognosis and guide medical therapy for patients with systolic HF.

Peripheral vascular disease and erectile dysfunction as predictors of mortality in heart failure patients.

INTRODUCTION: Seventy percent to 90% of patients with heart failure (HF) report erectile problems. There are no published data on whether erectile dysfunction (ED) and peripheral vascular disease (PVD) correlate with mortality in HF patients. Also, little is known regarding the impact of HF etiology on mortality in patients with ED. AIMS: Our aim was to investigate the relationship between ED and mortality in HF patients, to evaluate whether the etiology of HF carries a prognostic measure in patients with ED, and to assess the impact of PVD on mortality in optimally treated HF patients with ED. MAIN OUTCOME MEASURES: The measures are: (i) mortality by presence or absence of ED; (ii) mortality by HF etiology and presence or absence of ED; and (iii) PVD and mortality in HF patients on optimal medical therapy with ED. METHODS: This is a single-center, prospective cohort study of 328 male HF patients (ejection fraction < or = 40%) followed while being treated with optimal doses of beta blockers and angiotensin-converting enzyme inhibitors. The Sexual Health Inventory for Men survey was used to assess ED (no ED > or = 22 and ED < or = 21). Ankle brachial index (ABI) was used to assess PVD (normal ABI > or = 0.9 and abnormal ABI < 0.9). RESULTS: Kaplan-Meier curves were constructed to examine the relationship between the presence or absence of ED and PVD, and mortality in a HF population. Although not statistically significant, a trend for increased risk of death was demonstrated in the ischemic cardiomyopathy cohort with ED. CONCLUSIONS: ED, highly prevalent in this cohort, did not identify HF patients on optimal medical therapy at increased risk for mortality. Among the HF patients with ED, HF type was not associated with increased risk for mortality whereas PVD was independently associated with a statistically significant increase in mortality.

Induction of COX-2 expression by acrolein in the rat model of hemorrhagic cystitis.

AIM: Acrolein (ACR) is a urinary metabolite of cyclophosphamide (CPS) and ifosfamide (IFS), which has been demonstrated to be the causative agent of hemorrhagic cystitis (HC), induced by these compounds. In this study, we investigate the participation of cyclooxygenase-2 (COX-2) on ACR-induced HC. METHODS: Male Wistar rats (150-200g; six rats per group) were treated with distilled water or intravesical ACR and analyzed by changes in bladder wet weight, macroscopic and microscopic parameters and COX-2 expression. RESULTS: COX-2 immunohistochemical expression was significant 12h after ACR administration mainly in subepithelial cells. ACR injection also alters some macroscopic and microscopic parameters in bladder of rats analyzed by Gray's criteria. CONCLUSIONS: COX-2 participates in the pathogenesis of ACR-induced HC first seen 12h after initial contact between ACR and urothelium.

Cyclooxygenase-2 expression on ifosfamide-induced hemorrhagic cystitis in rats.

PURPOSE: Hemorrhagic cystitis (HC) is a limiting side effect of chemotherapy with ifosfamide (IFS). In this study, we investigated the participation of cyclooxygenase-2 (COX-2) upon ifosfamide-induced HC. METHODS: Male Wistar rats (150-200 g; six rats per group) were treated with saline, IFS (400 mg/kg, i.p.) and analyzed by changes in bladder wet weight, macroscopic and microscopic parameters, and COX-2 expression. In other groups etoricoxib (selective COX-2 inhibitor), indomethacin (non-selective COX inhibitor), thalidomide (selective TNF-alpha inhibitor), pentoxifyllin (non-selective TNF-alpha inhibitor) were added 1 h before IFS administration. The classical protocol using three doses of Mesna was also evaluated and compared with two extra doses of etoricoxib or indomethacin. RESULTS: COX-2 was expressed significantly 24 h after IFS administration mainly in myofibroblasts and mast cells evaluated by immunohistochemistry. Treatment 1 h before IFS injection with etoricoxib, indomethacin, thalidomide, and pentoxifylline reduced COX-2 expression and some macroscopic and microscopic parameters in IFS-induced HC. Moreover, addition of etoricoxib or indomethacin with the last two doses of Mesna was more efficient than three doses of Mesna alone when evaluated microscopically. CONCLUSIONS: COX-2 participates in the pathogenesis of IFS-induced HC and the treatment with COX and TNF-alpha inhibitors reduced COX-2 expression. The addition of COX-inhibitors to the last two doses of Mesna represents a new therapeutic strategy of preventing HC.

Histological changes in bladders of patients submitted to ifosfamide chemotherapy even with mesna prophylaxis.

PURPOSE: Hemorrhagic cystitis (HC) is a limiting side effect of chemotherapy with ifosfamide (IFS). Mesna is the drug of choice for prevention of HC. In this study, we analyzed cystoscopic and histological changes present in bladders of patients using IFS with mesna prophylaxis. METHODS: Thirty-three patients selected for IFS plus three doses of mesna chemotherapy regime were assigned at random to two groups: Group I or reference group consisted of 18 patients yet untreated. Group II consisted of 15 patients in whom urinalysis and cystoscopy plus vesical biopsy were performed only 24 h after receiving the last dose of IFS. The cystoscopic and histological findings were used as parameters for evaluating the results. For the former the criterion adopted was macroscopic vesical changes in accordance with Gray's criteria. Histological analyses were performed by evaluation method especially adapted to this study. RESULTS: Even under treatment with three doses of mesna, 66.7% of patients presented cystoscopic alterations and 100% showed bladder mucosa microscopic alterations such as edema, exocytosis, and hemorrhage. CONCLUSIONS: The standard protocol used for prevention of IFS-induced HC with three doses of mesna does not completely prevent bladder damage. The histopathological criteria used in this study for observation of inflammatory events allowed staging the intensity of IFS-induced urothelial and mucosal injury.

Ternatin, a flavonoid, prevents cyclophosphamide and ifosfamide-induced hemorrhagic cystitis in rats.

To compare the classical uroprotective efficacy of mesna (2-mercaptoethanesulfonic acid) with ternatin (flavonoid isolated from Egletes viscosa Less.) in cyclophosphamide (CYP) and ifosfamide (IFS) induced hemorrhagic cystitis (HC). Male Wistar rats received an intraperitoneal injection of saline, CYP or IFS and were treated with saline or mesna, 5 min before, 4 and 8 h after CYP or IFS administration. In other animals, 1, 2 or 3 doses of mesna were replaced with ternatin or 3 doses of mesna were replaced with dimethylsulphoxide (DMSO), ternatin diluent. In an additional group, the last 2 doses of mesna were replaced with saline. HC was evaluated 24 h after CYP or IFS administration. CYP or IFS treatment induced marked changes in macroscopic and microscopic evaluation and in bladder wet weight (BWW), and these alterations were significantly inhibited by treatment with 3 doses of mesna, as well as by the replacement of 1 or 2 doses of mesna with ternatin. The replacement of 2 doses of mesna with saline or all doses of mesna with ternatin or DMSO did not prevent HC. In conclusion, the replacement of 1 or 2 doses of mesna with ternatin efficiently blocked CYP- or IFS-induced HC, however mesna is necessary for initial uroprotection.

Use of dexamethasone with mesna for the prevention of ifosfamide-induced hemorrhagic cystitis.

AIM: Hemorrhagic cystitis (HC) is a limiting side-effect of chemotherapy with ifosfamide (IFS). In the study presented here, we investigated the use of dexamethasone in combination with mesna for the prevention of IFS-induced HC. METHODS: Male Wistar rats (150-200 g; 6 rats per group) were treated with saline or mesna 5 min (i.p.) before and 2 and 6 h after (v.o.) administration of IFS. One, two or three doses of mesna were replaced with dexamethasone alone or with dexamethasone plus mesna. Cystitis was evaluated 24 h after its induction by the changes in bladder wet weight and by macroscopic and microscopic analysis. RESULTS: The replacement of the last dose or the last two doses of mesna with dexamethasone reduced the increase in bladder wet weight induced by IFS by 84.79% and 89.13%, respectively. In addition, it almost abolished the macroscopic and microscopic alterations induced by IFS. Moreover, the addition of dexamethasone to the last two doses of mesna was more efficient than three doses of mesna alone when evaluated microscopically. CONCLUSION: Dexamethasone in combination with mesna was efficient in blocking IFS-induced HC. However, the replacement of last two doses of mesna with saline or all of the mesna doses with dexamethasone did not prevent HC.