Stroke volume index (SVI) predicts all-cause mortality following transcatheter aortic valve replacement (TAVR).

BACKGROUND: Left ventricular systolic dysfunction in patients with severe aortic stenosis (AS) may result in low transvalvular gradients and underestimation of AS severity. A low-flow state may occur with reduced LVEF. Little is known about the implications of low compared to normal flow in patients with reduced LVEF undergoing transcatheter aortic valve replacement (TAVR). OBJECTIVES: We compared survival rates with degree of flow across stenosed aortic valves and left ventricular dysfunction. We hypothesized that the stroke volume index (SVI) offers essential information regarding survival following TAVR. METHODS: We retrospectively reviewed patients with LVEF <50 % undergoing TAVR at the Gates Vascular Institute in Buffalo, New York, from 2012 to 2017. We performed Receiver Operator Characteristics to examine the value of SVI in predicting the postoperative outcome of patients. Kaplan-Meier and Cox regression analyses were used to investigate the effect of a low-flow state on five-year survival in patients with systolic dysfunction undergoing TAVR. RESULTS: Five-year survival following TAVR was decreased in patients with low-flow AS (SVI <35 mL/m2) compared to patients with normal flow. Seventy-four percent (n = 50) of patients with low-flow compared to 43 % (n = 22) of patients with normal flow were deceased five years post-TAVR (p ≤0.001). ROC curve indicated SVI to be a clinical predictor of five year survival (AUC 0.732, 95 % CI: 0.641-0.823, p < 0.001). CONCLUSION: Patients with systolic dysfunction and low transvalvular flow AS had increased mortality five years following TAVR. These findings highlight a better prognosis in patients with normal flow and LV systolic dysfunction. CONDENSED ABSTRACT: Low-flow aortic stenosis can occur with reduced left ventricular function. We compared survival rates of patients with known reduced left ventricular function in low-flow and normal flow aortic stenosis. This retrospective single-center study examined mortality rates following transcatheter aortic valve replacement. The mean gradient was not a predictor of mortality. This study shows patients with low-flow aortic stenosis have decreased five-year survival following valve replacement.

Energy loss index as a predictor of all-cause mortality after transcatheter aortic valve replacement: A long-term follow-up.

BACKGROUND: As transcatheter aortic valve replacement (TAVR) procedures become more widely available, there is a growing need to monitor and evaluate postoperative outcomes accurately. The energy loss index (ELI) of the ascending aorta has been commonly used to examine the agreement between the echocardiographic and Gorlin measurement of the aortic valve area. OBJECTIVES: This project aims to demonstrate a link between ELI values and mortality following implanted TAVR valves and determine an ELI cutoff value associated with post-TAVR events. METHOD: We retrospectively reviewed patients undergoing TAVR from 2012 to 2017. We calculated ELI values for patients immediately postoperative after a TAVR procedure. Using Receiver-Operator Characteristic and Cox Regression analyses, we identified a cutoff value to distinguish between "High ELI" (≥ 1.34) and "Low ELI" (< 1.34) patients. RESULTS: This study showed low ELI (hazard ratio, 2.30; 95% confidence interval 1.57-3.36, p < .001) as representative of patients with a high risk of mortality post-TAVR. Additionally, post-TAVR, ejection fraction increased by 3.6% (p < .001), and the aortic valve effective orifice area increased by 1.41 cm squared (p < .001) while the mean transvalvular gradient decreased by 32.8 mmHg (p < .001) and the peak transvalvular gradient decreased by 49.0 mmHg (p < .001). CONCLUSION: ELI is an additional prognostic factor that should be considered during risk assessment before TAVR. This study shows that patients with Low ELI had decreased cumulative survival post-TAVR. These patients almost had a fivefold increased risk of death following TAVR.

The Use of Contrast May Improve Aortic Valve Assessment During Transesophageal Echocardiography.

OBJECTIVES: The Doppler profile that quantifies the degree of aortic stenosis is essential, as an inaccurate measurement can alter the surgical plan. The authors aimed to examine the level of agreement between the contrast and noncontrast methods of aortic valve sizing during intraoperative transesophageal echocardiography (TEE). SETTING: At a tertiary hospital. PARTICIPANTS: A total of 30 patients undergoing surgical aortic valve replacement for a stenotic valve. INTERVENTIONS: Perflutren lipid microsphere contrast injection. MEASUREMENTS AND MAIN RESULTS: The authors reviewed Doppler studies of 30 consecutive patients undergoing aortic valve replacement in whom a contrast agent was given (perflutren lipid microsphere). They measured the peak and/or mean aortic valve gradients and velocity time integral readings through the left ventricular outflow tract (LVOT), and the aortic valve before and after administering the contrast agent. The aortic valve area was then calculated using both methods. Paired t tests and Bland-Altman analyses were used to examine the bias and the level of agreement between the 2 processes. By not using a contrast agent, the aortic valve area was overestimated by 0.26 cm2 compared to those measured by transthoracic echocardiography (TTE) (p < 0.001). Using a contrast agent, TEE measurements were comparable to those obtained by TTE. Moreover, the peak and mean aortic valve gradients were underestimated by 19 and 11 mmHg, respectively (p value <0.001). Adding contrast did not affect the pulse-wave Doppler readings of the V1 velocity of the LVOT. CONCLUSION: This discrepancy is significant and could affect the decision to replace the aortic valve. When evaluating the aortic valve with TEE, the authors recommend using a contrast agent to improve the Doppler profile and to obtain a more accurate measurement of the aortic valve area.

Aspirin responsiveness changes in obese patients following bariatric surgery.

AIMS: Bariatric surgery has emerged as a promising treatment option for weight loss and to counter the metabolic consequences of obesity. Obesity has been linked to a hyperaggregable state, as well as a blunted response to aspirin. This pilot study assessed the hypothesis that bariatric surgery would lead to an improvement in aspirin-induced platelet inhibition and a reduction in platelet aggregability. METHODS: Fifteen patients scheduled to undergo bariatric surgery were administered two 7-day courses of aspirin 81 mg: the first course administered before surgery and the second was 3 months following surgery. Platelet aggregation was measured before and after each aspirin course using VerifyNow-Aspirin. The primary endpoint was the change in on-treatment aspirin reactive units (ARU) pre- and postsurgery. Data from bariatric surgery study patients were compared to data of normal weighted subjects gathered in a previous study. RESULTS: Roux-en-Y gastric bypass was performed in 80%, and 20% underwent sleeve gastrectomy. The mean starting body mass index (BMI) was 46.9 kg/m2 . Patients lost on average 24.5 kg, resulting in a postsurgical BMI of 38.5 kg/m2 . Postbariatric surgery, off-treatment ARU was significantly reduced from presurgery levels (602±59 vs 531±78; P=.035). On-aspirin platelet reactivity was also significantly reduced following surgery (469±60 vs 432±143, P=.03). There was a significant correlation between the extent of weight loss and the degree of improvement in on-aspirin platelet reactivity (r2 =.49, P=.024). Presurgery on-aspirin platelet reactivity was significantly higher in obese patients compared to normal weighted subjects (469±60 vs 419±52; P=.016) and reduced to the baseline after the surgery (432±63 vs 419±52; P=.54). CONCLUSION: Aspirin-induced platelet inhibition may be more potent following bariatric surgery. The mechanisms behind this improvement require further investigation.

Cardiotoxicity as indicated by LVEF and troponin T sensitivity following two anthracycline-based regimens in lymphoma: Results from a randomized prospective clinical trial.

Anthracycline-induced cardiotoxicity influences treatment selection and may negatively affect clinical outcomes in lymphoma patients. While epirubicin induced cardiotoxicity less often than the same dose of doxorubicin in breast cancer, higher doses of epirubicin are required in lymphoma regimens for equivalent efficacy. Whether a higher dosage of epirubicin also induces cardiotoxicity less often than doxorubicin in lymphoma remains unknown. We therefore administered 6-8 cycles of cyclophosphamide, vincristine and prednisone (CEpOP) +/- rituximab (R) with either epirubicin (CEpOP) or doxorubicin (CHOP) to patients (N=398) with untreated diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma grade 3 (FLG3). Left ventricular ejection fraction (LVEF) and high-sensitivity serum cardiac troponin T (HsTnT) were assessed at baseline and after 4 cycles of treatment. Epirubicin (70 mg/m2/dose) was equivalent to doxorubicin (50 mg/m2/dose) in terms of 3-year progression-free survival. The risk of decreased LVEF was similar between the two regimens. CEpOP+/-R induced HsTnT elevation less often than CHOP+/-R. We conclude that CEpOP+/-R is a more acceptable regimen with short-term efficacy similar to CHOP+/-R in lymphoma patients. Longer follow-up is needed to monitor the risk of cardiac dysfunction and determine whether differences in the induction of elevated HsTnT between epirubicin and doxorubicin justify changes in clinical practice.

Prognostic Significance of Imaging Myocardial Sympathetic Innervation.

There has been a longstanding interest in understanding whether the presence of inhomogeneity in myocardial sympathetic innervation can predict patients at risk of sudden cardiac arrest from lethal ventricular arrhythmias. The advent of radiolabeled norepinephrine analogs has allowed this to be imaged in patients with ischemic and non-ischemic cardiomyopathy using single, photon emission computed tomography (SPECT) and positron emission tomography (PET). Several observational studies have demonstrated that globally elevated myocardial sympathetic tone (as reflected by reduced myocardial norepinephrine analog uptake) can predict composite cardiac end-points including total cardiovascular mortality. More recent studies have indicated that quantifying the extent of regional denervation can predict the risk of lethal ventricular arrhythmias and sudden cardiac death. This review will summarize our current understanding of the prognostic significance of altered myocardial sympathetic innervation.

Low pH environmental stress inhibits LPS and LTA-stimulated proinflammatory cytokine production in rat alveolar macrophages.

Gastric aspiration increases the risks for developing secondary bacterial pneumonia. Cytokine elaboration through pathogen recognition receptors (PRRs) is an important mechanism in initiating innate immune host response. Effects of low pH stress, a critical component of aspiration pathogenesis, on the PRR pathways were examined, specifically toll-like receptor-2 (TLR2) and TLR4, using isolated rat alveolar macrophages (aMØs). We assessed the ability of aMØs after brief exposure to acidified saline to elaborate proinflammatory cytokines in response to lipopolysaccharide (LPS) and lipoteichoic acid (LTA) stimulation, known ligands of TLR4 and TLR2, respectively. Low pH stress reduced LPS- and LTA-mediated cytokine release (CINC-1, MIP-2, TNF-α, MCP-1, and IFN-ß). LPS and LTA increased intracellular Ca²âº concentrations while Ca²âº chelation by BAPTA decreased LPS- and LTA-mediated cytokine responses. BAPTA blocked the effects of low pH stress on most of LPS-stimulated cytokines but not of LTA-stimulated responses. In vivo mouse model demonstrates suppressed E. coli and S. pneumoniae clearance following acid aspiration. In conclusion, low pH stress inhibits antibacterial cytokine response of aMØs due to impaired TLR2 (MyD88 pathway) and TLR4 signaling (MyD88 and TRIF pathways). The role of Ca²âº in low pH stress-induced signaling is complex but appears to be distinct between LPS- and LTA-mediated responses.

Hibernating myocardium results in partial sympathetic denervation and nerve sprouting.

Hibernating myocardium due to chronic repetitive ischemia is associated with regional sympathetic nerve dysfunction and spontaneous arrhythmic death in the absence of infarction. Although inhomogeneity in regional sympathetic innervation is an acknowledged substrate for sudden death, the mechanism(s) responsible for these abnormalities in viable, dysfunctional myocardium (i.e., neural stunning vs. sympathetic denervation) and their association with nerve sprouting are unknown. Accordingly, markers of sympathetic nerve function and nerve sprouting were assessed in subendocardial tissue collected from chronically instrumented pigs with hibernating myocardium (n = 18) as well as sham-instrumented controls (n = 7). Hibernating myocardium exhibited evidence of partial sympathetic denervation compared with the normally perfused region and sham controls, with corresponding regional reductions in tyrosine hydroxylase protein (-32%, P < 0.001), norepinephrine uptake transport protein (-25%, P = 0.01), and tissue norepinephrine content (-45%, P < 0.001). Partial denervation induced nerve sprouting with regional increases in nerve growth factor precursor protein (31%, P = 0.01) and growth associated protein-43 (38%, P < 0.05). All of the changes in sympathetic nerve markers were similar in animals that developed sudden death (n = 9) compared with electively terminated pigs with hibernating myocardium (n = 9). In conclusion, sympathetic nerve dysfunction in hibernating myocardium is most consistent with partial sympathetic denervation and is associated with regional nerve sprouting. The extent of sympathetic remodeling is similar in animals that develop sudden death compared with survivors; this suggests that sympathetic remodeling in hibernating myocardium is not an independent trigger for sudden death. Nevertheless, sympathetic remodeling likely contributes to electrical instability in combination with other factors.

Targeting tachycardia: diagnostic tips and tools.

Many narrow QRS complex tachycardias are benign, but some require rapid intervention. The review, EKG strips, and algorithm you'll find here will help you get to the source of the problem without delay.

Strategies in stable ischemic heart disease: lessons from the COURAGE and BARI-2D trials.

There is a continuing debate regarding the most effective strategy for treating stable ischemic heart disease (SIHD). Conflicting data have emerged from several small, randomized controlled trials and meta-analyses regarding the benefits of early revascularization in SIHD. Two recent multicenter, randomized trials, the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial and the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI-2D) trial, compared two management strategies in SIHD-an initial conservative approach with optimal medical therapy (OMT) versus a strategy of early revascularization in combination with OMT. COURAGE randomized SIHD patients who were candidates for percutaneous coronary intervention (PCI) to either a strategy of early PCI in combination with OMT or OMT alone, whereas BARI-2D randomized diabetic patients with coronary artery disease to either early revascularization (PCI or coronary artery bypass surgery [CABG]) versus OMT. This review examines the principal findings of these trials, with discussion of their strengths, limitations, and applicability to the general population. The results support the hypothesis that in patients with SIHD, early revascularization with PCI in combination with OMT is not superior to OMT alone in reducing mortality and other major cardiovascular events. Subset analysis from BARI-2D did suggest that early CABG, although it did not reduce mortality, significantly reduced the rate of nonfatal myocardial infarction compared with an initial OMT approach. Based on these data, the majority of patients with SIHD should be managed initially with medical therapy, a strategy that is also the most cost effective. Revascularization can be considered for patients with severe or refractory symptoms despite a trial of medical therapy. For diabetic patients who have extensive coronary artery disease, early revascularization with CABG may be reasonable.

Emerging medical treatment for angina pectoris.

IMPORTANCE OF THE FIELD: Despite improved mortality and morbidity in the treatment of coronary artery disease, a significant proportion of patients will continue to experience recurrent angina pectoris. AREAS COVERED IN THIS REVIEW: Anti-anginal therapy has long been dominated by the use of beta-blockers, Ca(2+) channel blockers and nitrates. Most recently, ranolazine was introduced as a new anti-anginal class. This review article presents current and novel anti-anginal strategies under development. A discussion of their molecular mechanisms that may complement traditional therapies is presented. Medline and PubMed scientific search tools were primarily used to identify relevant literature dating from 1970 to 2008. WHAT THE READER WILL GAIN: This review provides a summary of both traditional and emerging therapeutic approaches to angina pectoris management. A discussion on the mechanism of action and clinical efficacy of ranolazine, trimetazidine, nicorandil, ivabradine, fasudil and growth factor gene therapy as anti-anginal agents is provided. TAKE HOME MESSAGE: The need for multiple approaches cannot be over-emphasized. Availability of various modalities would strongly enhance the ability to meet the needs of a heterogeneous patient population. Patients with recurrent angina pectoris most likely will require multi-drug regimen where different mechanisms may complement each other and result in a more efficacious strategy.

Tight junction regulation by morphine and HIV-1 tat modulates blood-brain barrier permeability.

Human immunodeficiency virus (HIV)-1 patients who abuse opiates are at a greater risk of developing neurological complications of AIDS. Alterations in blood-brain barrier (BBB) integrity are associated with cytoskeletal disorganization and disruption of tight junction (TJ) integrity. We hypothesize that opiates in combination with HIV-1 viral proteins can modulate TJ expression in primary brain microvascular endothelial cells (BMVEC), thereby compromising BBB integrity and exacerbating HIV-1 neuropathogenesis. We investigated the effect of morphine and/or tat on the expression of TJ proteins ZO-1, JAM-2, Occludin and P-glycoprotein and the functional effects of TJ modulation in BMVEC. Morphine and/or tat, via the activation of pro-inflammatory cytokines, intracellular Ca(2+) release, and activation of myosin light chain kinase, modulated TJ expression resulting in decreased transendothelial electric resistance and enhanced transendothelial migration across the BBB. These studies may lead to the development of novel anti-HIV-1 therapeutics that target specific TJ proteins, thus preventing TJ disruption in opiate using HIV-1 patients.

FDI 2006: an eye-opening dental experience.

Although it may seem a daunting prospect, attending a large international dental conference can be an extremely rewarding experience from both a professional and a personal perspective. Here, three dentists recall their experiences at the 2006 FDI Annual World Dental Congress in Shenzhen, China.

Morphine exacerbates HIV-1 viral protein gp120 induced modulation of chemokine gene expression in U373 astrocytoma cells.

HIV-1 affects microglia and astroglia, which subsequently contributes to the neurodegenerative changes. Viral proteins cause neurotoxicity by direct action on the CNS cells or by activating glial cells to cause the release of cytokines, chemokines or neurotoxic substances. Opioid abuse has been postulated as a cofactor in the immunopathogenesis of human immunodeficiency virus (HIV) infection and AIDS. HIV-induced pathogenesis is exacerbated by opiate abuse and that the synergistic neurotoxicity is a direct effect of opiates on the CNS. Chemokines and their receptors have been implicated in the pathogenesis of neuroAIDS. Herein we describe the effects of morphine and/or gp120 on the expression of the genes for the beta-chemokine MIP-1beta and its receptors CCR3 and CCR5 by the U373 cells which are a human brain-derived astrocytoma/glioblastoma cell line. Our results indicate that treatment of U373 cells with morphine significantly downregulated the gene expression of the beta chemokine, MIP-1 beta, while reciprocally upregulating the expression of its specific receptors, CCR3 and CCR5 suggesting that the capacity of mu-opioids to increase HIV-1 co-receptor expression may promote viral binding, trafficking of HIV-1-infected cells, and enhanced disease progression. Additionally, opiates can enhance the cytotoxicity of HIV-1 viral protein gp120 via mechanisms that involve intracellular calcium modulation resulting in direct actions on astroglia, making them an important cellular target for HIV-opiate interactions.

Mechanisms of angiotensin II-mediated decreases in intraneuronal Ca2+ in calcium-loaded stellate ganglion neurons.

Our laboratory has reported previously that angiotensin II, type-1 (AT(1)) receptor stimulation in isolated stellate ganglion neurons decreases intraneuronal calcium concentration ([Ca(2+)]i) acutely if baseline [Ca(2+)]i is high and increases [Ca(2+)]i if baseline [Ca(2+)]i is low. Part of the angiotensin II (Ang II) effect in high Ca(2+) neurons is mediated through stimulation of Na(+)-Ca(2+) exchange. Current experiments were conducted to identify additional steps in the signaling pathways. In Ca(2+)-loaded neurons, Ang II-induced decreases in [Ca(2+)]i were attenuated by phospholipase C inhibition (U73122) or nitric oxide (NO) synthase inhibition (L-NMMA) and were mimicked by the cGMP analogue 8-Br-cGMP. Protein kinase C (PKC) inhibition (bisindolylmaleimide I or Go6976) and protein kinase G (PKG) inhibition (KT5823) partially blocked Ang II-mediated decreases in [Ca(2+)]i, but complete blockade of Ang II effects was obtained with combined PKC and PKG inhibition. Modulation of inositol triphosphate (IP(3))-inducible ER Ca(2+) release by [Ca(2+)]i was investigated using furaptra, an ER-retaining dye. IP(3)-mediated ER Ca(2+) release in beta-escin-permeabilized neurons was measured after clamping of [Ca(2+)]i from 50 nM to 800 nM. Maximal ER Ca(2+) release was observed at approximately 200 nM [Ca(2+)]i, with noted blunting of release at higher [Ca(2+)]i. Steady-state mRNA transcript and protein levels revealed that the principal IP(3)R isoform expressed was IP(3)R-II. These results suggest that Ca(2+) loading in stellate ganglion neurons promotes Ang II-mediated decreases in [Ca(2+)]i via PKC and NO/cGMP/PKG pathways and inhibits IP(3)R-II-mediated ER Ca(2+) release.

Modulation of angiotensin II responses in sympathetic neurons by cytosolic calcium.

Both stimulatory and suppressive responses of the sympathetic nervous system to angiotensin II (AII) have been reported in intact animals. To elucidate possible cellular mechanisms, we studied AII-induced changes in cytosolic Ca2+ ([Ca2+]i) in primary cultures of rat stellate ganglion neurons. Two different patterns of [Ca2+]i responses to AII were observed: dose-dependent increases in [Ca2+]i in cells with intrinsically low baseline [Ca2+]i (n=64) and dose-dependent suppression of [Ca2+]i in neurons with intrinsically higher baseline [Ca2+]i (n=46). Individual neurons could express both response patterns to AII. In neurons with low basal [Ca2+]i, superfusion with Ca2+ ionophore (ionomycin) increased [Ca2+]i and reversed the initial AII-induced stimulatory pattern. L-type Ca2+ channel antagonism (nifedipine) in neurons with high baseline [Ca2+]i lowered [Ca2+]i and reversed the initial AII-induced suppressive response. Both stimulatory and suppressive responses were abolished by AT1 receptor antagonism (losartan). AII-induced stimulatory responses were blocked by IP3 receptor antagonism (2-APB) and by thapsigargin. AII-induced suppression of neuronal [Ca2+]i was blunted when Na-Ca exchange was impaired. We conclude that [Ca2+]i acts as a switch for AII-mediated stimulatory and suppressive responses in individual sympathetic neurons. AT1 receptor-mediated neuronal stimulation and suppression may allow local homeostatic adaptation to meet complex systemic needs.