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Background: Posterior cerebral artery (PCA) stroke is a common cause of homonymous hemianopia and other neurologic deficits associated with more proximal ischemia in the vertebrobasilar circuit. Localization of the process can be challenging unless the symptom complex is well recognized, yet early diagnosis is critical to forestall dangerous driving and repeated stroke. We undertook this study to provide additional detail about the presenting symptoms and signs and their correlation with imaging abnormalities and stroke etiology., Methods: Retrospective study of medical records of patients presenting to a single tertiary care academic center between 2009 and 2020 with homonymous hemianopia from PCA stroke. We excerpted data on symptoms, visual and neurologic signs, incident medical procedures and diagnoses, and imaging features. We determined stroke etiology using the Causative Classification Stroke system., Results: In a cohort of 85 patients, 90% of strokes occurred without preceding symptoms. But in retrospect, 10% of strokes did have warning symptoms. In 20% of patients, strokes followed within 72 hours of a medical or surgical procedure or newly identified medical condition. In the subgroups of patients whose records contained a description of visual symptoms, 87% reported the visual sensation as negative, and 66% realized that it was located in a hemifield in both eyes. Concurrent nonvisual symptoms were present in 43% of patients, consisting commonly of numbness, tingling, and new headache. Infarction located outside the visual cortex affected primarily the temporal lobe, thalamus, and cerebellum, reflecting the widespread nature of ischemia. Nonvisual clinical manifestations and arterial cutoffs on imaging were associated with thalamic infarction, but the clinical features and location of the infarction did not correlate with the etiology of the stroke., Conclusions: In this cohort, clinical localization of the stroke was aided by the fact that many patients could lateralize their visual symptoms and had nonvisual symptoms suggestive of ischemia affecting the proximal vertebrobasilar circuit. Numbness and tingling were strongly linked to concurrent thalamic infarction. Clinical features and infarct location were not associated with the etiology of the stroke., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by North American Neuro-Ophthalmology Society.)

Background: Posterior cerebral artery (PCA) strokes account for up to 10% of all ischemic strokes, often presenting with homonymous hemianopia. The proportion of these strokes attributed to various etiologies varies widely in previously published studies, owing largely to differing patient populations, definitions of stroke pathogenesis, and vascular territories involved. The Causative Classification System (CCS), an automated version of the Stop Stroke Study (SSS) Trial of Org 10,172 in Acute Stroke Treatment (TOAST) system, allows for a more rigorous assignment of stroke etiology., Methods: We excerpted clinical and imaging data on 85 patients who had PCA stroke with homonymous hemianopia examined at the University of Michigan. We compared the stroke risk factor profile of our PCA cohort with that of 135 patients with stroke in the distribution of the internal carotid artery (ICA) and middle cerebral artery (MCA) in an unpublished University of Michigan registry. We applied the CCS web-based calculator to our PCA cohort to determine stroke etiology., Results: In our PCA cohort, 80.0% had at least 2 conventional stroke risk factors and 30.6% had 4 risk factors, most commonly systemic hypertension. The risk factor profile of our PCA cohort resembled that of our ICA/MCA cohort except that the mean age of our PCA cohort was more than a decade younger and had a significantly lower frequency of atrial fibrillation (AF) than our ICA/MCA cohort. In nearly half of the patients with AF in our PCA cohort, AF was diagnosed after the stroke. Among stroke etiologies in our PCA cohort, 40.0% were of undetermined cause, 30.6% were from cardioaortic embolism, 17.6% were from other determined causes, and only 11.8% were from supra-aortic large artery atherosclerosis. Strokes after endovascular or surgical interventions were prominent among other determined causes., Conclusions: Most patients in our PCA cohort had multiple conventional stroke risk factors, a finding not previously documented. Mean age at stroke onset and AF frequency were lower than in our ICA/MCA cohort, in agreement with previous studies. As some other studies have found, nearly 1/3 of strokes were attributed to cardioaortic embolism. Within that group, AF was often a poststroke diagnosis, a finding not previously highlighted. Compared with earlier studies, a relatively high portion of strokes were of undetermined etiology and of other determined etiologies, including stroke after endovascular or surgical interventions. Supra-aortic large artery atherosclerosis was a relatively uncommon explanation for stroke., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by North American Neuro-Ophthalmology Society.)

Objective: To examine whether depression status before metabolic and bariatric surgery (MBS) influenced 5-year weight loss, diabetes, and safety/utilization outcomes in the PCORnet Bariatric Study., Summary of Background Data: Research on the impact of depression on MBS outcomes is inconsistent with few large, long-term studies., Methods: Data were extracted from 23 health systems on 36,871 patients who underwent sleeve gastrectomy (SG; n=16,158) or gastric bypass (RYGB; n=20,713) from 2005-2015. Patients with and without a depression diagnosis in the year before MBS were evaluated for % total weight loss (%TWL), diabetes outcomes, and postsurgical safety/utilization (reoperations, revisions, endoscopy, hospitalizations, mortality) at 1, 3, and 5 years after MBS., Results: 27.1% of SG and 33.0% of RYGB patients had preoperative depression, and they had more medical and psychiatric comorbidities than those without depression. At 5 years of follow-up, those with depression, versus those without depression, had slightly less %TWL after RYGB, but not after SG (between group difference = 0.42%TWL, P = 0.04). However, patients with depression had slightly larger HbA1c improvements after RYGB but not after SG (between group difference = - 0.19, P = 0.04). Baseline depression did not moderate diabetes remission or relapse, reoperations, revision, or mortality across operations; however, baseline depression did moderate the risk of endoscopy and repeat hospitalization across RYGB versus SG., Conclusions: Patients with depression undergoing RYGB and SG had similar weight loss, diabetes, and safety/utilization outcomes to those without depression. The effects of depression were clinically small compared to the choice of operation., Competing Interests: The other authors report no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Women comprise approximately one-third of the advanced heart failure population but may receive fewer advanced heart failure therapies including left ventricular assist devices (LVADs). During the early pulsatile-flow device era, women had higher post-LVAD mortality and increased complications. However, knowledge about these differences in the continuous-flow device era is limited. Therefore, we sought to explore temporal trends in LVAD utilization and post-LVAD mortality by sex., Methods and Results: Patients with LVAD implantation from 2004 to 2016 were identified using the Nationwide Inpatient Sample. Trends in LVAD utilization and post-LVAD inpatient mortality were compared by sex and device era. Although LVADs are being increasingly utilized for patients with advanced systolic heart failure, women continue to represent a smaller proportion of LVAD recipients-25.8% in 2004 to 21.9% in 2016 ( P for trend, 0.91). Women had increased inpatient mortality after LVAD implantation compared with men in the pulsatile-flow era (46.9% versus 31.1%, P <0.0001) but not in the continuous-flow era (13.3% versus 12.1%, P =0.27; P for interaction=0.0002). Inpatient mortality decreased for both sexes over time after LVAD, with a sharp fall in 2008 to 2009. Female sex was independently associated with increased post-LVAD inpatient mortality beyond adjustment for demographics and risk factors during the pulsatile-flow era (odds ratio, 2.13; 95% CI, 1.45-3.10; P <0.0001) but not during the continuous-flow era (1.18; 0.93-1.48; P =0.16)., Conclusions: Although utilization of LVAD therapy increased over time for both sexes, LVAD implantation remains stably lower in women, which may suggest a potential underutilization of this potentially life-saving therapy. Prospective studies are needed to confirm these findings.

Current risk stratification models to predict outcomes after a left ventricular assist device (LVAD) are limited in scope. We assessed the performance of Bayesian models to stratify post-LVAD mortality across various International Registry for Mechanically Assisted Circulatory Support (INTERMACS or IM) Profiles, device types, and implant strategies. We performed a retrospective analysis of 10,206 LVAD patients recorded in the IM registry from 2012 to 2016. Using derived Bayesian algorithms from 8,222 patients (derivation cohort), we applied the risk-prediction algorithms to the remaining 2,055 patients (validation cohort). Risk of mortality was assessed at 1, 3, and 12 months post implant according to disease severity (IM profiles), device type (axial versus centrifugal) and strategy (bridge to transplantation or destination therapy). Fifteen percentage (n = 308) were categorized as IM profile 1, 36% (n = 752) as profile 2, 33% (n = 672) as profile 3, and 15% (n = 311) as profile 4-7 in the validation cohort. The Bayesian algorithms showed good discrimination for both short-term (1 and 3 months) and long-term (1 year) mortality for patients with severe HF (Profiles 1-3), with the receiver operating characteristic area under the curve (AUC) between 0.63 and 0.74. The algorithms performed reasonably well in both axial and centrifugal devices (AUC, 0.68-0.74), as well as bridge to transplantation or destination therapy indication (AUC, 0.66-0.73). The performance of the Bayesian models at 1 year was superior to the existing risk models. Bayesian algorithms allow for risk stratification after LVAD implantation across different IM profiles, device types, and implant strategies.

Acid ceramidase is the key enzyme of the ceramide metabolic pathway, which plays a vital role in regulating ceramide - sphingosine-1-phosphate rheostat. Ceramide acts as a proapoptotic molecule, but its metabolite sphingosine-1-phosphate, in contrast, signals for cell proliferation, cell survival, and angiogenesis. Acid ceramidase is highly upregulated in breast tumors and treatment with an acid ceramidase inhibitor, ceranib-2, significantly induced apoptosis in human breast cancer cell lines. However, the mechanisms underlying the induction of apoptosis remain ambiguous to date. Hence, in the present study, we have explored ceranib-2-mediated apoptotic signaling pathways in human breast cancer cell lines. MCF-7 and MDA MB-231 cells were treated with IC50 doses of ceranib-2 and tamoxifen. Nuclear changes showed the apoptotic effect of ceranib-2 in both the cell lines. Loss in the mitochondrial membrane potential was observed only in ceranib-2-treated MCF-7 cells. Ceranib-2 activated intrinsic and extrinsic apoptotic pathways in MCF-7 cells, but only the extrinsic apoptotic pathway was activated in MDA MB-231 cells. Further, ceranib-2 induced apoptosis by activating SAPK/JNK (stress-activated protein kinase/c-Jun N-terminal kinase), p38 MAPK (mitogen-activated protein kinase) apoptotic pathways and by inhibiting the Akt (antiapoptotic) pathway in both the cell lines. Most importantly, ERα (estrogen receptor-α) expression was highly downregulated after ceranib-2 treatment and a docking study predicted the highest binding affinity of ceranib-2 than tamoxifen with ERα in MCF-7 cells. Hence, ceranib-2 may have potential as a chemotherapeutic drug of breast cancer.

Selection is a key determinant of clinical outcomes after left ventricular assist device (LVAD) placement in patients with end-stage heart failure. The HeartMate II risk score (HMRS) has been proposed to facilitate risk stratification and patient selection for continuous flow pumps. This study retrospectively assessed the performance of HMRS in predicting 90 day and 1 year mortality in patients within the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS). A total of 11,523 INTERMACS patients who received a continuous flow LVAD between 2010 and 2015 were retrospectively categorized per their calculated HMRS to predict their 90 day and 1 year risk of mortality. The performance of the score was evaluated by the area under curve (AUC) of the receiver operator characteristic. We also performed multiple regression analysis using variables from the HMRS calculation on the INTERMACS data. The HMRS model showed moderate discrimination for both 90 day and 1 year mortality prediction with AUCs of 61% and 59%, respectively. The predictions had similar accuracy irrespective of whether the pump was axial or centrifugal flow. Multivariable analysis using independent variables used in the original HMRS analysis revealed different set of variables to be predictive of 90 day mortality than those used to calculate HMRS. HMRS predicts both 90 day and 1 year mortality with poor discrimination when applied to a large cohort of LVAD patients. Newer risk prediction models are therefore needed to optimize the therapeutic application of LVAD therapy. Patient selection for appropriate use of LVADs is critical. Currently available risk stratification tools (HMRS) continue to be limited in their ability to accurately predict mortality after LVAD. This study highlights these limitations when applied to a large, comprehensive, multicenter database. HMRS predicts mortality with only modest discrimination when applied to a large cohort of LVAD patients. Better risk stratification tools are needed to optimize outcomes.

Existing risk assessment tools for patient selection for left ventricular assist devices (LVADs) such as the Destination Therapy Risk Score and HeartMate II Risk Score (HMRS) have limited predictive ability. This study aims to overcome the limitations of traditional statistical methods by performing the first application of Bayesian analysis to the comprehensive Interagency Registry for Mechanically Assisted Circulatory Support dataset and comparing it to HMRS. We retrospectively analyzed 8,050 continuous flow LVAD patients and 226 preimplant variables. We then derived Bayesian models for mortality at each of five time end-points postimplant (30 days, 90 days, 6 month, 1 year, and 2 years), achieving accuracies of 95%, 90%, 90%, 83%, and 78%, Kappa values of 0.43, 0.37, 0.37, 0.45, and 0.43, and area under the receiver operator characteristic (ROC) of 91%, 82%, 82%, 80%, and 81%, respectively. This was in comparison to the HMRS with an ROC of 57% and 60% at 90 days and 1 year, respectively. Preimplant interventions, such as dialysis, ECMO, and ventilators were major contributing risk markers. Bayesian models have the ability to reliably represent the complex causal relations of multiple variables on clinical outcomes. Their potential to develop a reliable risk stratification tool for use in clinical decision making on LVAD patients encourages further investigation.

Rationale: There is mounting evidence of a higher incidence of coronary heart disease in cytomegalovirus-seropositive individuals., Objective: The aim of this study was to investigate whether acute myocardial infarction triggers an inflammatory T-cell response that might lead to accelerated immunosenescence in cytomegalovirus-seropositive patients., Methods and Results: Thirty-four patients with acute myocardial infarction undergoing primary percutaneous coronary intervention were longitudinally studied within 3 months after reperfusion (Cohort A). In addition, 54 patients with acute myocardial infarction and chronic myocardial infarction were analyzed in a cross-sectional study (Cohort B). Cytomegalovirus-seropositive patients demonstrated a greater fall in the concentration of terminally differentiated CD8 effector memory T cells (TEMRA) in peripheral blood during the first 30 minutes of reperfusion compared with cytomegalovirus-seronegative patients (-192 versus -63 cells/μL; P=0.008), correlating with the expression of programmed cell death-1 before primary percutaneous coronary intervention (r=0.8; P=0.0002). A significant proportion of TEMRA cells remained depleted for ≥3 months in cytomegalovirus-seropositive patients. Using high-throughput 13-parameter flow cytometry and human leukocyte antigen class I cytomegalovirus-specific dextramers, we confirmed an acute and persistent depletion of terminally differentiated TEMRA and cytomegalovirus-specific CD8(+) cells in cytomegalovirus-seropositive patients. Long-term reconstitution of the TEMRA pool in chronic cytomegalovirus-seropositive postmyocardial infarction patients was associated with signs of terminal differentiation including an increase in killer cell lectin-like receptor subfamily G member 1 and shorter telomere length in CD8(+) T cells (2225 versus 3397 bp; P<0.001)., Conclusions: Myocardial ischemia and reperfusion in cytomegalovirus-seropositive patients undergoing primary percutaneous coronary intervention leads to acute loss of antigen-specific, terminally differentiated CD8 T cells, possibly through programmed cell death-1-dependent programmed cell death. Our results suggest that acute myocardial infarction and reperfusion accelerate immunosenescence in cytomegalovirus-seropositive patients., (© 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wolters Kluwer.)

Management for continuous flow left ventricular assist device (LVAD) thrombosis often relies on speculation of individual clinical risk factors and integration of indirect evidence for device dysfunction. There are no comprehensive guidelines for treatment of this serious complication, and most of our current knowledge comes from anecdotal experience or observational study. More data on effective treatment, both with aggressive pharmacologic and device-based interventions, are needed for improving our understanding of mechanisms driving device thrombosis and for preventing future events. We present a case of LVAD thrombosis with emphasis on recognition and treatment of acute pump thrombosis, and discuss a potentially novel strategy using percutaneous mechanical circulatory support for pump salvage.

Background: The instant blood-mediated inflammatory response (IBMIR) has been shown as a major factor that causes damage to transplanted islets. Withaferin A (WA), an inhibitor of nuclear factor (NF) κB, was shown to suppress the inflammatory response in islets and improve syngeneic islet graft survival in mice. We investigated how treating islets with NF-κB inhibitors affected IBMIR using an in vitro human autologous blood islet model., Methods: Human islets were pretreated with or without NF-κB inhibitors WA or CAY10512 before mixing autologous blood in a miniaturized in vitro tube model. Plasma samples were collected at multiple time points and used for the measurement of C-peptide, proinsulin, thrombin-antithrombin (TAT) complex, and a panel of proinflammatory cytokines. Infiltration of neutrophils into islets was analyzed using immunohistochemistry., Results: Rapid release of C-peptide and proinsulin was observed 3 hr after mixing islets and blood in the control group, but not in the NF-κB inhibitor-treated groups, whereas TAT levels were elevated in all three groups with a peak at 6 hr. Significant elevation of proinflammatory cytokines was observed in the control group after 3 hr, but not in the treatment groups. Significant inhibition of neutrophil infiltration was also observed in the WA group compared with the control (P<0.001) and CAY10512 (P<0.001) groups., Conclusions: A miniaturized in vitro tube model can be useful in investigating IBMIR. The presence of NF-κB inhibitor could alleviate IBMIR, thus improving the survival of transplanted islets. Protection of islets in the peritransplant phase may improve long-term graft outcomes.

Background and Objective: Memory disturbance is a frequent cognitive complaint by patients with multiple sclerosis (MS). Recent dementia research suggests a beneficial role for vitamin D in long-term memory functioning. While data suggest ameliorative effects of vitamin D for the physical impairments of MS, it is unknown whether vitamin D can benefit the cognitive sequelae. We examined the relationship between serum levels of vitamin D and performance on verbal and nonverbal tests of long-term memory in patients with MS., Methods: A sample of 35 adults with relapsing-remitting MS completed cognitive testing and a vitamin D serum (25[OH]D) assay. Memory assessment used clinically established neuropsychological tests with multiple testing formats to determine whether vitamin D level was associated with memory during conditions of varying retrieval demands. Intellectual functioning and mood were also assessed to control for potential confounds., Results: Vitamin D level was positively associated with performance on immediate and delayed recall trials of the Rey Complex Figure Test, effects that held after controlling for intelligence and disease duration. Vitamin D level was not associated with mood, intelligence, or verbal memory performance on the California Verbal Learning Test, Second Edition., Conclusions: Higher vitamin D level was associated with better nonverbal long-term memory performance in MS, particularly in conditions when no aid was given to help retrieval. These results supplement the literature on the neuroprotective effects of vitamin D and suggest that vitamin D is a worthwhile adjunct treatment for MS.

Objective: Atrial fibrillation (AF) may be present within a subset of patients with presumed cryptogenic TIA or stroke and remains undetected by standard diagnostic methods. We hypothesized that AF may be an under-recognized mechanism for cryptogenic TIA/stroke., Methods: A consecutive series of 56 patients with cryptogenic TIA/stroke was analyzed after diagnostic evaluation and Mobile Cardiac Outpatient Telemetry (MCOT) for up to 21 days. Demographic, radiographic, echocardiographic, and MCOT results were reviewed. Predictors of AF detection by MCOT were determined by univariate analysis including Student t test and Fisher exact tests and multivariate analysis., Results: The median MCOT monitoring duration was 21 (range 5-21) days resulting in an AF detection rate of 23% (13/56). AF was first detected after a median of 7 (range 2-19) days of monitoring. Twenty-seven asymptomatic AF episodes were detected in the 13 patients, of which 85% (23/27) were <30 seconds and the remaining 15% (4/27) were 4-24 hours in duration. Diabetes was predictive of AF detection by both univariate (p = 0.024) and multivariate analysis (OR 6.15; 95% CI 1.16 to 32.73; p = 0.033)., Conclusions: There is a high rate of atrial fibrillation (AF) detection by Mobile Cardiac Outpatient Telemetry (21 days) in patients with cryptogenic TIA/stroke that may be related to extended monitoring duration, patient selection, and inclusion of all new onset AF episodes. Brief AF episodes (<30 seconds) may be biomarkers of more prolonged and clinically significant AF.

Purpose of Review: The prevalence of pulmonary arterial hypertension is rising worldwide. Significant progress in our understanding of the pathobiology of pulmonary arterial hypertension has resulted in a shift from vasodilator therapy to the development of specific drugs targeting seminal molecular derangements of this disorder. This review highlights the recent advances in treatment and provides directions for the future care., Recent Findings: Induction of endothelin-1 and decreased transcription of nitric oxide and prostacyclin leads to pulmonary vasoconstriction that triggers several downstream molecular events which result in pulmonary vascular remodeling. Treatment with endothelin receptor antagonists, prostanoids and phosphodiesterase-5 inhibitors that prevent breakdown of cGMP have all demonstrated benefits in prospective, randomized, controlled trials of pulmonary arterial hypertension patients. Future strategies will combine these therapies to explore whether targeting more than one pathway provides synergistic long-term benefit., Summary: Treatment guidelines developed by the American College of Chest Physicians aim to ensure that evidence-based approaches are practiced. Because of genetic heterogeneity in treatment effects and outcomes among patients, pharmacogenetics which will study polymorphisms that modulate the response to treatment will enable physicians to deliver cost-effective, tailored treatments for all pulmonary arterial hypertension patients in the future.

Objective: To provide a review of the cardiac and obstetrical literature regarding the development of peripartum cardiomyopathy and, in particular, to examine risk factors, incidence, diagnosis, prognosis, and evidence-based treatment modalities., Design: An extensive review of the current literature., Results: Peripartum cardiomyopathy is a cardiomyopathy of unknown cause that occurs in pregnant females, most commonly in the early postpartum period. It shares many clinical characteristics with idiopathic dilated cardiomyopathy but occurs at a younger age and is associated with a better prognosis. Diagnosis is based upon the clinical presentation of congestive heart failure and objective evidence of left ventricular systolic dysfunction. Conventional pharmacologic therapy for congestive heart failure, such as diuretics, digoxin, angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, and beta-adrenergic blockers, are routinely used and are quite effective. For those patients who remain refractory to conventional pharmacologic therapy, cardiac transplantation and mechanical circulatory support are viable options., Conclusion: Mortality rates in peripartum cardiomyopathy have decreased, and this is most likely related to advances over the past 5 yrs in medical therapy for heart failure. Aggressive use of implantable defibrillators has significantly reduced the risk of sudden death in these patients. For >50% of peripartum cardiomyopathy patients, left ventricular function normalizes with pharmacologic therapy. However, subsequent pregnancies almost always are associated with recurrence of left ventricular systolic dysfunction.

Background: Activation of the renin-angiotensin and sympathetic nervous systems adversely affect heart failure progression. The ACE deletion allele (ACE D) is associated with increased renin-angiotensin activation; however, its influence on patient outcomes remains uncertain, and the pharmacogenetic interactions with beta-blocker therapy have not been previously evaluated., Methods and Results: We prospectively followed 328 patients (age, 56.1+/-11.9 years) with systolic dysfunction (left ventricular ejection fraction, 0.24+/-0.08) to assess the impact of the ACE D allele on transplant-free survival (median follow-up, 21 months). Transplant-free survival was compared by genotype for the whole cohort and separately in patients with (n=120) and those without beta-blocker therapy (n=208) at the time of entry. Transplant-free survival was significantly poorer for patients with the D: allele (1-year percent survival II/ID/DD=94/77/75; 2-year=78/65/60; ordered log-rank test, P:=0.044). In patients not treated with beta-blockers, the adverse impact of ACE D allele was dramatically increased (1-year percent survival II/ID/DD=95/75/67; 2-year=81/61/48; P:=0.005). In contrast, in patients receiving beta-blocker therapy, no influence of ACE genotype on transplant-free survival was evident (1-year percent survival II/ID/DD=91/80/86; 2-year=70/71/77; P:=0.73)., Conclusions: In a cohort of patients with systolic dysfunction, the ACE D allele was associated with a significantly poorer transplant-free survival. This effect was primarily evident in patients not treated with beta-blockers and was not seen in patients receiving therapy. These findings suggest a potential pharmacogenetic interaction between the ACE D/I polymorphism and therapy with beta-blockers in the determination of heart failure survival.

Background: Primary pulmonary hypertension results from progressive narrowing of the precapillary pulmonary vasculature. A variety of endothelial abnormalities have been identified, including a net reduction in pulmonary clearance of the vasoconstrictor and smooth muscle mitogen endothelin-1. In many patients, net pulmonary release of endothelin-1 is observed. Chronic infusions of epoprostenol (prostacyclin) improve functional capacity, survival, and hemodynamics in patients with advanced primary pulmonary hypertension. We hypothesized that the epoprostenol infusions, as compared with conventional therapy, might alter the abnormal pulmonary endothelin-1 homeostasis., Methods and Results: Using a subset of patients from a larger randomized study comparing epoprostenol plus conventional therapy (n=11 in the present study) with conventional therapy alone (n=7 in the present study), we determined the ratio of plasma endothelin-1 levels in systemic arterial blood leaving the lung to levels in mixed venous blood entering the lung both before randomization and after 88 days of continuous therapy. There were no differences between the 2 groups before therapy, but by day 88, the epoprostenol-treated group had a greater proportion of patients (82%) with an arterial/venous ratio <1 than did the conventional therapy group, in which only 29% of patients had a ratio <1 (P<0.05)., Conclusions: These results suggest that continuous epoprostenol therapy may have a beneficial effect on the balance between endothelin-1 clearance and release in many patients with primary pulmonary hypertension and may provide one explanation for the salutary effect of epoprostenol in this disease.

Background: Transplant-associated coronary arteriopathy is manifested in its early stages by paradoxical coronary artery constriction in response to endothelium-dependent vasodilator stimuli such as the cold pressor test (CPT) and is a major cause of death or retransplantation. Estrogen has vasoactive properties that abolish coronary artery endothelial dysfunction in native hearts. We hypothesized that estrogen attenuates inappropriate coronary artery constriction in cardiac allografts., Methods and Results: Coronary artery diameter and systemic hemodynamic responses to a 90-second CPT were measured before and 15 minutes after double-blind, randomized administration of intravenous conjugated estrogens (1.25 mg) or placebo in men with male cardiac allografts. Before estrogen, 9 men exhibited an abnormal 15.1 +/- 3.0% CPT-induced decrease in coronary artery diameter. However, repeat CPT did not induce significant coronary artery constriction when performed 15 minutes after estrogen. CPT responses before and after estrogen were significantly different (P=.02). Placebo did not influence coronary artery responses to CPT in 6 men. Systemic hemodynamic responses to CPT were not influenced by estrogen or placebo. Estrogen was the only significant determinant of changes in coronary artery responses to CPT., Conclusions: Conjugated estrogens acutely abolish abnormal CPT-induced coronary artery constriction in male cardiac allografts. This favorable vasomotor effect suggests that estrogen may prevent inappropriate coronary artery constriction in men with cardiac transplants.

Background: Although an autoimmune pathogenesis has been postulated for dilated cardiomyopathy, immunosuppressive therapy has not been shown to be effective in clinical trials. Immune modulatory therapy with immune globulin is an effective therapy for Kawasaki disease in children, and recent data suggest that it improves ventricular function in children with new-onset dilated cardiomyopathies. The role of immune globulin therapy in adults with this disorder has not previously been evaluated., Methods and Results: Ten patients were treated with high-dose intravenous immune globulin infusions (2 g/kg). All were hospitalized with NYHA class III to IV heart failure, left ventricular ejection fraction (LVEF) < 0.40, and symptoms for < 6 months at the time of presentation. One patient died before the completion of therapy. The remaining 9 were discharged, and LVEF was reassessed 12 months after therapy. LVEF improved from 0.24 +/- 0.02 (mean +/- SEM) at baseline to 0.41 +/- 0.04 at follow-up (P = .003). All 9 patients improved functionally to NYHA class I to II, and there have been no subsequent hospitalizations for heart failure during the course of follow-up., Conclusions: In this series of patients with new-onset dilated cardiomyopathy treated with high-dose immune globulin, LVEF improved 17 EF units. The effectiveness of intravenous immune globulin therapy in this disorder should be evaluated in a randomized, multicenter trial.

Background: Right heart failure is an important cause of morbidity and mortality in primary pulmonary hypertension. In a recent prospective, randomized study of severely symptomatic patients, treatment with prostacyclin (epoprostenol) produced improvements in hemodynamics, quality of life, and survival. This article describes the echocardiographic characteristics of participants in this trial; the relationship of echocardiographic variables to hemodynamic parameters, exercise capacity, and quality of life; and the echocardiographic changes associated with prostacyclin therapy., Methods and Results: The 81 patients enrolled in this multicenter trial were randomized to treatment with a long-term infusion of prostacyclin in addition to conventional therapy (n = 41) or conventional therapy alone (n = 40) for 12 weeks. Echocardiograms and assessments of hemodynamics, exercise capacity, and quality of life were performed before and after the treatment phase. On baseline evaluation, patients had marked right ventricular dilatation and dysfunction, abnormal septal curvature, and significant tricuspid regurgitation with a high regurgitant velocity. Pericardial effusions were common. More pronounced abnormalities in right heart structure and function were associated with higher pulmonary arterial and mean right atrial pressures, lower cardiac index, and impaired exercise capacity but had no predictable relationship to quality-of-life indicators. The 12-week infusion of prostacyclin had beneficial effects on right ventricular size, curvature of the interventricular septum, and maximal tricuspid regurgitant jet velocity., Conclusions: The echocardiographic manifestations of severe primary pulmonary hypertension reflect abnormalities in hemodynamics and exercise capacity. Prostacyclin has beneficial effects on right heart structure and function that may contribute to the clinical improvement and prolonged survival observed with this drug.

Background: Right ventricular (RV) performance appears to be important in patients with severe heart failure. Although clinical assessments of RV function previously have been limited to load-dependent ejection phase indices, a new method has been developed using the relatively load-insensitive concepts of pressure-volume relations with automated echocardiographic measures of RV cross-sectional area as a surrogate for volume., Methods and Results: Sixteen patients with New York Heart Association functional class IV heart failure and group mean left ventricular ejection fraction of 20 +/- 5% were studied. RV pressure-area loops were recorded on-line from echocardiographic measures of RV area and high-fidelity pressure during transient inferior, vena caval balloon occlusions. RV contractile reserve was assessed as its functional response to an increase in dobutamine from 5.7 +/- 4.1 to 13.1 +/- 4.7 micrograms/kg per minute. Complete data sets were available in 13 patients. Group mean RV end-systolic elastance (E'es) and maximal elastance (E'max) increased with augmented dobutamine infusion (2.9 +/- 1.5 to 5.5 +/- 3.3 mm Hg/cm2 and 3.3 +/- 1.6 to 6.4 +/- 3.9 mm Hg/cm2, respectively; P < .01 versus baseline), although individual responses were variable. During a 30-day follow-up, 9 patients remained unstable, requiring continuous intravenous inotropic therapy; 6 of these had profound deterioration requiring mechanical circulatory support. The remaining 4 patients had a comparatively good short-term outcome with clinical stability. A 100% increase in RV E'es or E'max was associated with a good short-term outcome (P < .05)., Conclusions: RV performance can be assessed by pressure-area relations in patients with heart failure. RV contractile reserve in response to increases in dobutamine was associated with a good short-term outcome and may be of prognostic value in patients with severe heart failure.

A multicenter double-blind, randomized, placebo-controlled trial of oral enoximone, a phosphodiesterase inhibitor, was conducted in 102 outpatients (50 receiving enoximone and 52 receiving placebo) with moderate to moderately severe congestive heart failure. All were on a long-term regimen of digoxin and diuretics without vasodilators and converting enzyme inhibitors. Symptom score was obtained, and exercise testing was performed monthly for 4 months. There were no differences between groups in symptoms or exercise duration at the end of 4 months. A subgroup undergoing analysis of oxygen consumption with measurement of anaerobic threshold during exercise showed an increase (p less than 0.05) in anaerobic threshold at 1 month with enoximone. (2.7 +/- 0.8 ml O2/kg/min) compared with placebo (-0.8 +/- 1.2 ml O2/kg/min). This improvement was not sustained at 4 months (0.5 +/- 1.7 ml O2/kg/min with enoximone and 0.2 +/- 1.5 ml O2/kg/min with placebo). The dropout rate was significantly higher (p less than 0.02) with enoximone (46%) than with placebo (25%). Adverse effects other than death were slightly, but not significantly, higher with enoximone (32%) than with placebo (22%). During therapy, five deaths occurred in the enoximone group, and none occurred in the placebo group (p less than 0.05). Two deaths were sudden, two were from progressive congestive heart failure, and one was from acute myocardial infarction. With intention-to-treat analysis and inclusion of patients who were removed from therapy because of lack of study drug effect, 10 deaths occurred in the enoximone group, and three occurred in the placebo group (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary artery disease (CAD) has been shown in previous uncontrolled studies to be a limiting factor to long-term survival in patients undergoing cardiac transplantation and who were taking conventional immunosuppressive agents. To study the development of CAD after cardiac transplantation in patients taking the newer immunosuppressive agent cyclosporine, we prospectively performed yearly coronary arteriography on all eligible transplantation patients (first year, 57 patients; second year, 30 patients; third year, 14 patients). The prevalence of CAD by life table analysis was 18% at 1 year, 27% at 2 years, and 44% at 3 years. The occurrence of two or more major rejection episodes was associated (p less than .005) with the development of CAD. In two patients who died of CAD, coronary artery histology revealed subintimal inflammatory cellular infiltration in some lesions. These data demonstrate that the prevalence of CAD rises progressively over time and immunologic factors may be important in its development.