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Light Chain (AL) and transthyretin (ATTR) amyloidosis are the most common forms of amyloid cardiomyopathy. Population based studies describing the epidemiology and clinical features of amyloid cardiomyopathy are often based in tertiary medical centers and thus may be limited by referral bias.We performed a cohort study of 198 patients diagnosed and treated in the Kaiser Permanente Northern California health care system who had a confirmed diagnosis of cardiac amyloidosis between 2001 and 2016. Associations between demographic, clinical, laboratory and imaging data and patient outcomes were quantified using multivariable Cox proportional hazard models for both the AL and ATTR groups. The average length of follow up was 2.8 years (SD 2.9 years) and overall survival was 69.1 percent at one year and 35.4 percent at five years. In the AL group, lower left ventricular ejection fraction (HR 1.33 per 5-point decrease, P .001), coronary artery disease (HR 3.56, P .001), and diabetes mellitus (HR 3.19, P .001) were associated with all-cause mortality. Increasing age at the time of diagnosis with associated with higher all-cause mortality in both the AL and ATTR groups. Higher levels of B-type natriuretic peptide were associated with all-cause mortality in both groups: Top quartile BNP HR 6.17, P .001 for AL and HR 8.16, P = .002 for ATTR.This study describes a large cohort of patients with amyloid cardiomyopathy derived from a community based, integrated healthcare system and describes demographic, clinical, and laboratory characteristics associated with mortality and heart failure hospitalization. In this population, coronary artery disease, diabetes mellitus, and high BNP levels were strongly associated with mortality.

Bosentan (Tracleer) is an endothelin receptor antagonist prescribed for the treatment of pulmonary arterial hypertension (PAH). Its use is limited by drug-induced liver injury (DILI). To identify genetic markers of DILI, association analyses were performed on 56 Caucasian PAH patients receiving bosentan. Twelve functional polymorphisms in five genes (ABCB11, ABCC2, CYP2C9, SLCO1B1, and SLCO1B3) implicated in bosentan pharmacokinetics were tested for associations with alanine aminotransferase (ALT), aspartate aminotransferase (AST), and DILI. After adjusting for body mass index, CYP2C9*2 was the only polymorphism associated with ALT, AST, and DILI (β = 2.16, P = 0.024; β = 1.92, P = 0.016; odds ratio 95% CI = 2.29-∞, P = 0.003, respectively). Bosentan metabolism by CYP2C9*2 in vitro was significantly reduced compared with CYP2C9*1 and was comparable to that by CYP2C9*3. These results suggest that CYP2C9*2 is a potential genetic marker for prediction of bosentan-induced liver injury and warrants investigation for the optimization of bosentan treatment.

Background The majority of patients with pulmonary hypertension (PH) have non-pulmonary arterial hypertension PH (non-PAH PH) or multifactorial PH. The REVEAL score was designed to predict 1-year survival in patients with pulmonary arterial hypertension (PAH) only. It is unknown whether this model is applicable to a more general population of PH patients. Methods Both newly diagnosed and previously diagnosed patients with PH of any etiology ( n = 200) were enrolled in an observational cohort between the years 2003 and 2009. REVEAL scores were assessed for the ability to predict 1-year survival in the following groups: (1) PAH; (2) non-PAH PH; (3) multifactorial PH; and (4) the entire cohort. Results Of the 200 patients, 126 (63%) had PAH, 32 (16%) had non-PAH PH and 42 (21%) had multifactorial PH. The concordance indices for the model when applied to the various groups were: PAH, 0.72; non-PAH PH, 0.97; multifactorial PH, 0.77; and entire cohort, 0.775. Observed and predicted survivals of the entire cohort according to model-assigned risk strata were not statistically different from one another ( p = 0.60), suggesting adequate model calibration. Conclusions The REVEAL survival prediction model for PAH has comparable performance when applied to a broad population of PH patients. The data suggest that the model may have utility in PH patients in general, subject to validation in a larger cohort.

Pulmonary hypertension associated with left heart disease is the most common form of pulmonary hypertension encountered in clinical practice today. Although frequently a target of therapy, its pathophysiology remains poorly understood and its treatment remains undefined. Pulmonary hypertension in the context of left heart disease is a marker of worse prognosis and disease severity, but whether its primary treatment is beneficial or harmful is unknown. An important step to the future study of this important clinical problem will be to standardize definitions across disciplines to facilitate an evidence base that is interpretable and applicable to clinical practice. In this current statement, we provide an extensive review and interpretation of the current available literature to guide current practice and future investigation. At the request of the Pulmonary Hypertension (PH) Council of the International Society for Heart and Lung Transplantation (ISHLT), a writing group was assembled and tasked to put forth this document as described above. The review process was facilitated through the peer review process of the Journal of Heart and Lung Transplantation and ultimately endorsed by the leadership of the ISHLT PH Council.

Background: Endothelial and leukocytes-derived microparticles (EMPs and LMPs, respectively) are increased in patients with pulmonary hypertension (PH). We hypothesized that the levels of circulating EMPs and LMPs could predict outcome in these patients. Methods: Patients undergoing right heart catheterization for untreated pre-capillary PH were eligible for the study. Baseline hemodynamics and biologic and clinical parameters were measured at the time of enrollment. Measurements of CD62e, CD144 and CD31/CD41 EMPs and CD45 LMPs were performed using flow cytometry in venous platelet-free plasma samples. After inclusion, patients were treated at the discretion of the physician and prospectively followed for 12 months. The primary end-point was the combined occurrence of death and re-admission for right heart failure (RHF) or worsening of RHF symptoms. Results: Seven of 21 patients (mean age 54.1 3.5 years, 62% female) experienced the primary end-point during the study period. These patients had higher baseline levels of CD62e EMPs, LMPs and hsCRP (high sensitivity C-reactive protein) compared to patients without events (p 0.05), whereas no difference was observed for other microparticles and functional and hemodynamics parameters. Receiver operating curve analysis showed that baseline CD62e EMPs levels of 353 events/l predicted clinical complications. Kaplan‐Meier analysis revealed that patients with baseline CD62e EMPs above this cut-off value had a significantly worse prognosis compared with those subjects who had levels below this cut-off (p 0.02, log-rank statistics). Conclusions: Elevated levels of circulating CD62e EMPs but not LMPs in PH patients prior to treatment are associated with adverse clinical events. Assessment of CD62e EMPs levels may represent a new tool for stratification of PH patients. J Heart Lung Transplant 2009;28:1081‐6. Copyright © 2009 by the International Society for Heart and Lung Transplantation.

Pulmonary hypertension has been shown to predict hospitalizations and mortality in patients with heart failure. We aimed to define the prevalence of mixed pulmonary hypertension (MPH; mean pulmonary artery pressureor = 25 mm Hg, pulmonary capillary wedge pressure15 mm Hg, and pulmonary vascular resistanceor = 3 Wood units), identify clinical predictors of MPH, and determine whether MPH predicts adverse outcomes in patients hospitalized with severe heart failure.This is a subgroup analysis of patients assigned to pulmonary artery catheter placement in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial. Patients with and without MPH were compared with respect to baseline characteristics and clinical outcomes, including NYHA class, 6-minute walk distance, quality of life, days hospitalized, and 6-month mortality.Of the 171 patients studied, 80 (47%) had MPH. Older age was the only significant predictor of MPH. MPH patients had lower cardiac index (1.8 +/- 0.5 L/min vs 2.1 +/- 0.5 L/min, P = .001) and higher systemic vascular resistance index (3,179 +/- 1,454 vs 2,550 +/- 927 dynes x s/cm5 x m2, P.001) compared to those without MPH. Importantly, right ventricular function was relatively preserved (median RVSWI 8.7 gm-m/m2/beat) in MPH patients. There were no significant differences in clinical outcomes between the two groups.Mixed pulmonary hypertension is common in patients hospitalized with advanced heart failure and is not associated with adverse short-term clinical outcomes over and above the poor prognosis of ADHF patients without MPH.

Although cardiogenic shock, whether acute or chronic, most frequently results from depressed left ventricular systolic function, the same syndrome can occur in patients with preserved systolic function. The etiologies and the pathophysiology of the syndrome of cardiogenic shock with preserved ejection fraction are distinctly different from those with reduced ejection fraction. The therapeutic approaches are also different. The prognosis of the patients with acute subset of this syndrome is very favorable, provided prompt diagnosis is made and appropriate treatment is provided. In this review, the important causes, pathophysiology, diagnosis, and therapies of patients with ``cardiogenic shock with preserved ejection fraction'' are discussed.

Pulmonary arterial hypertension (PAH) is a disease of the pulmonary vasculature that is characterized by a progressive increase in pulmonary vascular resistance (PVR) and pulmonary artery pressure (PAP) resulting in the development of right ventricular (RV) failure, inadequate oxygenation, and ultimately death. Anesthesia and surgery, both cardiac and noncardiac, are associated with significantly increased morbidity and mortality in patients with PAH due mainly to RV failure, arrhythmias, postoperative hypoxemia, and myocardial ischemia. Preoperative risk assessment and successful management of patients with PAH undergoing general surgery involves an understanding of the pathophysiology of the disease, analysis of preoperative and operative risk factors, intraoperative management, and early recognition and treatment of postoperative complications.

Any form of pulmonary hypertension (PH) uniformly increases the perioperative risks of both cardiac and noncardiac surgery. Specific perioperative management of PH patients is dependent upon the etiology and severity of disease as well as the planned operation. A detailed understanding of right ventricular (RV) physiology and the impact of chronic as well as acute-on-chronic PH is paramount to decisions on selection for surgery, preoperative preparation, anesthetic plan and postoperative care. The highest risk PH patients should be referred to PH centers where a multidisciplinary approach to patient care can be planned and where expertise exists in using a multitude of inhaled and systemic pulmonary vasodilators, as well as pharmacological and emergent mechanical interventions for right ventricular failure. This chapter is intended to be a guide for all physicians managing the perioperative care of patients with pulmonary hypertension, with an emphasis on noncardiac surgery.

Heart transplantation is greatly limited by a scarcity of donor organs. Despite this critical organ shortage, only one third of available donor hearts are recovered for transplantation. Although there are many potential reasons for non-use of a donor heart, 25% to 50% of organs are declined due to reported echocardiographic abnormalities.1 Echocardiographic assessment of potential hearts for transplantation was first reported in 19882 and is now performed on almost all potential heart donors. The ubiquitous use of transthoracic echocardiography (TTE) for cardiac donor evaluation has raised the concern that an error of interpretation may cause a viable organ to be discarded, prompting the consideration of centralized expert interpretation of donor TTEs.3 The question of whether centralized TTE interpretation yields more reliable measurements of donor heart structure and function, however, has never been systematically assessed. We therefore aimed to compare the reliability of core versus community donor TTE interpretation in a contemporary cohort of potential adult organ donors. Approval for this study was obtained from the California Transplant Donor Network (CTDN). The medical records of all adult brain-dead organ donors managed by CTDN who were considered for heart donation (age 18 to 59 years, no known coronary or structural heart disease) from 2011 to 2012 were reviewed to determine whether a TTE had been performed, in which case the digital images were requested from the donor hospital with the local cardiologist’s interpretation. Once 100 donor echocardiograms had been obtained, the following data were extracted from community interpretation reports: left ventricular ejection fraction (EF); internal diameter in diastole and systole (LVIDd, LVIDs); end-diastolic septal and posterior wall dimensions (LVSd, LVPWd); and pattern of LV regional wall motion abnormalities (RWMA). Seventy TTEs were selected to represent a mix of “normal” (normal LV systolic function, no structural heart disease) and “abnormal” studies. These were uploaded into Digisonics Digiview echocardiographic analysis software in the core laboratory at Kaiser Northern California Division of Research. All personal identifiers and study dates were removed to ensure blinding. Each of the 70 studies was assigned a unique study ID. Twenty-nine TTEs that represented a mix of normal and abnormal studies were then duplicated, to test intra-rater reliability, for a total of 99 unique study IDs. The 99 selected TTEs were independently interpreted by two core reviewers. Detailed methods of core TTE interpretation and statistical analyses are presented in the Supplementary Material (available online at www.jhltonline.org). Mean donor age was 35.5 years (range 24.5 to 50 years). The most common cause of death was head trauma (47%), followed by cerebrovascular causes (41%). The mean time from brain death to TTE acquisition was 21 hours (range 17.7 to 24.6 hours). Of the 70 donor hearts studied, 11 were considered unsuitable for transplant by CTDN and were not offered, 16 were offered for transplant but not accepted, 40 were accepted for transplant, and 3 hearts were initially accepted but not recovered due to an aborted transplant. Of the 11 hearts considered unsuitable for transplant, 5 had left ventricular hypertrophy (LVH) and 3 had LV dysfunction by community interpretation; one of these TTEs was classified as normal by both core reviewers. Of the 16 hearts offered but not accepted for transplant, 4 were declined due to LV dysfunction or RWMA and 3 for LVH, based on community interpretation; 2 of these TTEs were subsequently interpreted as normal by core review. Table 1 summarizes the mean differences between core and community TTE measurements. There was no significant difference in LV wall thickness between core and community readers. The core readers reported smaller end-diastolic dimensions, on average, than community readers. The magnitude of this difference, however, was relatively small (0.15 to 0.19 cm). We did find significant differences in LVEF measurements between core and community reviewers, particularly for studies with depressed LV systolic function. Overall, community readers reported lower LVEF values than core readers. Figure 1 shows the Bland–Altman plots comparing core and community values for LV wall thickness and ejection fraction. Figure 1 Bland–Altman plots comparing core and community values for three echocardiographic measurements of interest: LVSd (left ventricular septal wall dimension); LVPWd (left ventricular posterior wall dimension); and LVEF (left ventricular ejection ... Table 1 Mean Differences in Measurements Between Core and Community Readers When LV wall thickness was classified as normal (≤1.1 cm) or abnormal, we found modest inter-rater reliability, with slightly greater agreement between the two core reviewers (kappa = 0.54) compared with core vs community (kappa = 0.48 for Core 1-community and Core 2-community). Overall, core reviewers were more likely to report LVH than were community reviewers. There was great variability in interpretation of RWMA. Of the 70 echocardiograms examined, Core 1 reported an apical-sparing pattern of RWMA, as described in neurocardiogenic injury4 in 9 studies, and global hypokinesis in 7 studies. Core 2 reported an apical-sparing pattern in 3 studies (2 of which were described similarly by Core 1), and diffuse hypokinesis in 6 studies. Community cardiologists reported an apical-sparing pattern in 4 studies (2 of which were described similarly by Core 1, no overlap with Core 2) and global hypokinesis in 4 studies. Overall, interpretation was most likely to concur in the setting of global LV dysfunction, with little agreement between core and community cardiologists with respect to regional patterns. Intra- and inter-rater reliability within and between the two core readers was high, whereas measurement differences between core and community tended to be greater. For example, there was a 5% absolute difference in LVEF measurements within a given reviewer, 6% across the two core reviewers, and 9% and 10% between the two core and community readers. The optimal way to evaluate donor hearts is a matter of debate, but most protocols are based on a consensus report that highlights the use of echocardiography.5 Unfortunately, the accuracy of TTE interpretation can vary. We therefore performed this study to quantify intra- and inter-rater agreement in donor echocardiogram interpretation between two core cardiologists with expertise in donor TTE interpretation, and a pooled sample of cardiologists at local hospitals. We found no significant difference between core and community LV wall thickness measurements. There were significant differences in LV dimensions; in general, core measurements were approximately 0.1 to 0.3 cm smaller than community measurements. The most notable finding from our study was a discrepancy between core and community assessment of LV systolic function. Precise quantification of LVEF is not crucial in hearts with normal systolic function, but is very important in the assessment of hearts with compromised function, when a few percentage points may determine whether or not a heart is accepted for transplantation. Core EF measurements were, on average, higher than community reads. Also, as demonstrated by Bland–Altman plots (Figure 1), there was more consistency in LVEF assessment between the two core reviewers than core vs community measurements for donor hearts with LV dysfunction. In our cohort, two donor hearts that were not accepted for transplant due to LV dysfunction were subsequently interpreted as normal by core review. In cases where acquisition of diagnostic quality echocardiographic images is difficult, such as in donors with chest trauma, use of myocardial contrast echocardiography may enable more accurate assessment of LV function.6 In conclusion, we compared core and community interpretation of LV structure and function, and several significant differences were found, particularly in the evaluation of donor hearts with LV dysfunction. These results provide data supporting the use of real-time expert interpretation of donor echocardiograms, particularly when a donor heart may be declined for transplantation based on abnormal TTE findings.

Anesthesia and surgery are associated with significantly increased morbidity and mortality in patients with pulmonary hypertension due mainly to right ventricular failure, arrhythmias, postoperative hypoxemia, and myocardial ischemia. Preoperative risk assessment and successful management of patients with pulmonary hypertension undergoing cardiac surgery involve an understanding of the pathophysiology of the disease, screening of patients at-risk for pulmonary arterial hypertension, analysis of preoperative and operative risk factors, thorough multidisciplinary planning, careful intraoperative management, and early recognition and treatment of postoperative complications. This article will cover each of these aspects with particular focus on the anesthetic approach for non-cardiothoracic surgeries.

Pulmonary hypertension (PH) can develop in association with many different diseases and risk factors, and its presence is nearly always associated with reduced survival. The prognosis and management of PH is largely dependent upon its underlying etiology and severity of disease. The combination of clinical and hemodynamic classifications of PH provides a framework for the diagnostic evaluation of PH to establish a final clinical diagnosis that guides therapy. As our understanding of the different pathologic mechanisms that underlie the syndrome of PH evolves, so too will the classification and treatment of PH.

Information about a real patient is presented in stages (boldface type) to an expert clinician (Dr John R. Teerlink), who responds to the information, sharing his or her reasoning with the reader (regular type). A discussion by the authors follows. A 51-year-old woman presented to the emergency room with progressive dyspnea on exertion. She was an avid runner, and had completed a half-marathon 2 months before presentation. Since then, she had experienced a rapid decline in exercise capacity such that, on presentation, she was unable to climb a flight of stairs without stopping to catch her breath. She had recently completed a course of azithromycin prescribed by her primary care physician without benefit. She denied chest pain, lower extremity swelling, fevers, chills, or cough. She had had stage II left breast adenocarcinoma successfully treated 2 years before with Adriamycin-containing chemotherapy, radiation to the left chest, and bilateral mastectomy. Her only medication was fexofenadine for seasonal allergies. She had no previous heart disease or cardiovascular risk factors, with the exception of a distant 10–pack-year smoking history. She had no family history of premature cardiovascular disease. There was no history of illicit substance abuse. Dr John R. Teerlink: The differential diagnosis for rapidly progressive dyspnea on exertion includes cardiac, pulmonary, rheumatologic, and hematologic disorders. The notable aspects of the patient's history include her dyspnea on exertion in the absence of any other symptoms and her previous vigorous exercise capacity, which suggests a rapidly progressive process. Her previous breast cancer and associated treatment raises the possibility of Adriamycin-induced cardiomyopathy, radiation-induced coronary artery disease or constrictive pericarditis, or pulmonary embolus. On examination, the patient was comfortable but tachypneic. Her temperature was 36.6°C and her blood pressure was 112/73 mm Hg. Her heart rate was 100 bpm with a respiratory rate of 22 breaths per …

Considerable progress in pediatric cardiac surgery has led to more patients with congenital heart disease surviving into adulthood. However, progressive cardiopulmonary dysfunction often occurs late after palliative or corrective surgeries to the point where transplantation becomes the only treatment option. Adult congenital heart disease represents a growing population of patients being referred for heart, lung, and combined heart-lung transplantation. This group of patients presents multiple unique surgical and medical challenges to transplantation owing to their complex anatomy, multiple prior palliative and corrective procedures, frequently increased pulmonary vascular resistance, and often debilitated condition. Consequently, transplantation in adults with congenital heart disease is associated with a relatively high operative mortality secondary to increased bleeding, infection, and graft failure rates compared with noncongenital heart disease transplant recipients. However, those who survive of the first posttransplant year enjoy an excellent long-term prognosis.

Mutations in genes that encode components of the sarcomere are well established as the cause of hypertrophic and dilated cardiomyopathies. Sarcomere genes, however, are increasingly being associated with other cardiomyopathies. One phenotype more recently recognized as a disease of the sarcomere is restrictive cardiomyopathy (RCM). We report on two patients with RCM associated with multiple mutations in sarcomere genes not previously associated with RCM. Patient 1 presented with NYHA Class III/IV heart failure at 22 years of age. She was diagnosed with RCM and advanced heart failure requiring heart transplantation. Sequencing of sarcomere genes revealed previously reported homozygous p.Glu143Lys mutations in MYL3, and a novel heterozygous p.Gly57Glu mutation in MYL2. The patient's mother is a double heterozygote for these mutations, with no evidence of cardiomyopathy. Patient 2 presented at 35 years of age with volume overload while hospitalized for oophorectomy. She was diagnosed with RCM and is being evaluated for heart transplantation. Sarcomere gene sequencing identified homozygous p.Asn279His mutations in TPM1. The patient's parents are consanguineous and confirmed heterozygotes. Her father was diagnosed with HCM at 42 years of age. This is the first report of mutations in TPM1, MYL3, and MYL2 associated with primary, non-hypertrophied RCM. The association of more sarcomere genes with RCM provides further evidence that mutations in the various sarcomere genes can cause different cardiomyopathy phenotypes. These cases also contribute to the growing body of evidence that multiple mutations have an additive effect on the severity of cardiomyopathies.

Pulmonary hypertension (PH) is characterized by vascular remodeling and endothelial dysfunction. Levels of endothelial (EMPs) and leukocytes-derived (LMPs) microparticles, which are submicron membrane fragments shed from damaged or activated cells, have been shown to be significantly increased in PH patients compared to healthy controls. We hypothesized that the levels of circulating endothelial and leukocytes-MPs could predict outcome in these patients. Patients undergoing right heart catheterization for untreated pre-capillary PH, and without any conditions associated with increased circulating MPs levels, were eligible for the study. The following were measured at the time of enrollment: body mass index, mean pulmonary artery pressure (mPAP), C reactive protein (CRP)and BNP. CD62e+, CD144+, and CD31+/CD41− EMPs and CD45+ LMPs were measured using flow cytometry in platelet-free plasma from venous blood. After inclusion, patients were treated at the discretion of the physician and prospectively followed for 12 months. The primary endpoint assessed was the combined occurrence of death and readmission for right heart failure (RHF) or worsening of RHF symptoms. Seven of 21 patients (mean age=54.1±3.5y/62% female) experienced an adverse clinical event during this period. These patients had significantly higher baseline levels of CD62e+ EMPs (581±123 vs. 202±52 ev/μL, p=0.003), CD45+ LMPs (500±141 vs. 247±44 ev/μL, p=0.03) and CRP (9.9±2.2 vs. 3.8±0.7 IU/L, p=0.004) than patients without events, whereas no difference was observed for CD31+/CD41− and CD144+ EMPs, mPAP or baseline plasma BNP values. Moreover, CD62e+ levels correlated significantly with CD45+ LMPs (r=0.70, p=0.001). Multivariate analysis revealed that 4th quartile levels of CD62e+ EMPs was an independent predictor of adverse event after adjustment for CRP, CD45+ LMPs levels, body mass index and gender. These preliminary results show that high levels of circulating CD62e+ EMPs prior to treatment, but not other MPs subpopulations, are associated with clinical adverse events in PH subjects. These data suggest that this new biological parameter may be useful to predict outcome in patients with PH.

Rationale: Circulating microparticles (MPs) are submicron membrane fragments shed from damaged or activated vascular cells. Endothelial MPs are a biological marker of dysfunctional endothelium. Vascular remodeling and endothelial dysfunction are involved in pulmonary hypertension (PH). Objectives: We tested the hypothesis that circulating MPs are increased in patients with PH and that identifiable subgroups of MPs predict the hemodynamic severity of this condition progression. Methods :P atients (n5 24; age, 54 6 4 yr) undergoing right heart catheterization for precapillary PH without any endothelium-active vasodilator therapy participated in the study. Age- and sex-matched healthycontrolsubjects(n 520)wereincluded.Endothelial(PECAM 1 [CD31 1 ]/CD41 2 ,VE-cadherin 1 [CD144 1 ],andE-selectin 1 [CD62e 1 ]), platelet (CD41 1 ), leukocyte-derived (CD45 1 ), and annexin V 1 MPs weremeasuredbyflowcytometryinplatelet-freeplasmafromvenous blood. Measurements and Main Results: Levels of circulating endothelial PECAM 1 , VE-cadherin 1 , E-selectin 1 , and leukocyte-derived MPs, but not platelet and annexin V1 MPs, were increased in subjects with PH compared with control subjects (P , 0.01 each). PECAM1 and VEcadherin1 MP levels significantly correlated with mean pulmonary artery pressure (r 5 0.92 and r 5 0.87, respectively), pulmonary vascular resistance (r 5 0.78 and r 5 0.73), and mean right atrial pressure(r 5 0.43,andr 5 0.46) andcorrelated inverselywithcardiac index (r 52 0.59 and r 52 0.52). These relationships were not observed for other MP subgroups, and persisted in multivariate analysis after adjustment for confounding factors. Conclusions: In subjects with precapillary PH, levels of circulating endothelialandleukocyteMPswereincreasedcomparedwithcontrol subjects. In addition, levels of PECAM1 and VE-cadherin1 ,b ut not E-selectin 1 , endothelial MPs predicted hemodynamic severity of

BackgroundWe studied the pharmacology of l-methamphetamine, the less abused isomer, when used as a nasal decongestant.Methods12 subjects self-administered l-methamphetamine from a nonprescription inhaler at the recommended dose (16 inhalations over 6 hours) then at 2 and 4 (32 and 64 inhalations) times this dose. In a separate session intravenous phenylephrine (200 microg) and l-methamphetamine (5 mg) were given to define alpha agonist pharmacology and bioavailability. Physiological, cardiovascular, pharmacokinetic, and subjective effects were measured.ResultsPlasma l-methamphetamine levels were often below the level of quantification so bioavailability was estimated by comparing urinary excretion of the intravenous and inhaled doses, yielding delivered dose estimates of 74.0 +/- 56.1, 124.7 +/- 106.6, and 268.1 +/- 220.5 microg for ascending exposures (mean 4.2 +/- 3.3 microg/inhalation). Physiological changes were minimal and not dose-dependent. Small decreases in stroke volume and cardiac output suggesting mild cardiodepression were seen.ConclusionInhaled l-methamphetamine delivered from a non-prescription product produced minimal effects but may be a cardiodepressant.

Despite the possible risk of stroke, over-the-counter (OTC) nasal decongestants are widely used but there are little published data on pharmacodynamic effects. We studied the cardiovascular (CV) pharmacodynamics of the Vicks™ Vapor Inhaler™, an OTC decongestant that has 1-methamphetamine (1-MA; nominally a DEA schedule II drug) as its active ingredient. Twelve normotensive nondrug using subjects were enrolled in an ascending dose, open-label, 3 treatment, 3 period study and dosed with the Vicks inhaler at the manufacturer's maximum recommended dose, and 2 and 4 times that dose over 8 hours. In a separate session, a 200 μg iv dose of phenylephrine was given as a comparator for alpha-adrenergic response. Cardiovascular effects were non-invasively assessed with impedance and 2D stress echocardiography; data were analyzed by ANOVA. Results show that inhaled 1-MA had no acute effects on CV measures; measures were sensitive enough to detect circadian variation and the effects of exercise on multiple CV parameters, but there were no effects of 1-MA. Plasma 1-MA levels were always below detection limits; urine 1-MA concentration increased in a dose proportional manner. Visual analog measures of 'any drug', 'good drug', and 'dizziness' significantly increased from baseline (p