Positive Pressure Ventilation in the Cardiac Intensive Care Unit.

Contemporary cardiac intensive care units (CICUs) provide care for an aging and increasingly complex patient population. The medical complexity of this population is partly driven by an increased proportion of patients with respiratory failure needing noninvasive or invasive positive pressure ventilation (PPV). PPV often plays an important role in the management of patients with cardiogenic pulmonary edema, cardiogenic shock, or cardiac arrest, and those undergoing mechanical circulatory support. Noninvasive PPV, when appropriately applied to selected patients, may reduce the need for invasive mechanical PPV and improve survival. Invasive PPV can be lifesaving, but has both favorable and unfavorable interactions with left and right ventricular physiology and carries a risk of complications that influence CICU mortality. Effective implementation of PPV requires an understanding of the underlying cardiac and pulmonary pathophysiology. Cardiologists who practice in the CICU should be proficient with the indications, appropriate selection, potential cardiopulmonary interactions, and complications of PPV.

The effect of an adenosine A2A agonist on intra-tumoral concentrations of temozolomide in patients with recurrent glioblastoma.

BACKGROUND: The blood-brain barrier (BBB) severely limits the entry of systemically administered drugs including chemotherapy to the brain. In rodents, regadenoson activation of adenosine A2A receptors causes transient BBB disruption and increased drug concentrations in normal brain. This study was conducted to evaluate if activation of A2A receptors would increase intra-tumoral temozolomide concentrations in patients with glioblastoma. METHODS: Patients scheduled for a clinically indicated surgery for recurrent glioblastoma were eligible. Microdialysis catheters (MDC) were placed intraoperatively, and the positions were documented radiographically. On post-operative day #1, patients received oral temozolomide (150 mg/m2). On day #2, 60 min after oral temozolomide, patients received one intravenous dose of regadenoson (0.4 mg). Blood and MDC samples were collected to determine temozolomide concentrations. RESULTS: Six patients were enrolled. Five patients had no complications from the MDC placement or regadenoson and had successful collection of blood and dialysate samples. The mean plasma AUC was 16.4 ± 1.4 h µg/ml for temozolomide alone and 16.6 ± 2.87 h µg/ml with addition of regadenoson. The mean dialysate AUC was 2.9 ± 1.2 h µg/ml with temozolomide alone and 3.0 ± 1.7 h µg/ml with regadenoson. The mean brain:plasma AUC ratio was 18.0 ± 7.8 and 19.1 ± 10.7% for temozolomide alone and with regadenoson respectively. Peak concentration and Tmax in brain were not significantly different. CONCLUSIONS: Although previously shown to be efficacious in rodents to increase varied size agents to cross the BBB, our data suggest that regadenoson does not increase temozolomide concentrations in brain. Further studies exploring alternative doses and schedules are needed; as transiently disrupting the BBB to facilitate drug entry is of critical importance in neuro-oncology.

Advanced Percutaneous Mechanical Circulatory Support Devices for Cardiogenic Shock.

OBJECTIVES: To review temporary percutaneous mechanical circulatory support devices for the treatment of cardiogenic shock, including current evidence, contraindications, complications, and future directions. DATA SOURCES: A MEDLINE search was conducted with MeSH terms: cardiogenic shock, percutaneous mechanical circulatory support, extracorporeal membrane oxygenation, Impella, and TandemHeart. STUDY SELECTION: Selected publications included randomized controlled trial data and observational studies describing experience with percutaneous mechanical circulatory support in cardiogenic shock. DATA EXTRACTION: Studies were chosen based on strength of association with and relevance to cardiogenic shock. DATA SYNTHESIS: Until recently, there were few options if cardiogenic shock was refractory to vasopressors or intra-aortic balloon pump counterpulsation. Now, several percutaneous mechanical circulatory support devices, including Impella (Abiomed, Danvers, MA), TandemHeart (CardiacAssist, Pittsburgh, PA), and extracorporeal membrane oxygenation, are more accessible. Compared with intra-aortic balloon pump, Impella provides greater hemodynamic support but no reduction in mortality. Similarly, TandemHeart improves hemodynamic variables but not survival. Comparative studies have been underpowered for mortality because of small sample size. Veno-arterial extracorporeal membrane oxygenation offers the advantage of biventricular circulatory support and oxygenation, but there are significant vascular complications. Comparative studies with extracorporeal membrane oxygenation have not been completed. Despite lack of randomized controlled data, there has been a substantial increase in use of percutaneous mechanical circulatory support. Several ongoing prospective studies with larger sample sizes may provide answers, and newer devices may become smaller, easier to insert, and more effective. CONCLUSIONS: Mortality from cardiogenic shock remains unacceptably high despite early coronary revascularization or other therapies. Although evidence is lacking and complications rates are high, improvements and experience with percutaneous mechanical circulatory support may offer the prospect of better outcomes.

T-cell Activation and E-selectin Are Associated With Coronary Plaque in HIV-infected Young Adults.

We evaluated immune activation and coronary artery plaque in young adults with human immunodeficiency virus acquired in early life (n = 31). Coronary plaque was positively associated with lipids, immune activation marker %CD8+CD38+DR+ and E-selectin, a marker of endothelial inflammation. Immune activation and endothelial inflammation may drive coronary plaque formation during the early stages of atherosclerosis in the context of chronic human immunodeficiency virus.

Midlife Cardiovascular Risk Factors and Late-Life Unrecognized and Recognized Myocardial Infarction Detect by Cardiac Magnetic Resonance: ICELAND-MI, the AGES-Reykjavik Study.

BACKGROUND: Associations of atherosclerosis risk factors with unrecognized myocardial infarction (UMI) are unclear. We investigated associations of midlife risk factors with UMI and recognized MI (RMI) detected 31 years later by cardiac magnetic resonance. METHODS AND RESULTS: The Reykjavik Study (1967-1991) collected serial risk factors in subjects, mean (SD) age 48 (7) years. In ICELAND-MI (2004-2007), 936 survivors (76 (5) years) were evaluated by cardiac magnetic resonance. Analysis included logistic regression and random effects modeling. Comparisons are relative to subjects without MI. At baseline midlife evaluation, a modified Framingham risk score was significantly higher in RMI and in UMI versus no MI (7.4 (6.3)%; 7.1 (6.2)% versus 5.4 (5.8)%, P<0.001). RMI and UMI were more frequent in men (65%, 64% versus 43%; P<0.0001). Baseline systolic and diastolic blood pressure were significantly higher in UMI (138 (17) mm Hg versus 133 (17) mm Hg; P<0.006; 87 (10) mm Hg versus 84 (10) mm Hg; P<0.02). Diastolic BP was significantly higher in RMI (88 (10) mm Hg versus 84 (10) mm Hg; P<0.02). Cholesterol and triglycerides were significantly higher in RMI (6.7 (1.1) mmol/L versus 6.2 (1.1) mmol/L; P=0.0005; and 1.4 (0.7) mmol/L versus 1.1 (0.7) mmol/L; P<0.003). Cholesterol trended higher in UMI (P=0.08). Serial midlife systolic BP was significantly higher in UMI versus no MI (ß [SE] = 2.69 [1.28] mm Hg, P=0.04). Serial systolic and diastolic BP were significantly higher in RMI versus no MI (4.12 [1.60] mm Hg, P=0.01 and 2.05 [0.91] mm Hg, P=0.03) as were cholesterol (0.43 [0.11] mmol/L, P=0.0001) and triglycerides (0.3 [0.06] mmol/L, P<0.0001). CONCLUSIONS: Midlife vascular risk factors are associated with UMI and RMI detected by cardiac magnetic resonance 31 years later. Systolic blood pressure was the most significant modifiable risk factor associated with later UMI.

A Longitudinal Regional Educational Model for Pulmonary and Critical Care Fellows Emphasizing Small Group- and Simulation-based Learning.

Recent trends have necessitated a renewed focus on how we deliver formal didactic and simulation experiences to pulmonary and critical care medicine (PCCM) fellows. To address the changing demands of training PCCM fellows, as well as the variability in the clinical training, fund of knowledge, and procedural competence of incoming fellows, we designed a PCCM curriculum that is delivered regionally in the Baltimore/Washington, DC area in the summer and winter. The educational curriculum began in 2008 as a collaboration between the Critical Care Medicine Department at the National Institutes of Health and the Pulmonary and Critical Care Section of the Department of Medicine at MedStar Washington Hospital Center and now includes 13 individual training programs in PCCM, critical care medicine, and pulmonary diseases in Baltimore and Washington, DC. Informal and formal feedback from the fellows who participated led to substantial changes to the course curriculum, allowing for continuous improvement. The educational consortium has helped build a local community of educators to share ideas, support each other's career development, and collaborate on other endeavors. In this article, we describe how we developed and deliver this curriculum and report on lessons learned.

Increased coronary vessel wall thickness in HIV-infected young adults.

BACKGROUND: Individuals with long-term human immunodeficiency virus (HIV) infection are at risk for premature vasculopathy and cardiovascular disease (CVD). We evaluated coronary vessel wall thickening, coronary plaque, and epicardial fat in patients infected with HIV early in life compared with healthy controls. METHODS: This is a prospective cross-sectional study of 35 young adults who acquired HIV in early life and 11 healthy controls, free of CVD. Time resolved phase-sensitive dual inversion recovery black-blood vessel wall magnetic resonance imaging (TRAPD) was used to measure proximal right coronary artery (RCA) wall thickness, and multidetector computed tomography (CT) angiography was used to quantify coronary plaque and epicardial fat. RESULTS: RCA vessel wall thickness was significantly increased in HIV-infected patients compared with sex- and race-matched controls (1.32 ± 0.21 mm vs 1.09 ± 0.14 mm, P = .002). No subject had discrete plaque on CT sufficient to cause luminal narrowing, and plaque was not related to RCA wall thickness. In multivariate regression analyses, smoking pack-years (P = .004) and HIV infection (P = .007) were independently associated with thicker RCA vessel walls. Epicardial fat did not differ between groups. Among the HIV-infected group, duration of antiretroviral therapy (ART) (P = .02), duration of stavudine exposure (P < .01), low-density lipoprotein cholesterol (P = .04), and smoking pack-years (P < .01) were positively correlated with RCA wall thickness. CONCLUSIONS: This investigation provides evidence of subclinical coronary vascular disease among individuals infected with HIV in early life. Increased duration of ART, hyperlipidemia, and smoking contributed to proximal RCA thickening, independent of atherosclerotic plaque quantified by CT. These modifiable risk factors appear to influence early atherogenesis as measured by coronary wall thickness and may be important targets for CVD risk reduction.

Optimization of free-breathing whole-heart 3-dimensional cardiac magnetic resonance imaging at 3 tesla to identify coronary vein anatomy and to compare with multidetector computed tomography.

OBJECTIVE: This study optimizes use of 3-T magnetic resonance imaging (MRI) to delineate coronary venous anatomy and compares 3-T MRI with multidetector computed tomography (MDCT) measurements. METHODS: The study population included 37 consecutive subjects (22 men, 19-71 years old). Whole-heart contrast-enhanced MRI images at 3 T were acquired using segmented k-space gradient echo with inversion recovery prepared technique. The MDCT images were obtained using nonionic iodinated contrast. RESULTS: The coronary sinus and great cardiac, posterior interventricular, and anterior interventricular veins were visualized in 100% of cases by both MRI and MDCT. Detection of the posterior vein of the left ventricle and the left marginal vein by MRI was 97% and 81%, respectively. Bland-Altman plots showed agreement in ostial diameter measured by both modalities with correlation coefficients ranging from 0.5 to 0.76. Vein length and distances also agreed closely. CONCLUSIONS: Free-breathing whole-heart 3-dimensional MRI at 3 T provides high-spatial-resolution images and could offer an alternative imaging technique instead of MDCT scans.

Noncompaction of the ventricular myocardium and hydrops fetalis in cobalamin C disease.

Cobalamin C disease (cblC), a form of combined methylmalonic acidemia and hyperhomocysteinemia caused by mutations in the MMACHC gene, may be the most common inborn error of intracellular cobalamin metabolism. The clinical manifestations of cblC disease are diverse and range from intrauterine growth retardation to adult onset neurological disease. The occurrence of structural heart defects appears to be increased in cblC patients and may be related to the function of the MMACHC enzyme during cardiac embryogenesis, a concept supported by the observation that Mmachc is expressed in the bulbis cordis of the developing mouse heart. Here we report an infant who presented with hydrops fetalis, ventricular dysfunction, and echocardiographic evidence of LVNC, a rare congenital cardiomyopathy. Metabolic evaluations, complementation studies, and mutation analysis confirmed the diagnosis of cblC disease. These findings highlight an intrauterine cardiac phenotype that can be displayed in cblC disease in association with nonimmune hydrops.

Pulmonary vein morphology by free-breathing whole heart magnetic resonance imaging at 3 Tesla versus breathhold multi-detector computed tomography.

PURPOSE: To compare pulmonary vein and left atrial anatomy using three-dimensional free-breathing whole-heart magnetic resonance imaging (MR) at 3 Tesla (T) and multi-detector computed tomography (MDCT). MATERIALS AND METHODS: Thirty-three subjects (19 male, age 49 ± 12 years) underwent free-breathing 3T MR and contrast-enhanced MDCT during inspiratory breath hold. Pulmonary vein parameters (ostial areas, diameters, angles) were measured. RESULTS: All pulmonary veins and anomalies were identified by 3T MR and by MDCT. The right-sided pulmonary veins were directed more posteriorly, the right superior pulmonary vein more inferiorly, and the right inferior pulmonary vein more superiorly by 3T MR when compared with MDCT. The cross-sectional area, perimeters and minimum diameters of right-sided pulmonary vein ostia were significantly larger by MR, as were the maximum diameters of right and left inferior pulmonary veins. There were no significant differences between techniques in distance to first pulmonary vein branch. CONCLUSION: Pulmonary vein measurements demonstrated significant differences in angulations and dimensions when 3T MR is compared with MDCT. These differences likely represent hemodynamic and respiratory variation during free-breathing with MR versus breath-holding with MDCT. MR imaging at 3T during free-breathing offers an alternate method to define pulmonary vein and left atrial anatomy without exposure to radiation.

Aneurysmal dilatation of medium caliber arteries in Turner syndrome.

Turner syndrome is the most common chromosomal abnormality in female subjects, affecting 1 in 2000 live births. The condition is associated with a generalized vasculopathy as well as congenital cardiac and other defects. We report aneurysmal dilation of medium caliber arteries involving the celiac axis and coronary vessels in two women with Turner syndrome.

Myocardial perfusion scans: projected population cancer risks from current levels of use in the United States.

BACKGROUND: Myocardial perfusion scans contribute up to 20% of the estimated annual collective radiation dose to the US population. We estimated potential future cancer risk from these scans by age at exposure and current frequency of use in the United States. METHODS AND RESULTS: Usage patterns were determined from national survey data, and radionuclide dosage was based on current guidelines. Cancer risk projection models were generated on the basis of the National Research Council Biological Effects of Ionizing Radiation VII report, under the assumption that risk has a linear relationship with radiation exposure even at low doses. The mean projected number of radiation-related incident cancers and 95% uncertainty intervals were estimated with the use of Monte Carlo simulations. Estimated risks for a scan performed at age 50 years ranged from 2 cancers per 10,000 scans (95% uncertainty interval, 1 to 5) for a positron emission tomography ammonia-13 test to 25 cancers per 10,000 scans (95% uncertainty interval, 9 to 58) for a dual-isotope (thallium-201 plus technetium-99m) scan. Risks were 50% lower at age 70 years but were similar for men and women. The combination of cancer risk estimates and data on frequency of use suggests that the 9.1 million myocardial perfusion scans performed annually in the United States could result in 7400 (95% uncertainty interval, 3300 to 13,700) additional future cancers. CONCLUSIONS: The lifetime cancer risk from a single myocardial perfusion scan is small and should be balanced against likely benefit and appropriateness of the test. The estimates depend on a number of assumptions, including life expectancy. They apply directly to asymptomatic individuals with life expectancies similar to those of the general population. For individuals with a symptomatic clinical profile, on whom such scans are typically performed, the risks will be lower because of shorter life expectancy.

Correlation of echocardiographic findings with cerebral infarction in elderly adults: the AGES-Reykjavik study.

BACKGROUND AND PURPOSE: Chronic effects of hypertension may be observed in multiple end organs. Previous reports suggest that cardiovascular morphological features can mirror cerebral infarction. In this cross-sectional analysis of elderly subjects, we investigated the relationship of a comprehensive set of echocardiographic measures with cerebral infarction detected by MRI. METHODS: We compared echocardiographically determined left ventricular (LV) mass, left atrial volume, aortic root diameter, mitral annular calcification, and measures of diastolic function with cerebral infarction determined by MRI using logistic regression in a random sample drawn from the Age Gene/Environment Susceptibility-Reykjavik Study cohort. The model was first adjusted for age and gender, and then for age, gender, and vascular risk factors. RESULTS: Among 692 subjects aged 75 (standard deviation, 6) years, 28% had at least 1 cerebral infarct. When adjusted for age and gender, the presence of cerebral infarction was modestly related to LV mass (odds ratio [OR], 1.01; 95% confidence interval [CI], 1.00-1.02) and left atrial volume (OR, 1.03; 95% CI, 1.01-1.05), as well as the lowest quartile of early-to-late pulsed Doppler velocity ratio (early-to-late pulsed Doppler velocity ratio <0.75; OR, 1.87; 95% CI, 1.22-2.87). The latter relation remained significant after adjustment for vascular risk factors and LV ejection fraction (OR, 1.82; 95% CI, 1.16-2.86). CONCLUSIONS: Of all echocardiographic parameters, LV filling abnormality as indicated by low early-to-late pulsed Doppler velocity ratio displayed the strongest association with cerebral infarction and this relationship was independent of vascular risk factors. This simple marker of cerebral infarction may be useful when evaluating older patients.

Ventilatory efficiency and resting hemodynamics in hypertrophic cardiomyopathy.

PURPOSE: In patients with systolic heart failure, the ability of cardiopulmonary exercise testing (CPX) variables to reflect pathophysiology is well established. The relationship between CPX and pathophysiology has, however, not been thoroughly investigated in patients with nonobstructive hypertrophic cardiomyopathy (NHCM). The objective of this study was to assess the ability of CPX variables to reflect resting hemodynamics in patients with nonobstructive hypertrophic cardiomyopathy NHCM. METHODS: We performed CPX and right heart catheterization on 83 subjects with NHCM (51 male/32 female, mean age = 38 +/- 10 yr, NYHA I-III mean = 1.7). Peak oxygen consumption ( O2) and minute ventilation/carbon dioxide ratio (V E/VCO2) at peak exercise were compared to resting hemodynamics including pulmonary artery systolic, diastolic and mean pressures (PASP, PADP and MPAP), and pulmonary capillary wedge pressure (PCWP). RESULTS: Elevations in PCWP (> or = 15 mm Hg), PASP (> or =30 and > or = 40 mm Hg), PADP (> 15 mm Hg) and MPAP (> or = 20 mm Hg) were detected in 22, 33, 10, and 23% of subjects, respectively. Peak V E/VCO2 (positive correlation) and peak VO2 (negative correlation) correlated modestly with all pressure measurements (r = 0.33-0.51, P < 0.01 for all measurements). By receiver operating curve analysis, a V E/VCO2 >35.5 exhibited the best diagnostic accuracy with a curve areas of 0.81 for PAP > or = 30 mm Hg (sensitivity/specificity = 86%/67%), 0.87 for PAP > or = 40 mm Hg (77%/100%), 0.86 for MPAP > 20 mm Hg (83%/79%), and 0.84 for PCWP > or = 15 mm Hg (80%/76%). CONCLUSIONS: CPX can accurately identify abnormal resting hemodynamics in patients with NHCM. Further testing of this modality in other forms of diastolic dysfunction may be warranted.

Coronary artery and other vascular calcifications in patients with cystinosis after kidney transplantation.

Cystinosis, an autosomal recessive disorder of lysosomal cystine accumulation, results from mutations in the CTNS gene that encodes the lysosomal cystine transporter, cystinosin. Renal tubular Fanconi syndrome occurs in infancy, followed by rickets, growth retardation, photophobia, and renal failure, which requires renal transplantation at approximately 10 yr of age. Treatment with cysteamine decreases cellular cystine levels, retards renal deterioration, and allows for normal growth. Patients with a history of inadequate cystine depletion therapy may survive, after renal transplantation, into the third to fifth decades but will experience other, extrarenal complications of the disease. Routine chest and head computed tomography scans of 41 posttransplantation patients with cystinosis were reviewed for vascular calcification. The radiologic procedures had been performed to examine lung and brain parenchyma, so there was little ascertainment bias. Thirteen of the 41 patients had vascular calcification, including 11 with coronary artery calcification. One 25-yr-old man required three-vessel coronary artery bypass graft surgery. There were no significant differences between the 13 patients with calcification and the 28 without calcification in the following parameters: Time on dialysis, frequency of transplantation, hypertension, hypercholesterolemia, homozygosity for the 57-kb deletion in CTNS, serum creatinine, and calcium-phosphate product. However, the finding of vascular calcification correlated directly with duration of life without cysteamine therapy and inversely with duration of life under good cystine-depleting therapy. The accumulation of intracellular cystine itself maybe a risk factor for vascular calcifications, and older patients with cystinosis should be screened for this complication.

Cerebellar ataxia, seizures, premature death, and cardiac abnormalities in mice with targeted disruption of the Cacna2d2 gene.

CACNA2D2 is a putative tumor suppressor gene located in the human chromosome 3p21.3 region that shows frequent allelic imbalances in lung, breast, and other cancers. The alpha2delta-2 protein encoded by the gene is a regulatory subunit of voltage-dependent calcium channels and is expressed in brain, heart, and other tissues. Here we report that mice homozygous for targeted disruption of the Cacna2d2 gene exhibit growth retardation, reduced life span, ataxic gait with apoptosis of cerebellar granule cells followed by Purkinje cell depletion, enhanced susceptibility to seizures, and cardiac abnormalities. The Cacna2d2(tm1NCIF) null phenotype has much in common with that of Cacna1a mutants, such as cerebellar neuro-degeneration associated with ataxia, seizures, and premature death. A tendency to bradycardia and limited response of null mutants to isoflurane implicate alpha2delta-2 in sympathetic regulation of cardiac function. In summary, our findings provide genetic evidence that the alpha2delta-2 subunit serves in vivo as a component of P/Q-type calcium channels, is indispensable for the central nervous system function, and may be involved in hereditary cerebellar ataxias and epileptic disorders in humans.