Outcomes of outflow graft stenting in HeartMate 3 left ventricular assist devices: A systematic review and individual patient data meta-analysis.

PURPOSE: LVAD outflow graft stenosis continues to remain prevalent with a high complication rate. We sought to pool the existing evidence on indications, utilization patterns, and outcomes of transcatheter interventions for outflow graft stenosis in the HeartMate 3 LVAD. METHODS: An electronic search was performed to identify all studies in the English literature reporting on HeartMate 3 LVAD outflow graft stenting. Patient-level data were extracted for analysis. RESULTS: Thirteen published reports and one unpublished case comprising a total of 28 patients were included. Median patient age was 68.5 years [Interquartile range: 58, 71] and 25.9% (7/27) were female. Dyspnea [60.7% (17/28)] was the most common presenting symptom. Low flow alarms were present in 60% (15/25) of patients. Findings included external compression [35.7% (10/28)], graft twist [21.4% (6/28)], graft twist and external compression [14.3% (4.28)], intraluminal thrombus [10.7% (3/28)], graft twist and intraluminal thrombus [3.6% (1/28)], and pseudoaneurysm of outflow graft [3.6% (1/28)]. Median time from LVAD implantation to stenting was 2.1 years [1.4, 3]. Immediate flow normalization after stenting was observed in 85.7% (24/28). The 30-day mortality was 12% (3/25). Overall mortality was 12% (3/25) at a median follow-up of 3.9 months [1, 17]. CONCLUSION: Outflow graft stenting in the HeartMate 3 LVAD appears to be a reasonable treatment option for outflow graft stenosis, with low overall rates of complications and mortality. Further refinement of indications and approaches may improve outcomes.

Determinants of pulmonary hypertension in patients with end-stage kidney disease and arteriovenous access.

BACKGROUND: Pulmonary Hypertension (PH) is a sequela of arteriovenous (AV) fistulas (AVF) or AV grafts (AVG) in patients with end-stage kidney disease (ESKD) due to the creation of shunt physiology and increased pulmonary blood flow. PH has been consistently associated with increased mortality but there is a paucity of data regarding management. RESEARCH QUESTION: The objective of this study was to identify risk factors and outcomes in patients who develop PH after AVF or AVG creation for hemodialysis access. METHODS: Using the United States Renal Data System, we identified all patients over age 18 initiated on dialysis from 2012-2019 who did not receive renal transplant. We identified a) the predictors of PH in patients with ESKD on hemodialysis; b) the independent mortality risk associated with development of PH. RESULTS: We identified 478,896 patients initiated on dialysis from 2012-2019 of whom 27,787 (5.8 %) had a diagnosis of PH. The median age was 65 (IQR: 55-74) years and 59.1 % were male. Reduced ejection fraction, any congestive heart failure, obstructive sleep apnea, and female sex were the strongest predictors of PH diagnosis. Both AVG and AVF were also associated with an increased rate of PH diagnosis compared to catheter-based dialysis (p < 0.001). PH portended a poor prognosis and was associated with significantly increased mortality (p < 0.001). CONCLUSIONS: Patients with AVF or AVG should be screened using echocardiography prior to creation and monitored with serial echocardiography for the development of PH, and if present, considered for revision of the AVA. This is also the first study to identify that AVG are a risk factor for PH in dialysis patients.

Association of Heart Transplant Volume with Presence of Lung Transplant Programs and Heart Transplant's SRTR One-year Survival Rating.

BACKGROUND: Several factors affect heart transplant (HTx) and lung transplant (LTx) program outcomes. Variabilities in institutional and community characteristics have been shown to influence survival. At present, half of HTx centers in the United States do not possess a concomitant LTx program. This study sought to better understand the characteristics of HTx with and without LTx programs. METHODS: Nationwide transplant data were collected from the Scientific Registry of Transplant Recipients (SRTR) in August 2020. SRTR star rating ranges from tier 1 (lowest) to tier 5 (highest). HTx volumes and SRTR star ratings for survival were compared between the centers with heart-only (H0) programs and the centers with heart-lung (HL) programs. RESULTS: SRTR star ratings were available for 117 transplant centers with one or more HTx reported. The median number of HTx performed over 1 year was 16 (interquartile range [IQR]: 2-29). The number of HL centers (n = 67, 57.3%) were comparable to H0 centers (n = 50, 42.7%; p = 0.14). The HTx volume at the HL centers (28 [IQR: 17-41]) exceeded the HTx volume at the H0 centers (13 [IQR: 9-23]; p < 0.01), but were comparable to the LTx volume at the HL centers (31 [IQR: 16-46]; p = 0.25). The median HTx one-year survival rating was 3 (IQR: 2-4) at both the H0 and HL centers (p = 0.85). The HTx and LTx volumes were positively associated with the respective 1-year survivals (p < 0.01). CONCLUSION: While the presence of an LTx program is not directly associated with HTx survival, it has a positive association with the HTx volume. The HTx and LTx volumes are positively associated with the 1-year survival.

Transcatheter Aortic Valve Implantation in Cardiac Amyloidosis and Aortic Stenosis.

Aortic stenosis (AS) and cardiac amyloidosis (CA) occur concomitantly in a significant number of patients and portend a higher risk of all-cause mortality. Previous studies have investigated outcomes in patients with concomitant CA/AS who underwent transcatheter aortic valve implantation (TAVI) versus medical therapy alone, but no evidence-based consensus regarding the ideal management of these patients has been established. Medline, Scopus, and Cochrane Central Register of Controlled Trials were systematically searched to identify relevant studies. Methodologic bias was assessed using the modified Newcastle-Ottawa scale for observational studies. A total of 4 observational studies comprising 83 patients were included. Of these, 45 patients (54%) underwent TAVI, whereas 38 (46%) were managed conservatively. Of the 3 studies that included baseline characteristics by treatment group, 30% were women. The risk of all-cause mortality was found to be significantly lower in patients who underwent TAVI than those treated with conservative medical therapy alone (odds ratio 0.24, 95% confidence interval 0.08 to 0.73). In conclusion, this meta-analysis suggests a lower risk of all-cause mortality in patients with CA with AS who underwent TAVI than those managed with medical therapy alone.

PCI for acute myocardial infarction in patients with a pre-existing LVAD, does it improve survival?

BACKGROUND: It is well established that percutaneous coronary intervention (PCI) is a life-saving procedure for acute myocardial infarction (AMI) in the general population and is guideline-recommended for both STEMI and NSTEMI. There is little literature regarding its use in patients with a pre-implanted Left Ventricular Assist Device (LVAD). METHODS: We retrospectively analyzed data from the National Inpatient Sample (NIS) Database to select all US adult patients (>18 years) with an LVAD diagnosed with an AMI divided into two groups; those who received PCI during the hospitalization and those who did not. RESULTS: A total of 3722 LVAD patients with AMI were identified, of these 17% of patients received PCI and 83% did not. After propensity matching of LVAD patients with AMI, there were 626 patients who received PCI and 623 who did not. Of patients receiving PCI, 37.5% had a STEMI while 29.7% of patients who did not receive PCI had STEMI. Rates of kidney injury (36.5% vs. 43.3%, OR 0.75, 95% CI 0.60-0.94, p = 0.016), sepsis (3.2% vs. 11.4%, OR 0.26, 95% CI 0.15-0.43, p < 0.001), cardiogenic shock (44.1% vs. 50.4%, OR 0.78, 95% CI 0.62-0.97, p = 0.03) and mortality (17.4% vs. 28.9%, OR 0.52, 95% CI 0.40-0.68, p < 0.001) were all better for patients receiving PCI. Vascular complications (1.4% vs. 0%, p = 0.008) and intracerebral hemorrhage (ICH) (1.6% vs. 0, p = 0.004) were both more common in the group receiving PCI. CONCLUSIONS: In this study, patients supported by LVAD with AMI had an elevated risk of mortality compared to generally accepted mortality rates of patients without LVAD. In this analysis PCI was associated with a decreased risk of mortality, cardiogenic shock, and kidney injury while increasing the risk for vascular complications and intracranial hemorrhage.

Catheter ablation in patients with atrial fibrillation and heart failure with preserved ejection fraction: A systematic review and meta-analysis.

Background: Catheter ablation for atrial fibrillation (AF) is a proven alternative to pharmacologic rhythm control in patients with heart failure with reduced ejection fraction (HFrEF). Whether outcomes differ in patients with heart failure with preserved ejection fraction (HFpEF) is of interest. Methods: Medline, Scopus, and Cochrane Central Register of Controlled Trials were systematically searched to identify relevant studies. Primary efficacy outcomes of interest include atrial arrythmia recurrence and repeat ablation. Harm outcomes of interest include all-cause mortality, all-cause hospitalizations, cardiovascular hospitalizations, stroke/transient ischemic attack, and cardiac tamponade. Results: We included 7 observational studies comprising 2554 patients with HFpEF who underwent catheter ablation for AF. When comparing patients with HFpEF versus without HF, there was no significant difference in atrial arrhythmia recurrence (risk ratio [RR] 1.39; 95% confidence interval [CI] 0.91-2.13), stroke or transient ischemic attack (TIA) (RR 0.47; 95% CI 0.03-6.54), or cardiac tamponade (RR 1.20; 95% CI 0.12-12.20). When comparing patients with HFpEF versus HFrEF, there was no significant difference in atrial arrhythmia recurrence (RR 1.12; 95% CI 0.92-1.37), repeat ablation (RR 1.19; 95% CI 0.74-1.93), all-cause mortality (RR 0.87; 95% CI 0.67-1.13), all-cause hospitalizations (RR 1.10; 95% CI 0.94-1.30), cardiovascular hospitalizations (RR 0.83; 95% CI 0.69-1.01), stroke or TIA (RR 0.81; 95% CI 0.29-2.25), or cardiac tamponade (RR 0.98; 95% CI 0.19-5.16). Conclusions: Non-randomized studies suggest that catheter ablation for AF in patients with HFpEF is associated with similar arrythmia-free survival and safety profile when compared to patients with HFrEF or without heart failure.

Clinical Outcome of TAVR vs. SAVR in Patients With Cardiac Amyloidosis.

Data regarding the clinical outcomes of transcatheter aortic valve replacement (TAVR) vs. surgical aortic valve replacement (SAVR) in cardiac amyloidosis are lacking. Our study aimed to look at the clinical outcomes of TAVR vs. SAVR in patients with cardiac amyloidosis. METHOD: We queried the National Inpatient Sample database for the years 2009-2014 using validated ICD-9-CM codes for TAVR and SAVR. Propensity score matching (1:1; PSM) was performed and in-hospital outcomes were compared between matched cohorts. RESULTS: Before PSM, the TAVR group had a higher hospitalization cost ($59,192 vs. $56,171.1, p = 0.001) and in-hospital mortality (4.24% vs. 3.27%, p = 0.001) compared to the SAVR group. After PSM, mortality (41.3% vs. 5.81%, p = 0.001) and hospitalization cost ($5907 vs. $6280, p = 0.001) was higher in the SAVR group. Length of stay was shorter in the TAVR group compared to SAVR group before (8.7 vs 11.4 p = 0.001) and after (8.7 vs 0.13.7, p = 0.001) PSM. After PSM, the incidence of acute myocardial infarction (10.10% vs. 17.57%, p = 0.001), acute kidney injury (20.67% vs. 31.40%, p = 0.001) and major bleeding (39.18% vs. 47.90%, p = 0.001) were higher in the SAVR group while the TAVR group had a higher incidence of the stroke (12.47% vs. 11.97%, p = 0.001), vascular complication (14.59% vs. 12.97%, p = 0.001), and permanent pacemaker implantation (10.45% vs. 8.48%, p = 0.001). CONCLUSION: In CA patients, in-hospital mortality and hospitalization costs were higher in the SAVR group than in the TAVR group, while the length of stay was shorter in the TAVR group.

Assessing donor-recipient size metrics for heart transplant outcomes: UNOS database analysis.

STUDY: There is no widely accepted donor to recipient size-match metric to predict outcomes in cardiac transplant. The predictive ability of size-match metrics has not been studied when recipients are stratified by heart failure etiology. We sought to assess the performance of commonly used size metrics to predict survival after heart transplant, accounting for restrictive versus non-restrictive pathology. METHODS: The UNOS registry was queried from 2000 to 2017 for all primary isolated heart transplants. Donor-recipient ratios were calculated for commonly used size metrics and their association with survival was assessed using continuous, nonlinear analysis. RESULTS: 29 817 patients were identified. Height (P < .001), predicted heart mass (PHM) (P = .003), ideal body weight (IBW) (P < .001) and body mass index (BMI) (P = .003) ratios were significantly associated with survival, while weight and body surface area (BSA) ratios were not. When stratified, only BMI ratio retained significance for both restrictive (P = .051) and non-restrictive (P = .003) subsets. Recipients with restrictive etiology had increased risk of mortality with both a lower and higher BMI ratio. CONCLUSIONS: While many metrics show association with survival in the non-restrictive subset, BMI is the only metric that retains significance in the restrictive subset. Recipients with restrictive and non-restrictive etiologies of heart failure tolerate size mismatch differently.

3 Cases of Superior Vena Cava Syndrome Following Percutaneous Right Ventricular Assist Device Placement.

We present 3 cases of superior vena cava (SVC) syndrome following percutaneous right ventricular assist device (RVAD) placement. Each case underscores the importance of early recognition of SVC syndrome in patients with percutaneous RVAD insertion via the internal jugular vein and calls for heightened awareness of device-associated complications. (Level of Difficulty: Advanced.).

Continuous-flow LVAD exchange to a different pump model: Systematic review and meta-analysis of the outcomes.

Despite improved outcomes of modern continuous-flow left ventricular assist devices (CF-LVADs), device exchange is still needed for various indications. While the majority of CF-LVADs are exchanged to the same model, exchange to a different pump model is occasionally warranted. In this meta-analysis, we sought to consolidate the existing evidence to better elucidate the indications and outcomes in these cases. A comprehensive systematic search of adult patient cohorts who underwent CF-LVAD exchange to a different CF-LVAD model was performed. Study-level data from 10 studies comprising 98 patients were extracted and pooled for analysis. Mean patient age was 58 (95% CI: 48-65) and 81% were male. Indication for initial CF-LVAD was ischemic cardiomyopathy in 45% (34-57). Initial device was HeartMate II LVAD (HMII) in 93 (94.9%) and HeartWare HVAD (HW) in 5 (5.1%) patients. After mean CF-LVAD support time of 18.8 (15.2-22.4) months, exchange indications included thrombosis in 71% (43-89), infection in 21% (8-47) and device malfunction in 12% (7-21). HMII to HW exchange occurred in 53 (54.1%) patients, HMII to HeartMate III (HM3) in 32 (32.7%), and HM II to either HW or HM3 in 13 (13.2%) patients. Postoperatively, right ventricular assist device was required in 16% (8-32). Overall, 20% (8-40) of patients experienced a stroke, while HW patients had a significantly higher stroke incidence than HM3 patients (HW: 21% (8-47) vs. HM3: 5% (1-24), P < .01). Overall 30-day mortality was 10% (6-17), while HW had a significantly worse 30-day mortality than HM3 (HW: 13% (7-24) vs. HM3: 5% (1-24), P = .03). Following device exchange from a different CF-LVAD model, HM3 is associated with lower stroke and higher survival when compared to HW.

Outcomes of Mechanical Circulatory Support for Giant Cell Myocarditis: A Systematic Review.

Treatment of giant cell myocarditis (GCM) can require bridging to orthotopic heart transplantation (OHT) or recovery with mechanical circulatory support (MCS). Since the roles of MCS and immunotherapy are not well-defined in GCM, we sought to analyze outcomes of patients with GCM who required MCS. A systematic search was performed in June 2019 to identify all studies of biopsy-proven GCM requiring MCS after 2009. We identified 27 studies with 43 patients. Patient-level data were extracted for analysis. Median patient age was 45 (interquartile range (IQR): 32-57) years. 42.1% (16/38) were female. 34.9% (15/43) presented in acute heart failure. 20.9% (9/43) presented in cardiogenic shock. Biventricular (BiVAD) MCS was required in 76.7% (33/43) of cases. Of the 62.8% (27/43) of patients who received immunotherapy, 81.5% (22/27) used steroids combined with at least one other immunosuppressant. Cyclosporine was the most common non-steroidal agent, used in 40.7% (11/27) of regimens. Immunosuppression was initiated before MCS in 59.3% (16/27) of cases, after MCS in 29.6% (8/27), and not specified in 11.1% (3/27). Immunosuppression started prior to MCS was associated with significantly better survival than MCS alone (p = 0.006); 60.5% (26/43) of patients received bridge-to-transplant MCS; 39.5% (17/43) received bridge-to-recovery MCS; 58.5% (24/41) underwent OHT a median of 104 (58-255) days from diagnosis. GCM recurrence after OHT was reported in 8.3% (2/24) of transplanted cases. BiVAD predominates in mechanically supported patients with GCM. Survival and bridge to recovery appear better in patients on immunosuppression, especially if initiated before MCS.

Atrial Septostomy: A Contemporary Review.

Pulmonary arterial hypertension (PAH) is a rare disease, but it boasts significant morbidity and mortality. Although remarkable achievements have been made in the medical treatment of PAH, there is a role for invasive or surgical procedures in patients with progressive disease despite optimal medical therapy or with no access to such therapy. Atrial septostomy creates a right-to-left intracardiac shunt to decompress the overloaded right ventricle. Despite significant advances to validate and improve this palliative procedure, as well as recent reports of improved outcomes, it is only slowly being adopted. This article aims to detail the history, indications, contraindications, procedural techniques, and outcomes of atrial septostomy. We will also shed light on some of the newer interventions, inspired by the same physiological concept, that are being evaluated as potential palliative modalities in patients with PAH.

Aldosterone antagonists in heart failure.

BACKGROUND: Chronic, systolic heart failure is an increasing and costly health problem, and treatments based on pathophysiology have evolved that include the use of aldosterone antagonists. PURPOSE: Advances in the understanding of neurohormonal responses to heart failure have led to better pharmacologic treatments. The steroid hormone aldosterone has been associated with detrimental effects on the cardiovascular system, such as ventricular remodeling and endothelial dysfunction. This article will review the literature and guidelines that support the use of aldosterone antagonists in the treatment of chronic, systolic heart failure. CONCLUSIONS: Aldosterone antagonists are life-saving drugs that have been shown to decrease mortality in patients with New York Heart Association class III to IV heart failure and in patients with heart failure after an acute myocardial infarction. Additional studies are being conducted to determine if the role of aldosterone antagonists can be expanded to patients with less severe forms of heart failure. CLINICAL IMPLICATIONS: Aldosterone antagonists are an important pharmacologic therapy in the neurohormonal blockade necessary in the treatment of systolic heart failure. These drugs have been shown to decrease mortality and reduce hospital readmission rates. The major complication of aldosterone antagonists is hyperkalemia, which can be avoided with appropriate patient selection and diligent monitoring.

A positive 2-item Patient Health Questionnaire depression screen among hospitalized heart failure patients is associated with elevated 12-month mortality.

BACKGROUND: Given the association of depression with poorer cardiac outcomes, an American Heart Association Science Advisory has advocated routine screening of cardiac patients for depression using the 2-item Patient Health Questionnaire (PHQ-2) "at a minimum." However, the prognostic value of the PHQ-2 among HF patients is unknown. METHODS AND RESULTS: We screened hospitalized HF patients (ejection fraction [EF] <40%) that staff suspected may be depressed with the PHQ-2, and then determined vital status at up to 12-months follow-up. At baseline, PHQ-2 depression screen-positive patients (PHQ-2+; n = 371), compared with PHQ-2 screen-negative patients (PHQ-2-; n = 100), were younger (65 vs 70 years) and more likely to report New York Heart Association (NYHA) functional class III/IV than class II symptoms (67% vs. 39%) and lower levels of physical and mental health-related quality of life (all P ≤ .002); they were similar in other characteristics (65% male, 26% mean EF). At 12 months, 20% of PHQ-2+ versus 8% of PHQ-2- patients had died (P = .007) and PHQ-2 status remained associated with both all-cause (hazard ratio [HR] 3.1, 95% confidence interval [CI] 1.4-6.7; P = .003) and cardiovascular (HR 2.7, 95% CI 1.1-6.6; P = .03) mortality even after adjustment for age, gender, EF, NYHA functional class, and a variety of other covariates. CONCLUSIONS: Among hospitalized HF patients, a positive PHQ-2 depression screen is associated with an elevated 12-month mortality risk.

Valve surgery in a mucopolysaccharidosis type I patient: early prosthetic valve endocarditis.

Mucopolysaccharidosis (MPS) are rare genetic disorders, caused by enzymatic defects that lead to abnormal glycosaminoglycan metabolism and its accumulation. Hurler-Scheie syndrome (MPS I) is associated with a deficiency of the lysosomal enzyme α-L-iduronidase. Enzymatic replacement with intravenous laronidase is a frequently utilized therapeutic option. In patients with MPS I, progressive glycosaminoglycan storage in the heart can lead to valvular abnormalities; however, few surgical heart valve interventions have been reported in MPS I patients. We present an unusual case of a double-valve replacement in an MPS I patient, complicated by early infective endocarditis requiring surgical reintervention. We also present a comprehensive literature review of valve surgery in patients with MPS I and a brief summary of the most relevant surgical considerations, including valve selection and infection prevention.

Coronary angiography predicts improved outcome following cardiac arrest: propensity-adjusted analysis.

OBJECTIVES: Determine if clinical parameters of resuscitated patients predict coronary angiography (CATH) performance and if receiving CATH after cardiac arrest is associated with outcome. INTRODUCTION: CATH is associated with survival in patients suffering out-of-hospital cardiac arrest (OHCA) from ventricular fibrillation or ventricular tachycardia(VF/VT). Its effect on outcome in other cohorts is unknown. METHODS: Chart review of resuscitated cardiac arrest patients between 2005 and 2007. EXCLUSION CRITERIA: immediate withdrawal of care, hemodynamic collapse, or neurologic exam under sedation. Clinical parameters included Glasgow Coma Scale (GCS) arrest location, presenting rhythm, age, and acute ischemic ECG changes (new left bundle branch block or ST-elevation myocardial infarction-STEMI). Logistic regression identified clinical parameters predicting CATH. The association between CATH and good outcome (discharge home or to acute rehabilitation facility) was determined using logistic regression adjusting for likelihood of receiving CATH via propensity score. RESULT: Of the 241 patients, 96 (40%) received CATH. Significant disease (>or=70% stenosis) of >or=1 coronary arteries was identified in 69% of patients including 57% of patients without acute ischemic ECG changes. Unadjusted predictors of CATH were sex, method of arrival, OHCA, presenting rhythm, acute ischemic ECG changes, and GCS. Propensity adjusted logistic regression demonstrated an association between CATH and good outcome (OR 2.16; 95% CI 1.12, 4.19; P<0.02). CONCLUSION: CATH is more likely to be performed in certain patients and identifies a significant number of high-grade stenoses in this population. Receiving CATH was independently associated with good outcome.

Outcomes of a hospital-wide plan to improve care of comatose survivors of cardiac arrest.

BACKGROUND: Therapeutic hypothermia (TH) improves outcomes in comatose survivors of cardiac arrest. Few hospitals have protocol-driven plans that include TH. We implemented a series of process interventions designed to increase TH use and improve outcomes in patients successfully resuscitated from out-of-hospital cardiac arrest (OHCA) or in-hospital cardiac arrest (IHCA). METHODS AND RESULTS: Linked interventions including a TH order sheet, verbal and written feedback to individual providers, an educational program, TH "kit" and on-call consultants to assist with patient care and hypothermia induction were implemented between January 1, 2005 and December 31, 2007 in a large, university-affiliated, tertiary care center. We then completed a retrospective review of all patients treated for cardiac arrest during the study period. Descriptive statistics, chi-squared analyses, or Fisher's exact test were used as appropriate. A p value <0.05 was considered significant. 135 OHCA patients and 106 IHCA patients were eligible for post-arrest care. TH use increased each year in the OHCA group (from 6% to 65% to 76%; p<0.001) and IHCA group (from 0% to 36% to 53%; p=.02). A good outcome was achieved in 21% and 8% of comatose patients with OHCA and IHCA, respectively. Patients with OHCA and ventricular dysrhythmia were more likely to have a good outcome with TH treatment than without it (good outcome in 57% vs. 8%; p=.005). CONCLUSION: Implementing a series of aggressive interventions increased appropriate TH use and was associated with improved outcomes in our facility.

Myocardial Fas and cytokine expression in end-stage heart failure: impact of LVAD support.

Left ventricular assist device (LVAD) support may facilitate myocardial recovery. We evaluated the impact of LVAD support on Fas expression in a cohort with end-stage heart failure. Myocardial gene expression was assessed pre- and post-LVAD by RNase protection assay and compared to control donor hearts. The expression of Fas is markedly elevated at the time of LVAD support and is tightly correlated with TNF expression. While interleukin (IL)-6 was significantly reduced by LVAD support, the impact of support on Fas was highly variable and tightly linked to tumor necrosis factor (TNF). The role of Fas in predicting recovery after LVAD support requires further investigation.

Pathophysiology of plaque instability: insights at the genomic level.

Atherosclerosis and plaque rupture represent complex "traits" of unknown cause that involve multiple genes and their variants. Novel genomic technologies provide us with the tools that will allow for the identification of groupings of genes that determine either susceptibility or resistance relative to the development of atherosclerosis and its thromboembolic complications. This information may, in turn, lead to a clearer understanding of the cause and risk for atherosclerosis. Diagnostic tools, as well as preventive and therapeutic strategies, will be derived from such heightened understanding of the disease process. With this chapter, we have presented the current state of knowledge of atherosclerosis genomics.

Deficient Smad7 expression: a putative molecular defect in scleroderma.

Scleroderma is a chronic systemic disease that leads to fibrosis of affected organs. Transforming growth factor (TGF) beta has been implicated in the pathogenesis of scleroderma. Smad proteins are signaling transducers downstream from TGF-beta receptors. Three families of Smads have been identified: (i) receptor-regulated Smad2 and -3 (R-Smads); (ii) common partner Smad4 (Co-Smad); and (iii) inhibitory Smad6 and -7 (I-Smads, part of a negative feedback loop). We have investigated the signaling components for the TGF-beta pathway and TGF-beta activity in scleroderma lesions in vivo and in scleroderma fibroblasts in vitro. Basal level and TGF-beta-inducible expression of Smad7 are selectively decreased, whereas Smad3 expression is increased both in scleroderma skin and in explanted scleroderma fibroblasts in culture. TGF-beta signaling events, including phosphorylation of Smad2 and -3, and transcription of the PAI-1 gene are increased in scleroderma fibroblasts, relative to normal fibroblasts. In vitro adenoviral gene transfer with Smad7 restores normal TGF-beta signaling in scleroderma fibroblasts. These results suggest that alterations in the Smad pathway, including marked Smad7 deficiency and Smad3 up-regulation, may be responsible for TGF-beta hyperresponsiveness observed in scleroderma.