Bone Marrow Cells Improve Coronary Flow Reserve in Ischemic Nonrevascularized Myocardium: A MiHeart/IHD Quantitative Perfusion CMR Substudy.

OBJECTIVES: This study investigated whether intramyocardial bone marrow-derived hematopoietic progenitor cells (BMCs) increase coronary flow reserve (CFR) in ischemic myocardial regions where direct revascularization was unsuitable. BACKGROUND: Patients with diffuse coronary artery disease frequently undergo incomplete myocardial revascularization, which increases their risk for future adverse cardiovascular outcomes. The residual regional ischemia related to both untreated epicardial lesions and small vessel disease usually contributes to the disease burden. METHODS: The MiHeart/IHD study randomized patients with diffuse coronary artery disease undergoing incomplete coronary artery bypass grafting to receive BMCs or placebo in ischemic myocardial regions. After the procedure, 78 patients underwent cardiovascular magnetic resonance (CMR) at 1, 6, and 12 months and were included in this cardiac magnetic resonance substudy with perfusion quantification. Segments were classified as target (injected), adjacent (surrounding the injection site), and remote from injection site. RESULTS: Of 1,248 segments, 269 were target (22%), 397 (32%) adjacent, and 582 (46%) remote. The target had significantly lower CFR at baseline (1.40 ± 0.79 vs 1.64 ± 0.89 in adjacent and 1.79 ± 0.79 in remote; both P < 0.05). BMCs significantly increased CFR in target and adjacent segments at 6 and 12 months compared with placebo. In target regions, there was a progressive treatment effect (27.1% at 6 months, P = 0.037, 42.2% at 12 months, P = 0.001). In the adjacent segments, CFR increased by 21.8% (P = 0.023) at 6 months, which persisted until 12 months (22.6%; P = 0.022). Remote segments in both the BMC and placebo groups experienced similar improvements in CFR (not significant at 12 months compared with baseline). CONCLUSIONS: BMCs, injected in severely ischemic regions unsuitable for direct revascularization, led to the largest CFR improvements, which progressed up to 12 months, compared with smaller but persistent CFR changes in adjacent and no improvement in remote segments.

Outcomes in the ISCHEMIA Trial Based on Coronary Artery Disease and Ischemia Severity

BACKGROUND: The ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) postulated that patients with stable coronary artery disease (CAD) and moderate or severe ischemia would benefit from revascularization. We investigated the relationship between severity of CAD and ischemia and trial outcomes, overall and by management strategy. METHODS: In total, 5179 patients with moderate or severe ischemia were randomized to an initial invasive or conservative management strategy. Blinded, core laboratory­interpreted coronary computed tomographic angiography was used to assess anatomic eligibility for randomization. Extent and severity of CAD were classified with the modified Duke Prognostic Index (n=2475, 48%). Ischemia severity was interpreted by independent core laboratories (nuclear, echocardiography, magnetic resonance imaging, exercise tolerance testing, n=5105, 99%). We compared 4-year event rates across subgroups defined by severity of ischemia and CAD. The primary end point for this analysis was all-cause mortality. Secondary end points were myocardial infarction (MI), cardiovascular death or MI, and the trial primary end point (cardiovascular death, MI, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest). RESULTS: Relative to mild/no ischemia, neither moderate ischemia nor severe ischemia was associated with increased mortality (moderate ischemia hazard ratio [HR], 0.89 [95% CI, 0.61­1.30]; severe ischemia HR, 0.83 [95% CI, 0.57­1.21]; P=0.33). Nonfatal MI rates increased with worsening ischemia severity (HR for moderate ischemia, 1.20 [95% CI, 0.86­1.69] versus mild/no ischemia; HR for severe ischemia, 1.37 [95% CI, 0.98­1.91]; P=0.04 for trend, P=NS after adjustment for CAD). Increasing CAD severity was associated with death (HR, 2.72 [95% CI, 1.06­6.98]) and MI (HR, 3.78 [95% CI, 1.63­8.78]) for the most versus least severe CAD subgroup. Ischemia severity did not identify a subgroup with treatment benefit on mortality, MI, the trial primary end point, or cardiovascular death or MI. In the most severe CAD subgroup (n=659), the 4-year rate of cardiovascular death or MI was lower in the invasive strategy group (difference, 6.3% [95% CI, 0.2%­12.4%]), but 4-year all-cause mortality was similar. CONCLUSIONS: Ischemia severity was not associated with increased risk after adjustment for CAD severity. More severe CAD was associated with increased risk. Invasive management did not lower all-cause mortality at 4 years in any ischemia or CAD subgroup.

Evaluation of adenosine deaminase activity in the Mycobacterium tuberculosis culture supernatants.

BACKGROUND: Adenosine deaminase (ADA) catalyzes hydrolytic and irreversible deamination of deoxyadenosine into deoxyinosine and of adenosine into inosine, and is related to lymphocytic proliferation and differentiation. The measurement of ADA activity in body fluids is a useful tool in the evaluation of mycobacterial infections. Elevated ADA activity has been found in pleural effusions of patients with pleural tuberculosis relative to those from patients with nontuberculous pleural diseases, and is mainly associated with cellular host factors such as monocyte-macrophages or lymphocytes. In contrast, there is little information about ADA activity measurement in mycobacteria culture supernatants. METHODS: We evaluated ADA activity as described by Giusti in the culture supernatants of eight Mycobacterium tuberculosis isolates. RESULTS: Mycobacteria culture supernatants did not display any ADA activity. CONCLUSIONS: This result supports the notion that Mycobacterium tuberculosis is not the source of ADA activity. However, increased ADA activity in biological fluids from tuberculosis patients might be due to the interaction of the mycobacterium with host factors.