Description: Background and Purpose— Blood pressure (BP) lowering is often conducted as part of general acute management in patients with acute intracerebral hemorrhage. However, the relationship between BP after antihypertensive therapy and clinical outcomes is not fully known. Methods— Hyperacute (〈3 hours from onset) intracerebral hemorrhage patients with initial systolic BP (SBP) 〉180 mm Hg were included. All patients received intravenous antihypertensive treatment, based on predefined protocol to lower and maintain SBP between 120 and 160 mm Hg. BPs were measured every 15 minutes during the initial 2 hours and every 60 minutes in the next 22 hours (a total of 30 measurements). The mean achieved SBP was defined as the mean of 30 SBPs, and associations between the mean achieved SBP and neurological deterioration (≥2 points’ decrease in Glasgow Coma Score or ≥4 points’ increase in National Institutes of Health Stroke Scale score), hematoma expansion (〉33% increase), and unfavorable outcome (modified Rankin Scale score 4–6 at 3 months) were assessed with multivariate logistic regression analyses. Results— Of the 211 patients (81 women, median age 65 [interquartile range, 58–74] years, and median initial National Institutes of Health Stroke Scale score 13 [8–17]) enrolled, 17 (8%) showed neurological deterioration, 36 (17%) showed hematoma expansion, and 87 (41%) had an unfavorable outcome. On multivariate regression analyses, mean achieved SBP was independently associated with neurological deterioration (odds ratio, 4.45; 95% confidence interval, 2.03–9.74 per 10 mm Hg increment), hematoma expansion (1.86; 1.09–3.16), and unfavorable outcome (2.03; 1.24–3.33) after adjusting for known predictive factors. Conclusions— High achieved SBP after standardized antihypertensive therapy in hyperacute intracerebral hemorrhage was independently associated with poor clinical outcomes. Aggressive antihypertensive treatment may ameliorate clinical outcomes.

Description: Rationale: Hypoplastic left heart syndrome (HLHS) remains a lethal congenital cardiac defect. Recent studies have suggested that intracoronary administration of autologous cardiosphere-derived cells (CDCs) may improve ventricular function. Objective: The aim of this study was to test whether intracoronary delivery of CDCs is feasible and safe in patients with hypoplastic left heart syndrome. Methods and Results: Between January 5, 2011, and January 16, 2012, 14 patients (1.8±1.5 years) were prospectively assigned to receive intracoronary infusion of autologous CDCs 33.4±8.1 days after staged procedures (n=7), followed by 7 controls with standard palliation alone. The primary end point was to assess the safety, and the secondary end point included the preliminary efficacy to verify the right ventricular ejection fraction improvements between baseline and 3 months. Manufacturing and intracoronary delivery of CDCs were feasible, and no serious adverse events were reported within the 18-month follow-up. Patients treated with CDCs showed right ventricular ejection fraction improvement from baseline to 3-month follow-up (46.9%±4.6% to 52.1%±2.4%; P =0.008). Compared with controls at 18 months, cardiac MRI analysis of CDC-treated patients showed a higher right ventricular ejection fraction (31.5%±6.8% versus 40.4%±7.6%; P =0.049), improved somatic growth ( P =0.0005), reduced heart failure status ( P =0.003), and lower incidence of coil occlusion for collaterals ( P =0.007). Conclusions: Intracoronary infusion of autologous CDCs seems to be feasible and safe in children with hypoplastic left heart syndrome after staged surgery. Large phase 2 trials are warranted to examine the potential effects of cardiac function improvements and the long-term benefits of clinical outcomes. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01273857.

Description: Background and Purpose— Faster heart rate predicts higher mortality in coronary heart disease and acute ischemic stroke, but its prognostic significance in intracerebral hemorrhage remains uncertain. We aimed to determine the effect of admission heart rate on clinical and imaging outcomes in patients with intracerebral hemorrhage. Methods— A post hoc pooled analysis of the pilot and main phases of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT 1 and 2). Clinical outcomes were mortality and modified Rankin Scale score at 90 days; and imaging outcome was absolute growth in hematoma volume during the initial 24 hours. Patients were divided into 4 categories according to baseline heart rate (〈65, 65–74, 75–84, and ≥85 bpm) and analyzed using multivariable adjusted models with the lowest heart rate group as the reference. Results— Of 3185 patients with available data, higher admission heart rate was associated with both mortality and worse modified Rankin Scale score: adjusted hazard ratio for heart rate (≥85 versus 〈65 bpm) 1.50 (95% confidence interval, 1.07–2.11) and adjusted odds ratio 1.33 (95% confidence interval, 1.08–1.63), respectively (both P -trend 〈0.05). There was no significant relationship between heart rate and absolute growth in hematoma volume ( P -trend, 0.196). Conclusions— Higher admission heart rate is independently associated with death and poor functional outcome after acute intracerebral hemorrhage. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00226096 and NCT00716079.

Description: Background and Purpose— Degree and timing of blood pressure (BP) lowering treatment in relation to hematoma growth were investigated in the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial-2 (INTERACT2). Methods— INTERACT2 was an international clinical trial of intensive (target systolic BP [SBP], 〈140 mm Hg) versus guideline-recommended (SBP, 〈180 mm Hg) BP lowering in 2839 patients within 6 hours of spontaneous intracerebral hemorrhage and elevated SBP (150–220 mm Hg), in which 964 had repeat cranial computed tomography at 24 hours. ANCOVA models assessed categories of SBP reduction and time to target SBP on 24-hour hematoma growth. Results— Greater SBP reduction was associated with reduced hematoma growth (13.3, 5.0, and 3.0 mL for 〈10, 10–20, and ≥20 mm Hg, respectively; P trend〈0.001). In the intensive treatment group (n=491), the least mean hematoma growth was in patients who achieved target SBP 〈1 hour (2.6 mL) versus to those in target at 1 to 6 (4.7 mL) and 〉6 hours (5.4 mL). The smallest mean absolute hematoma growth (2.0 mL) was in those achieving target SBP 5 to 8 times versus 3 to 4 (3.1 mL) and 0 to 2 times (5.2 mL). Conclusions— Intensive BP lowering with greater SBP reduction, which is achieved quickly and maintained consistently, seems to provide protection against hematoma growth for 24 hours. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00716079.

Description: Background and Purpose— In patients with acute intracerebral hemorrhage (ICH), the shape and density of the hematoma are associated with its subsequent growth, but the impact of these parameters on clinical outcome is uncertain. Methods— Baseline computed tomographic scans and clinical data were obtained in the Intensive Blood Pressure Reduction in Acute Intracerebral Hemorrhage Trial (INTERACT2). Three independent neurologists blind to clinical data assessed ICH for shape and density using a previously described scale. Shape was defined as irregular when the ICH had ≥2 extra lesions added to the ellipsoid-shaped ICH. Density was heterogeneous when there were ≥3 low-density lesions within the ICH. Outcome measures were death and major disability (modified Rankin scale score of 3–5), combined and separate at 90-day postrandomization. Multivariable logistic regression models were used to determine the significance of hematoma characteristics on outcome. Results— There were 2066 patient computed tomographic scans included in the analysis, with 46% and 38% having irregular and heterogeneous ICH, respectively. Irregular shape was independently associated with death/major disability (adjusted odds ratio, 1.60; 95% confidence interval [CI], 1.29–1.98) and major disability alone (adjusted odds ratio, 1.60; 95% CI, 1.31–1.95), but not with death alone (adjusted odds ratio, 0.97; 95% CI, 0.68–1.39). Heterogeneous density was not associated with clinical outcomes (adjusted odds ratio, 1.06; 95% CI, 0.85–1.33), 1.04 (95% CI, 0.73–1.48), and 1.14 (95% CI, 0.93–1.39), respectively, for death/major disability, death alone, and disability alone). Conclusions— Irregular shape, but not heterogeneous density, is independently associated with poor outcome after ICH. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00716079.

Description: Background and Purpose— The discrimination between paroxysmal and sustained (persistent or permanent) atrial fibrillation (AF) has not been considered in the approach to secondary stroke prevention. We aimed to assess the differences in clinical outcomes between mostly anticoagulated patients with sustained and paroxysmal AF who had previous ischemic stroke or transient ischemic attack. Methods— Using data from 1192 nonvalvular AF patients with acute ischemic stroke or transient ischemic attack who were registered in the SAMURAI-NVAF study (Stroke Management With Urgent Risk-Factor Assessment and Improvement-Nonvalvular AF; a prospective, multicenter, observational study), we divided patients into those with paroxysmal AF and those with sustained AF. We compared clinical outcomes between the 2 groups. Results— The median follow-up period was 1.8 (interquartile range, 0.93–2.0) years. Of the 1192 patients, 758 (336 women; 77.9±9.9 years old) and 434 (191 women; 77.3±10.0 years old) were assigned to the sustained AF group and paroxysmal AF groups, respectively. After adjusting for sex, age, previous anticoagulation, and initial National Institutes of Health Stroke Scale score, sustained AF was negatively associated with 3-month independence (multivariable-adjusted odds ratio, 0.61; 95% confidence interval, 0.43–0.87; P =0.006). The annual rate of stroke or systemic embolism was 8.3 and 4.6 per 100 person-years, respectively (multivariable-adjusted hazard ratio, 1.95; 95% confidence interval, 1.26–3.14) and that of major bleeding events was 3.4 and 3.1, respectively (hazard ratio, 1.13; 95% confidence interval, 0.63–2.08). Conclusions— Among patients with previous ischemic stroke or transient ischemic attack, those with sustained AF had a higher risk of stroke or systemic embolism compared with those with paroxysmal AF. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01581502.

Description: Objective— Inflammation contributes to hypertension-induced cardiac damage and fibrotic remodeling. Complement activation produces anaphylatoxins, which are major inflammatory effectors. Here, we investigated the role of complement anaphylatoxins in angiotensin II (Ang II)–induced cardiac remodeling. Approach and Results— We measured human plasma levels of complement anaphylatoxins in hypertensive individuals and controls and studied the role of complement activation in a mouse model of Ang II–induced hypertension and cardiac injury. We found that complement 5a (C5a) concentration was more elevated in hypertensive individuals than in controls. Infusion of Ang II in mice for 7 days led to increased anaphylatoxin concentration in plasma and perivascular C3b deposition in the heart. C5a receptor (C5aR)–deficient but not C3a receptor–deficient mice exhibited markedly reduced cardiac remodeling and inflammation after Ang II infusion. Pharmacological inhibition of C5a production by an anti-C5 monoclonal antibody produced similar effects to C5aR deficiency. Bone marrow chimera experiments revealed that C5aR expression on bone marrow–derived cells was critical in mediating Ang II–induced cardiac injury and remodeling. The C5aR pathway regulated the expression of adhesion molecules on peripheral monocytes, as well as infiltration and cytokine production of macrophage in the heart. Conclusions— Complement is activated in hypertensive hearts, and the C5aR signaling pathway on blood monocytes/macrophages plays a pathological role in Ang II–induced cardiac inflammation and remodeling. Therapeutic inhibition of complement may protect patients from hypertension-related heart injury.

Description: Background and Purpose— A short duration (〈24 hours) of antihypertensive therapy (AHT) after acute intracerebral hemorrhage (ICH) may be sufficient because active bleeding generally ceases within several hours. We aimed to determine the association between sequential systolic blood pressure (SBP) levels during AHT and outcomes in ICH patients. Methods— In 211 hyperacute ICH patients who underwent AHT based on predefined protocol, the mean of hourly SBP (mSBP) measurements was calculated over 1 to 8 hours (first mSBP), 9 to 16 hours (second mSBP), and 17 to 24 hours (third mSBP) after the initiation of AHT. Outcomes included neurological deterioration (72-hour Glasgow Coma Scale decrease ≥2 or National Instititutes of Health Stroke Scale increase ≥4), hematoma expansion (〉33%), and unfavorable outcome (3-month modified Rankin Scale score 4–6). Results— The median first, second, and third mSBPs were 132, 131, and 137 mm Hg, respectively. A higher first mSBP (odds ratio [OR], 2.41; 95% confidence interval [CI], 1.34–4.69 per 10 mm Hg) or second mSBP (OR, 2.08; 95% CI, 1.20–3.80) was independently associated with neurological deterioration, and a higher second mSBP (OR, 1.40; 95% CI, 1.02–2.00) or third mSBP (OR, 1.45; 95% CI, 1.05–2.05) was associated with unfavorable outcome. None of the mSBPs was associated with hematoma expansion. Conclusions— The continuation of AHT throughout the initial 24 hours after ICH may improve outcomes.

Description: Background and Purpose— High-density lipoprotein (HDL) cholesterol is an established protective factor for ischemic stroke. However, the contribution of HDL subclasses to stroke risk and its subtypes is uncertain. Methods— A prospective nested case–control study of 40- to 85-year-old Japanese was undertaken using frozen serum samples collected from 5280 men and 7524 women. They participated in cardiovascular risk surveys from 1985 to 1999 (1 community) and 1989 to 1998 (2 communities) under Circulatory Risk in Communities Study. HDL cholesterol subclasses were classified by high-performance liquid chromatography into 3 subgroups: S-HDL (very small or small HDL), M-HDL (medium HDL), and L-HDL (large or very large HDL) cholesterol. One control subject per case was matched by sex, age, community, serum storage year, and fasting status. Results— In 2005, we identified 241 strokes (155 ischemic and 86 hemorrhagic). S-HDL and M-HDL cholesterol levels were inversely associated with total stroke risk, ischemic stroke, specifically lacunar infarction, and hemorrhagic stroke. After adjustment for cardiovascular risk factors, these associations remained statistically significant. Multivariable conditional odds ratios (95% confidence interval) for 1 SD (0.12 mmol/L) increment of S-HDL cholesterol levels were 0.34 (0.23–0.52) for total stroke, 0.38 (0.23–0.63) for ischemic stroke, 0.33 (0.18–0.61) for lacunar infarction, 0.30 (0.14–0.65) for hemorrhagic stroke, and 0.30 (0.12–0.77) for intraparenchymal hemorrhage. The respective multivariable odds ratios for 1SD (0.10 mmol/L) increment of M-HDL cholesterol levels were 0.56 (0.41–0.75), 0.63 (0.45–0.88), 0.59 (0.40–0.87), 0.41 (0.21–0.80), and 0.38 (0.16–0.90). No associations were found between L-HDL cholesterol levels and risk of total stroke and its subtypes. Conclusions— Small- to medium-sized HDL, not large HDL, cholesterol levels were inversely associated with total stroke risk.