bluuebunny/crossref_metadata_2025 huggingface dataset:
Angiotensin II Type 2 Receptor Overexpression Preserves Left Ventricular Function After Myocardial Infarction
Authors: Yang Zequan , Bove Christina M. , French Brent A. , Epstein Frederick H. , Berr Stuart S. , DiMaria Joseph M. , Gibson Jennifer J. , Carey Robert M. , Kramer Christopher M.
Published: July 2002

Background

—

The role of the angiotensin II type 2 receptor (AT
2
-R) in left ventricular (LV) remodeling may depend on the underlying stimulus. We hypothesized that cardiac AT
2
-R overexpression in transgenic (TG) mice would attenuate remodeling after myocardial infarction (MI).

Methods and Results

—

Ten wild-type (WT) C57BL/6 mice and 12 TG mice that overexpress the AT
2
-R in the heart were studied by cardiac MRI at baseline and days 1, 7, and 28 post-MI induced by 1 hour of occlusion of the LAD followed by reperfusion. Short-axis imaging from apex to base was used to determine LV mass index, end-diastolic and end-systolic volume indices (EDVI, ESVI), regional wall thickness and thickening, and ejection fraction (EF). Gadolinium-DTPA was infused 20 minutes before day 1 imaging to assess infarct size. At baseline, heart rate, blood pressure, LV mass index, and EDVI were similar between groups. Baseline ESVI was lower (0.20±0.07 versus 0.45±0.15 μL/g,
P
<0.001) and EF higher (82.3±4.9% versus 67.7±5.3%,
P
<0.001) in TG than WT. Infarct size was similar (36.6±7.2% in WT, 34.0±7.8% in TG,
P
=NS). When controlled for baseline differences, ESVI was significantly less and EF significantly higher at all time points in TG versus WT. At day 28, ESVI was 1.05±0.32 μL/g in TG and 1.63±0.41 μL/g in WT,
P
<0.03, and EF was 47.3±5.8% versus 34.1±9.2%,
P
<0.003, respectively. Regional wall thickness and thickening were greater in TG both at baseline and at day 28. At day 28, blood pressure and LV dP/dt were higher in TG.

Conclusions

—

Cardiac AT
2
-R overexpression improves LV systolic function at baseline and preserves function during post-MI remodeling.
Health Status Predicts Long-Term Outcome in Outpatients With Coronary Disease
Authors: Spertus John A. , Jones Philip , McDonell Mary , Fan Vincent , Fihn Stephan D.
Published: July 2002

Background

—

Although patient-reported health status measures have been used as end points in clinical trials, they are rarely used in other settings. Demonstrating that they independently predict mortality and hospitalizations among outpatients with coronary disease could emphasize their clinical value.

Methods and Results

—

This study evaluated the prognostic utility of the Seattle Angina Questionnaire (SAQ), a disease-specific health status measure for patients with coronary artery disease. Patients were enrolled in a prospective cohort study from 6 Veterans Affairs General Internal Medicine Clinics. All patients reporting coronary artery disease who completed a SAQ and had 1 year of follow-up were analyzed (n=5558). SAQ predictor variables were the physical limitation, angina stability, angina frequency, and quality-of-life scores. The primary outcome was 1-year all-cause mortality, and a secondary outcome was hospitalization for acute coronary syndrome (ACS). Lower SAQ scores were associated with increased risks of mortality and ACS admissions. Prognostic models controlling for demographic and clinical characteristics demonstrated significant independent mortality risk with lower SAQ physical limitation scores; odds ratios for mild, moderate, and severe limitation were 1.5, 2.0, and 4.0 versus minimal limitation (
P
<0.001). Odds ratios for mild, moderate, and severe angina frequency were 0.8, 1.2, and 1.6 (
P
=0.078). The odds ratios for ACS admission among those with mild, moderate, and severe angina frequency were 1.4, 2.0, and 2.2, respectively (
P
=0.016).

Conclusions

—

SAQ scores are independently associated with 1-year mortality and ACS among outpatients with coronary disease and may serve a valuable role in the risk stratification of such patients.
Circulating Human Heat Shock Protein 60 in the Plasma of British Civil Servants
Authors: Lewthwaite Jo , Owen Natalie , Coates Anthony , Henderson Brian , Steptoe Andrew
Published: July 2002

Background

—

The Whitehall cohort studies (I and II) of British civil servants have identified sociodemographic, psychosocial, and biological risk factors for coronary heart disease (CHD). To identify mechanisms responsible for susceptibility to CHD, specific biological markers of stress are increasingly being measured. One marker linked to susceptibility to CHD is heat shock protein (Hsp) 60.

Methods and Results

—

Blood was taken from 229 civil servants (126 men and 103 women) in the Whitehall II cohort drawn equally from the range of employment grades. Plasma was assayed for levels of Hsp60, tumor necrosis factor α (TNFα), C-reactive protein, von Willebrand factor, high density lipoprotein (HDL), total cholesterol, and total/HDL ratio. Psychosocial measures included socioeconomic status, psychological distress, and social isolation. The majority of the participants had Hsp60 in their plasma, and ≈20% had >1000 ng/mL of this protein (a concentration likely to induce biological effects). A positive association between plasma Hsp60 and TNFα and a negative association with von Willebrand factor was found. There was also a significant association between elevated Hsp60 levels, low socioeconomic status, and social isolation, together with an association with psychological distress in women.

Conclusions

—

The majority of participants exhibited Hsp60 in their plasma, and there was evidence of an association between levels of this stress protein and the proinflammatory cytokine, TNFα, and with various psychosocial measures.
Adverse Outcomes of Interrupted Precordial Compression During Automated Defibrillation
Authors: Yu Ting , Weil Max Harry , Tang Wanchun , Sun Shijie , Klouche Kada , Povoas Heitor , Bisera Joe
Published: July 2002

Background

—

Current versions of automated external defibrillators (AEDs) require frequent stopping of chest compression for rhythm analyses and capacity charging. The present study was undertaken to evaluate the effects of these interruptions during the operation of AEDs.

Methods and Results

—

Ventricular fibrillation was electrically induced in 20 male domestic swine weighing between 37.5 and 43 kg that were untreated for 7 minutes before CPR was started. Defibrillation was attempted with up to 3 sequential 150-J biphasic shocks, but each was preceded by 3-, 10-, 15-, or 20-second interruptions of chest compression. The interruptions corresponded to those that were mandated by commercially marketed AEDs for rhythm analyses and capacitor charge. The sequence of up to 3 electrical shocks and delays were repeated at 1-minute intervals until the animals were successfully resuscitated or for a total of 15 minutes. Spontaneous circulation was restored in each of 5 animals in which precordial compression was delayed for 3 seconds before the delivery of the first and subsequent shocks but in none of the animals in which the delay was >15 seconds before the delivery of the first and subsequent shocks. Longer intervals of CPR interventions were required, and there was correspondingly greater failure of resuscitation in close relationship to increasing delays. The durations of interruptions were inversely related to the durations of subthreshold levels of coronary perfusion pressure. Postresuscitation arterial pressure and left ventricular ejection fraction were more severely impaired with increasing delays.

Conclusions

—

Interruptions of precordial compression for rhythm analyses that exceed 15 seconds before each shock compromise the outcome of CPR and increase the severity of postresuscitation myocardial dysfunction.
Elevations in Troponin T and I Are Associated With Abnormal Tissue Level Perfusion
Authors: Wong Graham C. , Morrow David A. , Murphy Sabina , Kraimer Nicole , Pai Rupal , James David , Robertson Debbie H. , Demopoulos Laura A. , DiBattiste Peter , Cannon Christopher P. , Gibson C.Michael
Published: July 2002

Background

—

Cardiac troponin T (cTnT) and I elevations are associated with a higher risk of adverse events, a higher incidence of multivessel disease, complex lesions, and visible thrombus in the setting of non-ST elevation (NSTE) acute coronary syndromes (ACS). Other pathophysiological mechanisms underlying troponin elevation remain unclear.

Methods and Results

—

We evaluated the relationship between troponin elevation and tissue level perfusion using the TIMI myocardial perfusion grade (TMPG) in 310 patients with NSTE-ACS in the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction (TACTICS-TIMI) 18 trial. TMPG 0/1 (“closed” microvasculature) was observed more frequently in cTnT-positive patients both before (58.1% versus 42.1%;
P
=0.007) and after percutaneous coronary intervention (55.4% versus 35.6%;
P
=0.004). cTnT levels were higher among patients with TMPG 0/1 versus patients with TMPG 2/3 (0.50 versus 0.31 ng/mL;
P
=0.006). cTnT-positive patients were more likely to have thrombus (42.5% versus 29.3%), tighter stenoses (72.0% versus 64.8%), and higher rates of TIMI flow grade 0/1 (15.6% versus 7.0%; all
P
<0.05). TMPG 0/1 remained independently associated with cTnT elevation (odds ratio, 1.81;
P
=0.02), even after adjusting for epicardial TIMI flow grade, presence of thrombus, and prior myocardial infarction. TMPG 0/1 flow both before and after intervention was associated with increased risk of death or myocardial infarction at 6 months.

Conclusions

—

Similar to what has been observed in the setting of ST-elevation myocardial infarction, abnormal tissue level perfusion is also associated with adverse outcomes in the NSTE-ACS setting. Independent of the presence of thrombus and abnormal flow in the epicardial artery, impaired tissue level perfusion is associated with a 1.8-fold increased risk of cTnT elevation.
Prognosis of Aortic Intramural Hematoma With and Without Penetrating Atherosclerotic Ulcer
Authors: Ganaha Fumikiyo , Miller D. Craig , Sugimoto Koji , Do Young Soo , Minamiguchi Hiroki , Saito Haruo , Mitchell R. Scott , Dake Michael D.
Published: July 2002

Background

—

Advances in imaging techniques have increased the recognition of aortic intramural hematomas (IMHs) and penetrating atherosclerotic ulcers (PAUs); however, distinction between IMH and PAU remains unclear. We intended to clarify differences between IMH coexisting with PAU and IMH not associated with PAU by comparisons of clinical features, imaging findings, and patient outcome to derive the optimal therapeutic approach.

Methods and Results

—

We performed a retrospective analysis of 65 symptomatic patients with aortic IMH. There were 34 patients with IMH associated with PAU (group 1) and 31 patients with IMH unaccompanied by PAU (group 2). Involvement of the ascending aorta (type A) was more frequent in group 2 (8 of 31, 26%), whereas most of the patients in group 1 had exclusive involvement of the descending aorta (type B) (31of 34, 91%). Patients were subdivided into 2 categories, those with clinical progression and those with stable disease. Forty-eight percent of patients in group 1 and 8% in group 2 were in the progressive category (
P
=0.002). Clinical and radiological findings were compared between those group 1 patients who had a progressive disease course (n=12) and those who were stable (n=13). Sustained or recurrent pain (
P
<0.0001), increasing pleural effusion (
P
=0.0003), and both the maximum diameter (
P
=0.004) and maximum depth (
P
=0.003) of the PAU were reliable predictors of disease progression.

Conclusions

—

This study suggests a difference in disease behavior that argues for the prognostic importance of making a clear distinction between IMH caused by PAU and IMH not associated with PAU. IMH with PAU was significantly associated with a progressive disease course, whereas IMH without PAU typically had a stable course, especially when limited to the descending thoracic aorta.
Serotonin Transporter Gene Polymorphism and Myocardial Infarction
Authors: Fumeron Frédéric , Betoulle Dina , Nicaud Viviane , Evans Alun , Kee Frank , Ruidavets Jean-Bernard , Arveiler Dominique , Luc Gérald , Cambien François
Published: July 2002

Background

—

Depression is a risk factor for myocardial infarction (MI). Selective serotonin reuptake inhibitors reduce this risk. The site of action is the serotonin transporter (SLC6A4), which is expressed in brain and blood cells. A functional polymorphism in the promoter region of the SLC6A4 gene has been described. This polymorphism may be associated with the risk of MI.

Methods and Results

—

The SLC6A4 polymorphism has been investigated by polymerase chain reaction in 671 male patients with MI and in 688 controls from the Etude Cas-Témoins de l’Infarctus du Myocarde (ECTIM) multicentric study. Percentages for LL, LS, and SS genotypes were 35.5%, 45.4%, and 19.1%, respectively, for cases versus 28.1%, 49.1%, and 22.8%, respectively, for controls. S allele frequency was 41.8% and 47.4% for cases and controls, respectively. After adjustment for age and center by using multivariable logistic regression, the odds ratio for MI associated with the LL genotype was 1.40 (95% CI 1.11 to 1.76,
P
=0.0047).

Conclusions

—

The LL genotype of the SLC6A4 polymorphism is associated with a higher risk of MI. This could be attributable to the effect of the polymorphism on serotonin-mediated platelet activation or smooth muscle cell proliferation or on other risk factors, such as depression or response to stress.
Rate Dependence of [Na
+
]
i
and Contractility in Nonfailing and Failing Human Myocardium
Authors: Pieske Burkert , Maier Lars S. , Piacentino Valentino , Weisser Jutta , Hasenfuss Gerd , Houser Steven
Published: July 2002

Background

—

In the failing human heart, altered Ca
2+
homeostasis causes contractile dysfunction. Because Ca
2+
and Na
+
homeostasis are intimately linked through the Na
+
/Ca
2+
exchanger, we compared the regulation of [Na
+
]
i
in nonfailing (NF) and failing human myocardium.

Methods and Results

—

[Na
+
]
i
was measured in SBFI-loaded muscle strips. At slow pacing rates (0.25 Hz, 37°C), isometric force was similar in NF (n=6) and failing (n=12) myocardium (6.4±1.2 versus 7.2±1.9 mN/mm
2
), but [Na
+
]
i
and diastolic force were greater in failing (22.1±2.6 mmol/L and 15.6±3.2 mN/mm
2
) than in NF (15.9±3.1 mmol/L and 3.50±0.55 mN/mm
2
;
P
<0.05) myocardium. In NF hearts, increasing stimulation rates resulted in a parallel increase in force and [Na
+
]
i
without changes in diastolic tension. At 2.0 Hz, force increased to 136±17% of the basal value (
P
<0.05), and [Na
+
]
i
to 20.5±4.2 mmol/L (
P
<0.05). In contrast, in failing myocardium, force declined to 45±3%, whereas [Na
+
]
i
increased to 27.4±3.2 mmol/L (both
P
<0.05), in association with significant elevations in diastolic tension. [Na
+
]
i
was higher in failing than in NF myocardium at every stimulation rate. [Na
+
]
i
predicted in myocytes from Na
+
pipette
-contraction relations was 8.0 mmol/L in NF (n=9) and 12.1 mmol/L in failing (n=57;
P
<0.05) myocardium at 0.25 Hz. Reverse-mode Na
+
/Ca
2+
exchange induced significant Ca
2+
influx in failing but not NF myocytes, compatible with higher [Na
+
]
i
in failing myocytes.

Conclusions

—

Na
+
i
homeostasis is altered in failing human myocardium. At slow heart rates, the higher [Na
+
]
i
in failing myocardium appears to enhance Ca
2+
influx through Na
+
/Ca
2+
exchange and maintain sarcoplasmic reticulum Ca
2+
load and force development. At faster rates, failing myocytes with high [Na
+
]
i
cannot further increase sarcoplasmic reticulum Ca
2+
load and are prone to diastolic Ca
2+
overload.
Decreased Atherosclerotic Lesion Formation in Human Serum Paraoxonase Transgenic Mice
Authors: Tward Aaron , Xia Yu-Rong , Wang Xu-Ping , Shi Yi-Shou , Park Christina , Castellani Lawrence W. , Lusis Aldons J. , Shih Diana M.
Published: July 2002

Background

—

Serum paraoxonase (PON1), an enzyme carried on HDL, inhibits LDL oxidation, and in human population studies, low PON1 activity is associated with atherosclerosis. In addition, PON1 knockout mice are more susceptible to lipoprotein oxidation and atherosclerosis. To evaluate whether PON1 protects against atherosclerosis and lipid oxidation in a dose-dependent manner, we generated and studied human PON1 transgenic mice.

Methods and Results

—

Human PON1 transgenic mice were produced by using bacterial artificial chromosome genomic clones. The mice had 2- to 4-fold increased plasma PON1 levels, but plasma cholesterol levels were unchanged. Atherosclerotic lesions were significantly reduced in the transgenic mice when both dietary and apoE-null mouse models were used. HDL isolated from the transgenic mice also protected against LDL oxidation more effectively.

Conclusions

—

Our results indicate that PON1 protects against atherosclerosis in a dose-dependent manner and suggest that it may be a potential target for developing therapeutic agents for the treatment of cardiovascular disease.
Adjuvant Treatment With Neuroserpin Increases the Therapeutic Window for Tissue-Type Plasminogen Activator Administration in a Rat Model of Embolic Stroke
Authors: Zhang Zhenggang , Zhang Li , Yepes Manuel , Jiang Quan , Li Qingjiang , Arniego Polly , Coleman Timothy A. , Lawrence Daniel A. , Chopp Michael
Published: July 2002

Background

—

After stroke, the thrombolytic effect of tissue-type plasminogen activator (tPA) in the intravascular space is beneficial, whereas its extravascular effect on ischemic neurons is deleterious. We tested the hypothesis that neuroserpin, a natural inhibitor of tPA, reduces tPA-induced neuronal toxicity and increases its therapeutic window for treatment of embolic stroke.

Methods and Results

—

Rats were subjected to embolic middle cerebral artery occlusion (MCAO). Ischemic brains were treated with neuroserpin in combination with recombinant human tPA (n=7), tPA alone (n=7), or saline (n=9). Neuroserpin (20 μL of 16 μmol/L active neuroserpin) was intracisternally injected 3 hours and tPA (10 mg/kg) was intravenously administered 4 hours after ischemia. MRI measurements were performed to study blood brain barrier (BBB) leakage and ischemic lesion volume. Administration of tPA alone 4 hours after ischemia significantly (
P
<0.05) increased BBB leakage in the ischemic core measured by Gd-DTPA–enhanced MRI compared with rats treated with saline. However, treatment with neuroserpin in combination with tPA significantly (
P
<0.05) reduced BBB leakage, brain edema, and ischemic lesion volume compared with rats treated with tPA alone, although ischemic lesion volumes were the same in both groups before the treatment. Immunostaining revealed that MCAO resulted in reduction of neuroserpin immunoreactivity in the ipsilateral hemisphere after 2 to 6 hours of ischemia. Zymographic assay showed increased plasminogen activity in areas with BBB leakage in rats treated with tPA.

Conclusions

—

Administration of neuroserpin after stroke is neuroprotective, seemingly because it blocks the extravascular effect of tPA, leading to subsequent decrease in stroke volume and widening of the therapeutic window for the thrombolytic effect of tPA.
Impact of a Specific Echocardiographic Report Comment Regarding Endocarditis Prophylaxis on Compliance With American Heart Association Recommendations
Authors: Sanders Gregory P. , Yeon Susan B. , Grunes Jason , Seto Todd B. , Manning Warren J.
Published: July 2002

Background

—

There is substantial underuse and overuse of antibiotic prophylaxis. Current American Heart Association (AHA) recommendations are heavily dependent on echocardiographic data that may not be familiar to referring physicians. We sought to determine the impact of a specific prophylaxis report comment on compliance with AHA recommendations.

Methods and Results

—

Using a standardized electronic reporting system, physicians interpreting ≈50% of echocardiograms included a concluding comment classifying endocarditis risk and stating whether prophylaxis was indicated. The remaining reports were identical in format/content but did not include such comments. Of 1461 eligible outpatients during a 6-month period, 969 (66.3%) responded to a mail survey regarding prophylaxis instructions. Overall, 50% reported taking prophylaxes. Compliance with AHA recommendations was greater among those with a comment (73.2% versus 65.4% for those receiving versus those not receiving comments, respectively;
P
=0.011), with particular improvement among moderate-risk patients (69.5% versus 59.9%,
P
=0.024).

Conclusions

—

An echocardiographic report statement regarding endocarditis risk and need for prophylaxis is a simple low-cost intervention that improves compliance with AHA recommendations. Interpreting physicians should become familiar with AHA recommendations and include a concluding statement addressing prophylaxis.
Fish-Rich Diet, Leptin, and Body Mass
Authors: Winnicki Mikolaj , Somers Virend K. , Accurso Valentina , Phillips Bradley G. , Puato Massimo , Palatini Paolo , Pauletto Paolo
Published: July 2002

Background

—

Leptin has been implicated in cardiovascular disease. A diet rich in fish has been associated with decreased cardiac and vascular risk.

Methods and Results

—

We examined the relationship between diet and leptin in 2 related homogeneous African tribal populations of Tanzania. One tribe consumes freshwater fish as their main diet component (n=279), and the other tribe consumes a primarily vegetarian diet (n=329). In multivariate analysis, plasma leptin levels were associated with type of diet (F=14.3,
P
<0.001), independent of age, body mass index, body fat, alcohol consumption, or insulin. Both male (2.5±2 [fish diet] versus 11.2±2.4 [vegetarian diet] ng/mL,
P
=0.017) and female (5.0±1.9 [fish diet] versus 11.8±1.4 [vegetarian diet] ng/mL,
P
=0.007) fish eaters had lower plasma leptin levels than did their vegetable diet counterparts, even though body mass index values were virtually identical.

Conclusions

—

A diet rich in fish is associated with lower plasma leptin, independent of body fat. These findings may have implications for understanding the reduced cardiovascular risk in subjects on a high-fish diet.
Association Between Enhanced Soluble CD40L and Prothrombotic State in Hypercholesterolemia
Authors: Cipollone Francesco , Mezzetti Andrea , Porreca Ettore , Di Febbo Concetta , Nutini Michele , Fazia Maria , Falco Angela , Cuccurullo Franco , Davì Giovanni
Published: July 2002

Background

—

Hypercholesterolemia is associated with inflammation and the prothrombotic state. CD40-CD40 ligand (CD40L) interactions promote a prothrombotic response in nucleated cells. The aim of this study was to characterize the in vivo expression of soluble CD40L (sCD40L) in hypercholesterolemia, to correlate it with the extent of the prothrombotic state, and to investigate whether it may be modified by statins.

Methods and Results

—

We studied 80 hypercholesterolemic patients and 80 matched healthy subjects. Hypercholesterolemic subjects had enhanced levels of sCD40L, factor VIIa (FVIIa), and prothrombin fragment 1+2 (F1+2) compared with healthy subjects. sCD40L correlated with total cholesterol and LDL cholesterol. Moreover, sCD40L was positively associated with in vivo platelet activation, as reflected by plasma P-selectin and urinary 11-dehydro-thromboxane B
2
, and with procoagulant state, as reflected by FVIIa and F1+2. Inhibition of cholesterol biosynthesis by pravastatin or cerivastatin was associated with comparable, significant reductions in sCD40L, FVIIa, and F1+2.

Conclusions

—

This study suggests that sCD40L may represent the molecular link between hypercholesterolemia and the prothrombotic state and demonstrates that statin therapy may significantly reduce sCD40L and the prothrombotic state.
Neuronal NO Mediates Cerebral Vasodilator Responses to K
+
in Hypertensive Rats
Authors: Chrissobolis Sophocles , Ziogas James , Anderson Colin R. , Chu Yi , Faraci Frank M. , Sobey Christopher G.
Published: July 2002

Potassium ion (K
+
) normally causes cerebral vasodilatation by activating inwardly rectifying K
+
(K
IR
) channels. We tested whether chronic hypertension affects the magnitude and/or mechanism of K
+
-induced cerebral vasodilatation in vivo. Basilar artery responses were examined in anesthetized Wistar-Kyoto (WKY; mean arterial pressure, 114±4 mm Hg) and spontaneously hypertensive (SHR; 176±3 mm Hg) rats. In WKY, elevating cerebrospinal fluid K
+
concentration from 3 mmol/L to 5 and 10 mmol/L caused vasodilatation (percent maximum, 12±1 and 48±7, respectively). The response to 5 mmol/L K
+
was greater in SHR (percent maximum, 17±2 [
P
<0.05 versus WKY] and 49±4). The K
IR
channel inhibitor, barium ion (Ba
2+
, 100 μmol/L) selectively inhibited dilator responses to 5 and 10 mmol/L K
+
by ≈75% in WKY. In SHR, Ba
2+
had no effect on the response to 5 mmol/L K
+
, and only partially inhibited (by ≈40%) the response to 10 mmol/L K
+
. The nonselective NO synthase (NOS) inhibitor Nω-nitro-
l
-arginine methyl ester, the neuronal NOS (nNOS) inhibitor 1-(2-trifluromethyl-phenyl)imidazole, and the
N
-type calcium channel inhibitor ω-conotoxin GVIA, were all without effect in WKY, but markedly inhibited the response to 5 mmol/L K
+
in SHR. When applied together with Ba
2+
, each of these inhibitors also profoundly reduced responses to 10 mmol/L K
+
in SHR. Immunostaining of basilar arteries revealed that the perivascular nNOS-containing nerve plexus was denser in SHR. Thus, K
+
dilates the normotensive basilar artery predominantly via K
IR
channel activation. During chronic hypertension, small physiological elevations in K
+
dilate the basilar artery by an nNOS-dependent mechanism that appears to be upregulated in a compensatory manner.
Sympathetic Response to Ventricular Extrasystolic Beats in Hypertension and Heart Failure
Authors: Grassi Guido , Seravalle Gino , Bertinieri Giovanni , Stella Maria Luisa , Turri Carlo , Mancia Giuseppe
Published: July 2002

Provoked premature ventricular contractions (PVCs) evoke, in concomitance with an early and late blood pressure fall and overshoot, an early sympathoexcitation and a later period of sympathoinhibition, respectively. The present study was designed to examine whether in healthy subjects this is the case for spontaneous PVCs. Because of their pathophysiological relevance for arrhythmogenesis, it was also designed to determine whether the sympathetic responses are different from those seen in essential hypertension and congestive heart failure. In 14 untreated mild essential hypertensives (EH; age, 53.8±2.6 years; mean±SEM), 20 untreated congestive heart failure patients (CHF; age, 56.7±2.5 years; New York Heart Association class, II or III), and 16 age-matched healthy subjects (control) in Lown class <II, we evaluated the blood pressure (Finapres), heart rate (ECG), and muscle sympathetic nerve traffic (MSNA; by microneurography) responses to isolated monofocal PVCs. MSNA, quantified as bursts/100 heart beats, was significantly increased in EH (57.8±3.8,
P
<0.05) and CHF patients (77.7±4.0,
P
<0.01) compared with controls (44.6±4.4). In controls, the PVC-induced blood pressure fall and overshoot were accompanied by a sympathoexcitation (144.2±14%), followed by a period of sympathoinhibition (average duration, 12043±985 ms). The responses were similar in EH but not in CHF, in whom the magnitude of the sympathoexcitation and particularly the duration of the subsequent sympathoinhibition were strikingly reduced (average reduction, −46.1 and −72.8%, respectively). The most important factor accounting for this reduction appeared to be an altered baroreflex response to the PVC-induced BP changes. These data demonstrate that the MSNA responses to spontaneous PVCs are similar in controls and EH but markedly impaired in CHF, presumably because of the baroreflex alteration. This may represent an important factor for the genesis of the life-threatening ventricular arrhythmias that characterize CHF.
Impaired Stress-Induced Pressure Natriuresis Is Related to Left Ventricle Structure in Blacks
Authors: Harshfield Gregory A. , Treiber Frank A. , Davis Harry , Kapuku Gaston K.
Published: July 2002

The mechanisms through which stress may contribute to the racial difference in the prevalence of essential hypertension and associated target organ damage remain unclear. This study examined differences in stress-induced pressure natriuresis in 69 black and 52 white normotensives age 14 to 27 years, all with a positive family history of hypertension. Urine samples for sodium excretion were collected before and after a series of tasks (video game challenge, forehead cold stimulation). The average blood pressure across the 2 tasks and the average increase in blood pressure to the 2 tasks were calculated. Blacks had higher mean systolic (131±12 versus 126±12 mm Hg,
P
<0.02) and diastolic (77±8 versus 72±9 mm Hg,
P
<0.001) blood pressure and a greater average change in systolic blood pressure (15±9 versus 11±7 mm Hg,
P
<0.04). This was associated with a smaller change in sodium excretion (2±6 versus 7±10 mEq/h,
P
<0.002). The change in sodium excretion was related to the change in systolic (
r
=0.31,
P
<0.03) and diastolic (
r
=0.27,
P
<0.05) blood pressure in whites but not in blacks. Relative wall thickness was greater in blacks (0.31±0.04 versus 0.29±0.03,
P
<0.002). In conclusion, impaired stress-induced pressure natriuresis in blacks may contribute to racial differences in essential hypertension and its sequelae.
Methoxyestradiols Mediate Estradiol-Induced Antimitogenesis in Human Aortic SMCs
Authors: Barchiesi Federica , Jackson Edwin K. , Gillespie Delbert G. , Zacharia Lefteris C. , Fingerle Juergen , Dubey Raghvendra K.
Published: July 2002

Estrogen receptors (ERs) are considered to mediate the ability of 17β-estradiol (estradiol) to reduce injury-induced proliferation of vascular smooth muscle cells (VSMCs), leading to vascular lesions. However, the finding that estradiol attenuates formation of vascular lesions in response to vascular injury in knockout mice that lack either ER-α or ER-β challenges this concept. Our hypothesis is that the local metabolism of estradiol to methoxyestradiols, metabolites of estradiol with little affinity for ERs, mediates the ER-independent antimitogenic effects of estradiol on VSMCs. In human VSMCs, 2-methoxyestradiol and 2-hydroxyestradiol were more potent than was estradiol in inhibiting DNA synthesis (
3
[H]-thymidine incorporation), collagen synthesis (
3
[H]-proline incorporation), cell proliferation (cell number), and cell migration (movement of cells across a polycarbonate membrane). The inhibitory effects of estradiol on VSMCs were enhanced by cytochrome-P450 (CYP450) inducers 3-methylcholanthrene and phenobarbital. Moreover, the inhibitory effects of estradiol were blocked in the presence of the CYP450 inhibitor 1-aminobenzotriazole and the catechol-
O
-methyltransferase inhibitors quercetin and OR486. Both OR486 and quercetin blocked the conversion of 2-hydroxyestradiol to 2-methoxyestradiol; moreover, they blocked the antimitogenic effects of 2-hydroxyestradiol but not of 2-methoxyestradiol. The ER antagonist ICI182780 blocked the inhibitor effects of estradiol on VSMCs, but only at concentrations (>50 μmol/L) that also inhibit the metabolism of estradiol to hydroxyestradiols (precursors of methoxyestradiols). In conclusion, the inhibitory effects of locally applied estradiol on human VSMCs are mediated via a novel ER-independent mechanism involving estradiol metabolism. These findings imply that vascular estradiol metabolism may be an important determinant of the cardiovascular protective effects of estradiol and that nonfeminizing estradiol metabolites may confer cardiovascular protection regardless of gender.
Resistant Hypertension
Authors: Taler Sandra J. , Textor Stephen C. , Augustine Jo Ellen
Published: July 2002

Although resistant hypertension affects a minority of all hypertensives, this group continues to experience disproportionately high cardiovascular event rates despite newer antihypertensive agents. Hypertension represents an imbalance of hemodynamic forces within the circulation, usually characterized by elevated systemic vascular resistance. We studied the utility of serial hemodynamic parameters in the selection and titration of antihypertensive medication in resistant hypertensive patients using highly reproducible noninvasive measurements by thoracic bioimpedance. Resistant hypertension patients (n=104) were randomized to drug selection based either on serial hemodynamic (HD) measurements and a predefined algorithm or on drug selection directed by a hypertension specialist (SC) in a 3-month intensive treatment program. Blood pressure was lowered by intensified drug therapy in both treatment groups (169±3/87±2 to 139±2/72±1 mm Hg HD versus 173±3/91±2 to 147±2/79±1 mm Hg SC,
P
<0.01 for systolic and diastolic BP), using similar numbers and intensity of antihypertensive medications. Blood pressures were reduced further for those treated according to hemodynamic measurements, resulting in improved control rates (56% HD versus 33% SC controlled to ≤140/90 mm Hg,
P
<0.05) and incremental reduction in systemic vascular resistance measurements. Although the number of patients taking diuretics did not differ between groups, final diuretic dosage was higher in the hemodynamic cohort. Our results demonstrate superior blood pressure control using a treatment algorithm and serial hemodynamic measurements compared with clinical judgment alone in a randomized prospective study. Our measurements of thoracic fluid volume support occult volume expansion as a mediator of antihypertensive drug resistance and use of impedance measurements to guide advancing diuretic dose and adjustment of multidrug antihypertensive treatment.
Gender Differences in the Dietary Lard-Induced Increase in Blood Pressure in Rats
Authors: Tamaya-Mori Norika , Uemura Kazumasa , Iguchi Akihisa
Published: July 2002

We investigated the difference between male and female rats in the increase in blood pressure (BP) when they were fed a lard-enriched diet. We also investigated the effect of a gonadectomy, with or without testosterone treatment, on the dietary lard-induced increase in BP. Wistar-strain male or female rats were bilaterally castrated or ovariectomized. Some of them were implanted subcutaneously with silicon tubes containing crystalline testosterone. Each group was fed either chow alone or chow in which 50% of the energy content was from substituted lard. Systolic blood pressure (SBP) was determined weekly during each 7- or 11-week feeding period. A steady-state plasma glucose method was used to determine the insulin sensitivity. The dietary lard-induced increase in SBP was observed at 5 weeks after the start of the feeding in the sham-operated male rats. In the sham-operated female rats, SBP did not change from the basal values until 11 weeks into the experimental period. Castration eliminated the dietary lard-induced increase in SBP. Ovariectomy had no effect on SBP throughout the experimental period in both diet groups. In castrated males given testosterone, SBP increased in a dose-dependent manner. In ovariectomized females given testosterone, SBP increased significantly in the lard-enriched diet group. The dietary lard developed an insulin resistance in both the sham-operated and gonadectomized rats. However, SBP increased only in the sham-operated male rats. These results suggest that the dietary lard-induced increase in SBP depends on the presence of testosterone. The development of insulin resistance by dietary lard triggers the increase in SBP.
Validity and Reliability of Diastolic Pulse Contour Analysis (Windkessel Model) in Humans
Authors: Manning Timothy S. , Shykoff Barbara E. , Izzo Joseph L.
Published: July 2002

The present study assessed (1) the impact of the measurement site (lower versus upper extremity) on the corresponding compliance variables and (2) the overall reliability of diastolic pulse contour (Windkessel-derived) analysis in normal and hypertensive subjects. Arterial tonograms were recorded in the supine position from the radial and posterior tibial arteries in 20 normotensive (116±12/68±8 mm Hg) and 27 essential hypertensive subjects (160±16/94±14 mm Hg). Ensemble-averaged data for each subject were fitted to a first-order lumped-parameter model (basic Windkessel) to compute whole-body arterial compliance (C
A
) and to a third-order lumped-parameter model (modified Windkessel) to compute proximal compliance (C
1
) and distal compliance (C
2
). Despite high-fidelity waveforms in each subject, the first-order Windkessel model did not yield interpretable (positive) values for C
A
in 50% of normotensives and 41% of hypertensives, whereas the third-order model failed to yield interpretable C
1
or C
2
results in 15% of normotensives and 41% of hypertensives. No between-site correlations were found for the first-order time constant, 2 of the 3 third-order model curve-fitting constants, or C
A
, C
1
, or C
2
(
P
>0.50). Mean values for all 3 compliance variables were higher for the leg than the arm (
P
<0.05 each). We conclude that differences in Windkessel-derived compliance values in the arm and leg invalidate whole-body model assumptions and suggest a strong influence of regional circulatory properties. The validity and utility of Windkessel-derived variables is further diminished by the absence of between-site correlations and the common occurrence of uninterpretable values in hypertensive subjects.
Gene Transfer of Hepatocyte Growth Factor to Subarachnoid Space in Cerebral Hypoperfusion Model
Authors: Yoshimura Shin-ichi , Morishita Ryuichi , Hayashi Katsuhiko , Kokuzawa Jouji , Aoki Motokuni , Matsumoto Kunio , Nakamura Toshikazu , Ogihara Toshio , Sakai Noboru , Kaneda Yasufumi
Published: July 2002

Although cerebral hypoperfusion caused by cerebral occlusive disease leads to cerebral ischemic events, an effective treatment has not yet been established. Recently, a novel therapeutic strategy for ischemic disease using angiogenic growth factors to expedite and/or augment collateral artery development has been proposed. Therapeutic angiogenesis might be useful for the treatment of cerebral occlusive disease. Hepatocyte growth factor (HGF) is a potent angiogenic factor, in addition to vascular endothelial growth factor (VEGF), whereas in the nervous system HGF also acts as neurotrophic factor. Therefore, we hypothesized that gene transfer of these angiogenic growth factors could induce angiogenesis, thus providing an effective therapy for cerebral hypoperfusion or stroke. In this study, we employed a highly efficient gene transfer method, the viral envelop (Hemagglutinating Virus of Japan [HVJ]-liposome) method, because we previously documented that β-
galactosidase
gene could be transfected into the brain by the HVJ-liposome method. Indeed, we confirmed wide distribution of transgene expression using β-galactosidase via injection into the subarachnoid space. Of importance, transfection of
HGF
or
VEGF
gene into the subarachnoid space 7 days before occlusion induced angiogenesis on the brain surface as assessed by alkaline phosphatase staining (
P
<0.01). In addition, significant improvement of cerebral blood flow (CBF) was observed by laser Doppler imaging (LDI) 7 days after occlusion (
P
<0.01). Unexpectedly, transfection of
HGF
or
VEGF
gene into the subarachnoid space immediately after occlusion of the bilateral carotid arteries also induced angiogenesis on the brain surface and had a significant protective effect on the impairment of CBF by carotid occlusion (
P
<0.01). Interestingly, coinjection of recombinant
HGF
with
HGF
gene transfer revealed a further increase in CBF (
P
<0.01). Here, we demonstrated successful therapeutic angiogenesis using
HGF
or
VEGF
gene transfer into the subarachnoid space to improve cerebral hypoperfusion, thus providing a new therapeutic strategy for cerebral ischemic disease.
Chamber-Dependent Expression of Brain Natriuretic Peptide and Its mRNA in Normal and Diabetic Pig Heart
Authors: Christoffersen Christina , Goetze Jens P. , Bartels Emil D. , Larsen Marianne O. , Ribel Ulla , Rehfeld Jens F. , Rolin Bidda , Nielsen Lars B.
Published: July 2002

Brain natriuretic peptide (BNP) is produced in cardiac myocytes, and increased secretion is closely associated with cardiac dysfunction. However, several fundamental aspects of BNP expression in the myocardium have not yet been resolved. In the present study, we report the presence of a precursor BNP mRNA transcript and a mature BNP mRNA transcript in normal porcine hearts. In normal pigs, the amount of precursor BNP mRNA was similar in atrial and ventricular myocardium, whereas the mature BNP transcript was 10- to 50-fold more abundant in atrial than in ventricular myocardium. Quantitation of proBNP in normal porcine hearts by radioimmunoassay disclosed abundant proBNP in the atria, whereas proBNP was undetectable in the ventricles. Laser confocal microscopy revealed proBNP in secretory granules of atrial but not in the ventricular myocardium of normal pigs. Mild streptozotocin-induced diabetes doubled the expression of BNP mRNA in porcine atrial myocardium (
P
=0.03), but was without effect on BNP mRNA in the ventricular myocardium. The data suggest that BNP mRNA processing and proBNP storage differ between the atrial and ventricular myocardium. The results also imply that diabetes increases cardiac BNP expression in a chamber-dependent manner.
Von Willebrand Factor, Soluble P-Selectin, and Target Organ Damage in Hypertension
Authors: Spencer Charles G.C. , Gurney David , Blann Andrew D. , Beevers D. Gareth , Lip Gregory Y.H.
Published: July 2002

To investigate the relationship between soluble markers of platelet, endothelial and rheological function, and target organ damage and their response to intensified management in a population of middle-age hypertensive patients at high risk of cardiovascular complications, we studied 382 consecutive patients (308 men; mean age, 63 years, SD 8) along with 60 normotensive controls free of cardiovascular disease. Patients were divided into those with target organ damage (TOD; n=107) and those free of end-organ damage. Plasma levels of soluble P-selectin (sP-sel), a marker of platelet activation, and von Willebrand factor (vWF), an index of endothelial damage/dysfunction (both enzyme-linked immunosorbent assay), and the rheological indices fibrinogen, plasma viscosity, hematocrit, platelet, and white cell count were measured. In 53 patients, variables were further measured after 6 months of intensified cardiovascular risk management. Patients with TOD had significantly higher vWF, 137 (SD 33) versus 125 (SD 33) IU/dL (
P
=0.002,) and a greater proportion of smokers, 31% versus 16% (
P
=0.002). There were no statistically significant differences in plasma viscosity, fibrinogen, hematocrit, white blood cell count, platelet count, or sP-sel between the 2 subgroups. In multivariate analysis, vWF was a significant independent predictor for TOD. After 6 months of intensified management in 53 patients who entered the trial, there were significant reductions in systolic blood pressure, total cholesterol, hematocrit, plasma viscosity, sP-sel, and vWF (all
P
<0.01) but no significant change in fibrinogen. In conclusion, there is a relationship between TOD and endothelial damage/dysfunction in hypertension. Intensified management results in improvements in hemorheology, endothelial and platelet function.
Amiloride, a Specific Drug for Hypertension in Black People With T594M Variant?
Authors: Baker Emma H. , Duggal Ajay , Dong Yanbin , Ireson Nicola J. , Wood Monique , Markandu Nirmala D. , MacGregor Graham A.
Published: July 2002

The T594M polymorphism of the epithelial sodium channel is found in ≈5% of people of African origin and is significantly associated with high blood pressure. Although the T594M polymorphism could increase renal sodium absorption through affected channels, it is not known whether this polymorphism causes hypertension. Amiloride specifically inhibits overactive sodium channels and effectively controls blood pressure in Liddle’s syndrome, in which hypertension is caused by separate epithelial sodium channel mutations. The aim of this study was to determine whether amiloride was effective in lowering blood pressure in individuals with the T594M polymorphism. In an open, controlled study, 14 black hypertensive individuals with the T594M polymorphism were withdrawn from their usual medication and treated with amiloride. On entry to the study, individuals taking a mean of 2 drugs had blood pressure of 142/89±3/3 mm Hg. Amiloride alone (10 mg BID) controlled blood pressure effectively to the same level (140/91±4/2 mm Hg). When amiloride was withdrawn for 2 weeks, there was a large increase in blood pressure of 17/8±4/2 mm Hg (systolic,
P
<0.05; diastolic,
P
<0.01). On restarting amiloride, blood pressure was again controlled to 140/88±6/2 mm Hg. These results demonstrate that 10 mg BID amiloride is effective in controlling blood pressure in hypertensive individuals of African origin who have the T594M polymorphism. Our study supports the concept that the T594M polymorphism contributes to the elevation of blood pressure and suggests that consideration should be given to the use of amiloride in affected individuals.
Genes and Family Environment Explain Correlations Between Blood Pressure and Body Mass Index
Authors: Cui Jisheng , Hopper John L. , Harrap Stephen B.
Published: July 2002

The correlations between systolic blood pressure (SBP) and diastolic blood pressure (DBP), and between SBP and body mass index (BMI), might result from genetic or environmental factors that determine variation in 2 or more phenotypes and are shared by family members. In 767 adult nuclear families (n=2912 individuals, including 66 pairs of monozygotic twins and 84 pairs of dizygotic twins), we used a multivariate normal model and the software FISHER to estimate genetic and environmental components of variation and covariation. Mean phenotypes were adjusted for age, gender, and generation, and for antihypertensive treatment. Genetic and shared family environmental factors accounted for 46% and 31% of total variance in SBP, respectively. Adjustment of SBP for DBP reduced considerably both the additive genetic (86.7 to 21.0) and shared environmental (59.7 to 21.0) components of variance. Smaller reductions in genetic (86.7 to 84.9) and shared environmental (59.7 to 51.1) components were observed after adjustment of SBP for BMI. For SBP and DBP, the correlation between the effects of genes was 1.00 and between shared environmental effects was 0.52. For SBP and BMI the correlations were 0.30 for genetic and 0.22 for shared environmental effects. Our findings suggest that the same genes and many of the same family environmental factors determine variation in both SBP and DBP. In contrast, SBP and BMI share genetic and family environmental determinants to a lesser degree. These observations are relevant to multifactorial cardiovascular risk reduction based on genetic and family environmental approaches.