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The complexity of the pathophysiology of sepsis has led to controversy regarding optimal therapy. Nonetheless, it is possible to formulate an underlying approach to the hemodynamic support of patients with sepsis, with the understanding that the basic principles of the approach are more important than the specific recommendations. For example, as we advance our understanding of which parameters most accurately reflect the effects of therapy in septic patients, it seems clear that eventually a combination of these parameters will prove most useful. Similarly, although the particular endpoints that clinicians use may change, the notion that they should define the goals of therapy and evaluate the results of their interventions on the basis of those goals will remain. Therapies for sepsis will continue to evolve, but the notion that such therapies should be titrated to specific and definable endpoints remains a fundamental principle.

Septic shock is one of the most frequent causes of morbidity and mortality in intensive care units. Treatment of sepsis begins with support of blood pressure, organ blood flow, and ventilation, along with administration of appropriate antibiotics and eradication of sources of infection. Despite significant advances in therapies available and understanding of pathogenesis, the mortality from septic shock has improved little over the last several decades. The cardinal hemodynamic abnormalities in patients with septic shock include hypotension with a normal or high cardiac output, which result from vasodilation and vascular hyporeactivity to vasoconstrictors. 1 These vascular abnormalities originate in the microvasculature and contribute to multiorgan system failure and death.

Care of patients with heart failure is often challenging and involves proper therapeutic selection from the pharmacologic, interventional, and mechanical options available. In this article, Drs Almeda and Hollenberg discuss the latest approaches and guidelines to treatment of acute and chronic heart failure in patients with left ventricular systolic dysfunction. They review the benefits, risks, and myriad considerations that physicians need to assess before making choices about best medical management.

Objective Coronary endothelial dysfunction may be an early marker for cardiac allograft vasculopathy (CAV) in orthotopic heart transplant recipients. We used serial studies to evaluate changes in coronary endothelial function in patients with and without clinically evident CAV. Background In serial studies with intravascular ultrasound (IVUS) and Doppler flow wire measurements, we previously demonstrated that annual decrements in coronary endothelial function are associated with progressive intimal thickening. Methods We studied 45 patients annually, beginning at transplantation until pre-specified end-points (angiographic CAV or cardiac death) were reached. At each study, we measured coronary endothelial function using intracoronary infusions of adenosine, acetylcholine, and nitroglycerin. We simultaneously recorded IVUS images and Doppler velocities. Results Of the 45 patients studied, 9 reached end-points during the study (6 had CAV and 3 died). The mean annual change in area response to acetylcholine was −4.5% ± 3.0% in patients who reached end-points and −0.9% ± 1.5% in those who did not ( p = 0.04). The mean annual decrement in flow response to acetylcholine was greater in patients who reached end-points (−31% ± 11% vs −5% ± 5%, p = 0.08). Responses to adenosine and nitroglycerin did not differ. Conclusions When serial responses were evaluated, patients with end-points had more rapid decreases in endothelial function. The rate of disease progression may be more important than the absolute degree of intimal thickening in early CAV. These data implicate endothelial dysfunction in the development of clinically significant vasculopathy and suggest that serial studies of endothelial function may provide important prognostic information about the development of CAV after heart transplantation.

The ability of increased endogenous adenosine to mitigate microvascular derangements in sepsis was studied. Pentostatin (2'-deoxycoformycin), an inhibitor of adenosine deaminase, was administered to mice immediately after induction of sepsis by cecal ligation and puncture. Intravital video microscopy of cremasteric postcapillary venules was performed. Leukocyte rolling and adhesion were significantly increased in septic mice compared with control mice. Treatment of septic mice with pentostatin significantly decreased leukocyte rolling and adhesion (6.02 +/- 0.09 versus 1.72 +/- 0.12 rolling cells/min, 2.07 +/- 0.04 versus 0.62 +/- 0.05 adherent cells/100 microm per minute; p < 0.001). Albumin leakage (ratio) was significantly attenuated in septic animals treated with pentostatin (0.42 +/- 0.05 versus 0.21 +/- 0.04; p < 0.01). Circulating levels of interleukin-6, tumor necrosis factor-alpha, and soluble tumor necrosis factor type II receptor were decreased in septic mice treated with pentostatin. Survival was significantly improved at 48 hours in mice treated with pentostatin. These results suggest an important role for adenosine in modulating both leukocyte-dependent and -independent mechanisms of endothelial injury in sepsis. Exploiting the advantageous action of endogenous adenosine represents a potentially useful and novel therapeutic approach for the treatment of sepsis.

The aim of this study was to determine arterial elasticity in normotensive and hypertensive individuals.In addition to blood pressure, other parameters serve as markers for vascular disease. Arterial elasticity is one parameter that can be determined by a modified Windkessel model of the circulation. This model estimates, from a computerized pulse contour analysis, the proximal (capacitive) elasticity of the large arteries and the distal (reflective) elasticity of the small arteries.A prospective, multi-center, controlled clinical study evaluated large-artery and small-artery elasticity indices in four groups: (1) normotensives without a family history of hypertension; (2) normotensives with a family history of hypertension; (3) treated and controlled hypertensives; and (4) untreated and uncontrolled hypertensives. Blood pressure, using a mercury manometer, and arterial elasticity, using a CVProfilor DO-2020 CardioVascular Profiling System (Hypertension Diagnostics, Inc., Eagan, MN, USA), were measured supine in triplicate 3 min apart in a randomized sequence.There were 212 evaluable subjects of mean age 46 years; 57% were women, 51% Caucasian and 33% African-American. Comparing normotensives without a family history and untreated hypertensives, both large-artery and small-artery elasticity indices were significantly different (P0.0001). After controlling for age and body surface area, a significant linear trend (P = 0.0001) across the four groups was detected for both large- and small-artery elasticity indices.As the hypertension status worsened, large- and small-artery elasticity indices decreased, suggesting a potential for the diagnostic use of arterial elasticity determinations.

To determine arterial elasticity in normotensives and in treated and untreated hypertensive Black and White subjects.A prospective multicenter, controlled clinical trial evaluated large (C-) and small (C2) artery elasticity indices among 3 groups: 1) normotensive subjects with or without a family history of hypertension; 2) controlled and treated hypertensive subjects; and 3) untreated and uncontrolled hypertensive subjects. Blood pressure was measured using a mercury manometer and arterial compliance or elasticity was determined using a CVProfilor DO-2020 CardioVascular Profiling System (Hypertension Diagnostics, Inc, Eagan, Minn). These parameters were measured in triplicate 3 minutes apart in a random sequence, with the patient in a supine position. Two-way ANOVA was used for statistical evaluation.One hundred seventy eight subjects met stratification and enrollment criteria. The mean age was 46 years. 109 were White and 69 were Black. [table: see text]Small and large arterial elasticity indices are reduced as hypertension status worsens. Age and height were important covariates of C1 and C2. Race was not found to be a significant predictor of either C1 or C2. Large and small artery elasticity indices do not differ between White and Black subjects with varying degrees of hypertension after adjusting for covariates. More studies with a larger number of subjects are required.

Background: Echocardiography allows for sensitive and non-invasive assessment of cardiac function in mice, but requires sedation and immobility, which influences cardiac performance. Minimizing the hemodynamic effects of anesthesia is extremely important for improving the applicability of animal models to the clinical setting. We sought to evaluate the effects of isoflurane dose on myocardial function in a murine model.Methods: Twelve healthy C57BL/6 mice were studied with three different isoflurane anesthesia regimens: deep anesthesia with an objective of heart rate (HR) between 350 and 400 beats per minute (bpm), light anesthesia with an objective of HR between 475 and 525 bpm and just before the mice woke up (>575 bpm). Using a high-resolution ultrasound system, stroke volume, cardiac output, left ventricle dimension and fractional shortening were recorded.Results: Fractional shortening was not statistically different in the awake group and the light anesthesia group (49±5% in awake mice vs. 48±5%; p=0.62), whereas it was different compared to the deep anesthesia group (31±5%, pConclusions: Doppler echocardiography can be performed under very light anesthesia using small doses of isoflurane without influencing cardiac inotropic function. This technique allows for accurate and reproducible assessment of cardiac function while minimizing hemodynamic perturbations.

Background — Coronary endothelial dysfunction may be an early marker for cardiac allograft vasculopathy (CAV) in orthotopic heart transplant recipients. Using serial studies with intravascular ultrasound and Doppler flow-wire measurements, we have previously demonstrated that annual decrements in coronary endothelial function are associated with progressive intimal thickening. The present study tested whether endothelial dysfunction predicts subsequent clinical events, including cardiac death and CAV development. Methods and Results — Seventy-three patients were studied yearly beginning at transplantation until a prespecified end point was reached. End points were angiographic evidence of CAV (>50% stenosis) or cardiac death (graft failure or sudden death). At each study, coronary endothelial function was measured with intracoronary infusions of adenosine (32-μg bolus), acetylcholine (54 μg over 2 minutes), and nitroglycerin (200 μg) into the left anterior descending coronary artery; intravascular ultrasound images and Doppler velocities were recorded simultaneously. Of the 73 patients studied, 14 reached an end point during the study (6 CAV and 8 deaths, including 4 with known CAV, 1 graft failure, and 3 sudden). On the last study performed, the group with an end point had decreased epicardial (constriction of 11.1±2.9% versus dilation of 1.7±2.2%, P =0.01) and microvascular (flow increase of 75±20% versus 149±16%, P =0.03) endothelium-dependent responses to acetylcholine compared with the patients who did not reach an end point. Responses to adenosine and nitroglycerin did not differ significantly. Conclusions — Endothelial dysfunction, as detected by abnormal responses to acetylcholine, preceded the development of clinical end points. These data implicate endothelial dysfunction in the development of clinically significant vasculopathy and suggest that serial studies of endothelial function have clinical utility.

A small animal model of sepsis that reproduces the vasodilation, hypotension, increased cardiac output, and response to treatment seen in patients with septic shock would be useful for studies of pathophysiology and treatment, but no current models replicate all of these features. Mice were made septic by cecal ligation and puncture and resuscitated with fluids and antibiotics every 6 h. Blood pressure was measured in anesthetized mice with manometric catheters, and echocardiography was performed in these animals every 6 h. Survival in treated septic mice was improved compared with untreated mice (44% versus 0%, p < 0.01). In control mice, heart rate (HR, 420 +/- 31 beats/min), mean arterial pressure (Pa, 100 +/- 8 mm Hg), stroke volume (SV, 26 +/- 4 microl), and cardiac output (12.5 +/- 6.6 ml/min) were unchanged over 48 h. In septic mice Pa was significantly decreased (102 +/- 14 to 65 +/- 19 mm Hg, p < 0.02), starting at 12 h. HR and cardiac output increased significantly (HR, 407 +/- 70 to 524 +/- 76 beats/min, cardiac output, 11.6 +/- 2.0 to 17.1 +/- 1.5 ml/min, p < 0.01). SV (24 +/- 5 microl) remained constant. This fluid-resuscitated, antibiotic-treated model replicates the mortality, hypotension, and hyperdynamic state seen in clinical sepsis. Precise determination of serial hemodynamics in this model may be useful to elucidate pathophysiologic mechanisms and to evaluate new therapies for septic shock.

This study compared the TIMI frame count (TFC), which has been proposed as a method for quantifying coronary blood flow, with coronary flow and microvascular function measured with intracoronary Doppler and intracoronary ultrasound. Coronary blood flow volume was calculated from coronary blood velocity (by intracoronary Doppler) and lumen area (by intracoronary ultrasound) in the LAD in 46 post-heart transplant patients at baseline and after intracoronary adenosine. TFC correlated significantly with average peak coronary blood velocity (r = -0.42; P = 0.004) and coronary lumen area (r = 0.39; P = 0.008), but not with coronary blood flow volume (r = -0.01; P = 0.96) or the coronary flow reserve response to adenosine (r = 0.09; P = 0.58). In conclusion, TFC is a simple method of assessing coronary blood velocity but not volumetric flow. While TFC does not predict coronary flow reserve, as a measure of velocity it does provide an assessment of basal microvascular tone, information that is complementary to that afforded by flow reserve measurements.

The Worcester Heart Attack Study has followed up 5,270 residents of a metropolitan area since 1975. In this report examining incidence and mortality of acute myocardial infarction (MI) over a 20-year period, both age-adjusted incidence rates and riskadjusted mortality rates were declining. These results suggest that primary and secondary prevention strategies are having a beneficial effect, but there is clearly room for improvement.

Studies of septic shock published before the 1980s reported mortality rates to be consistently greater than 50%. Even with advent of recent technology and more focused therapy, mortality remains in the vicinity of 40%. 10 Shock is characterized by an inadequate supply of oxygen to the tissues and a lack of metabolic substrate needed for cellular metabolism, resulting in tissue damage and subsequent organ failure. Septic shock is associated with a nidus of infection. Infectious microorganisms release mediators, such as endotoxins or exotoxins, which stimulate the release of macrophage-derived cytokines. The principal proinflammatory cytokines are tumor necrosis factor (TNF), interleukin-1 (IL-1), and interleukin-8 (IL-8). 80 IL-1 and TNF directly affect organ function and act indirectly by stimulating secondary mediators, such as the inducible form of nitric oxide synthase, which leads to increased release of nitric oxide (NO). 1 IL-8 is integral to polymorphonuclear leukocyte (PMN)-induced organ injury. NO is a potent endogenous vasodilator and has been postulated to be an important mediator of sepsis-induced hypotension refractory to vasopressors. The initial hemodynamic parameters in the unresuscitated patient with septic shock are typically low or normal cardiac index, low blood pressure, low pulmonary artery occlusion pressure (PAOP), and low or normal systemic vascular resistance (SVR). With aggressive volume resuscitation, a hyperdynamic state results in high cardiac index, normal filling pressure, and low systemic vascular resistance. The primary mechanism for myocardial depression in septic shock is circulating toxin-induced mediators with some component of myocardial ischemia and down-regulation of β-receptor density and function. 11 Pulmonary vascular resistance is often elevated and results in elevated pulmonary arterial pressure. This elevation may further impair cardiac function in sepsis.

To review the cause, epidemiology, pathophysiology, and treatment of cardiogenic shock.A MEDLINE search of the English-language reports published between 1976 and 1998 and a manual search of bibliographies of relevant papers.Experimental, clinical, and basic research studies related to cardiogenic shock.Data in selected articles were reviewed, and relevant clinical information was extracted.Cardiogenic shock is a state of inadequate tissue perfusion due to cardiac dysfunction, most commonly caused by acute myocardial infarction. Mortality rates for patients with cardiogenic shock remain frustratingly high, ranging from 50% to 80%. The pathophysiology of cardiogenic shock involves a downward spiral: Ischemia causes myocardial dysfunction, which, in turn, worsens ischemia. Areas of nonfunctional but viable (stunned or hibernating) myocardium can also contribute to the development of cardiogenic shock. The key to achieving a good outcome is an organized approach that includes rapid diagnosis and prompt initiation of therapy to maintain blood pressure and cardiac output. Expeditious coronary revascularization is crucial. When available, emergency cardiac catheterization and angioplasty seem to improve survival. More recent developments, such as placement of coronary stents and use of glycoprotein IIb/IIIa antagonists, are promising but have not yet been well studied in patients with cardiogenic shock. In hospitals without direct angioplasty capability, stabilization with intra-aortic balloon counterpulsation and thrombolysis followed by transfer to a tertiary care facility may be the best option.Improved understanding of the pathophysiology of shock and myocardial infarction has led to improved treatment. If cardiogenic shock is managed with rapid evaluation and prompt initiation of supportive measures and definitive therapy, outcomes can be improved.

As we emerge from the tremendous progress of the last century, we can take genuine pride in the advances of modern treatments in reducing the morbidity and mortality of cardiovascular diseases, such as hypertension, myocardial infarction, and chronic heart failure. Unfortunately, acute heart failure (AHF) remained largely ignored during this period of discovery, with little research into its epidemiology, pathophysiology, diagnosis, or treatment. However, recent recognition of the significance of AHF has led to investigations that have provided important insights into this syndrome (1), guidelines for its treatment and diagnosis (2, 3), and novel therapies (4), as well as new chapters in leading cardiology textbooks (5). This supplement to Critical Care Medicine is intended to report on the current state of the art as presented by leaders in this rapidly evolving field. Acute heart failure can be defined as the rapid or gradual onset of signs and symptoms of heart failure that result in an urgent, unplanned need for medical care. This heterogeneous syndrome is the primary diagnosis in 1 million hospitalizations in the United States alone, constituting a 174% increase from 1979 to 2003. Drawing on contemporary studies and providing the context for further discourse, Drs. Dar and Cowie (6) present a survey of the epidemiology of AHF, revealing that AHF patients are typically elderly with a history of heart failure, coronary artery disease, and multiple other comorbidities. Our understanding of the pathogenesis of AHF has relied heavily on our models of chronic heart failure, which initially focused on hemodynamic derangements. It is becoming clear, however, that other important mechanisms may be operative in the development of AHF, such as cytokine activation, as described by Dr. Chen and colleagues (7). The potential role of inflammation and immune activation in myocardial dysfunction and damage in the setting of AHF not only may explain the increased morbidity and mortality observed in these patients but also may provide a rationale for future therapeutic targets. The diagnosis of AHF has dramatically improved in the last decade with the advent of new diagnostic modalities. Perhaps the most significant of these tests have been the assays for natriuretic peptides, B-type natriuretic peptide (BNP), and its precursor (NT-proBNP). Dr. Omland (8) discusses these new assays and their practical use in the clinical environment as well as their contributions to estimating clinical course and prognosis. Cardiac imaging technologies have also rapidly improved, and echocardiography is an essential tool in the diagnosis and management of patients with AHF. Dr. Ferrari (9) discusses the role of echocardiography and the exciting new techniques of cardiac computed tomography and magnetic resonance imaging in the management of patients with heart failure. Recent trials have provided new perspectives on the use of hemodynamic monitoring in patients with AHF. Dr. Cotter and associates (10) present the current data regarding invasive hemodynamic monitoring, provide guidance for the use of this important tool, and discuss new noninvasive measurement techniques. As noted previously, AHF is a heterogeneous syndrome, and defining the sub

Increased QT dispersion (QTmax-QTmin [QTd]) reflects inhomogeneous ventricular repolarization that may provide a substrate for serious arrhythmias and is associated with adverse clinical outcomes in patients with heart disease. Effective treatment of acute myocardial infarction or ventricular arrhythmias may reduce QTd, but the effect of coronary revascularization on QTd in patients without these conditions is unknown. In this study, QTd was measured before and 4 and 24 hours after successful angioplasty in 94 patients without ongoing symptomatic myocardial ischemia or malignant arrhythmias. QTd decreased from 434 +/- 17 msec before angioplasty to 354 +/- 15 msec 4 hours (p < 0.05) and 33 +/- 14 msec 24 hours after angioplasty (p < 0.05). QTd was improved in 64% of patients, worse in 28%, and unchanged in 8%. Thus angioplasty significantly improves QTd. This may reflect increased myocardial perfusion and may be inherently beneficial by reducing the propensity for arrhythmias.

Objective: To evaluate mechanisms of vasodilation in sepsis by comparing responses of resistance arterioles to vasopressin in rat cremaster muscle of septic and control rats. Design: Prospective, experimental study. Setting: Experimental animal laboratory. Subjects: Twenty male rats, anesthetized with ketamine and acepromazine. Interventions: Topical superfusion of vasoactive compounds on skeletal muscle resistance arterioles. Measurements and Main Results: The effect of sepsis on responses to local application of vasopressin was investigated using in vivo videomicroscopy. Vasopressin was superfused topically on the cremaster muscle resistance arterioles (15 to 25 μm) of rats made septic by cecal ligation and puncture, and the responses were compared with the responses of controls that underwent sham ligation. Responses to topically suffused vasopressin were also assessed in septic and control rats, before and after superfusion of the muscle with the nitric oxide synthase inhibitor N G -methyl-L-arginine (NMA). Sepsis produced a decrease in the vasoconstrictive effects of vasopressin; the maximal response was lower, and the concentration-response curve was shifted to the right in septic rats (p

Persistent vasodilation refractory to vasopressor agents is the hemodynamic abnormality characteristic of septic shock. Induction of nitric oxide synthase (NOS) by sepsis-induced cytokines has been hypothesized to play a pathogenetic role in this refractory vasodilation. To evaluate the mechanism of vasodilation in sepsis, we used in vivo videomicroscopy to measure responses of resistance arterioles (15-20 microm) to topical suffusion of the potent vasoconstrictor, endothelin-1 (ET-1), in rat cremaster muscle. Rats made septic by cecal ligation and puncture were compared with controls that underwent sham ligation. Responses to topically suffused ET-1 were assessed in septic and control rats before and after superfusion of the muscle with the NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA). Sepsis produced a decrease in ET-1-induced vasoconstriction; the ET-1 concentration-response curve was shifted to the right in septic rats (P < 0.05). Contractions at ET-1 concentrations of 1, 10, and 100 nM were 20, 28, and 32%, respectively, of sham controls. Superfusion of the muscle with L-NMMA restored arteriolar responsiveness to ET-1 in the septic rats, significantly increasing arteriolar constriction at 1 and 10 nM. This effect was reversed with superfusion of excess L-arginine (1 mM). This study demonstrates that impaired vasoconstriction in response to ET-1 in resistance arterioles of septic rats in vivo is reversed by NOS inhibition. Taken together with previous studies showing sepsis-induced impairment of vasoconstriction with norepinephrine, a vasopressor with a mechanism of action different from ET-1, these findings suggest a generalized abnormality in the responsiveness of resistance arterioles in sepsis. Reversal of hyporesponsiveness to both of these vasopressor agents by NOS inhibition suggests an important role for nitric oxide as a mediator of refractory vasodilation in sepsis.

Dopexamine is a dopamine analog that has been used for hemodynamic optimization in a number of clinical settings. This animal investigation showed anti-inflammatory effects of dopexamine in a rat endotoxin model without effects on global or regional flow, but it is not time to dispense with hemodynamics altogether just yet. Rather, an integrative approach to the effects of catecholamines, considering both inflammatory and hemodynamic effects, including those on the microcirculation, can help clinicians best understand how to employ them in clinical practice.

Emergency department (ED) sepsis patients without overt shock have a high incidence of clinical deterioration after admission. Heart rate variability (HRV) is decreased in severe sepsis. The objective was to determine the ability of a panel of HRV indices to identify physiologically stable ED sepsis patients who will develop worsening organ failure. We hypothesized that patients meeting the outcome of progressive organ failure will have decreased HRV on initial presentation.

To the Editor: Weappreciate the interest in our article and the comment of Pizzi et al highlighting that some types of antidepressants may have harmful effects in patients with coronary heart disease. The participants in the SWAN as well as in the substudy SWAN Heart were middle-aged women undergoing the menopausal transition. Because rates of cardiovascular disease (CVD) increase for women in this age group, it is important to find ways to reduce their CVD burden. In this healthy population, we found that depressive symptoms were significantly positively related to progression of coronary artery calcification (CAC), an early marker of CVD, especially heart disease. In a recent review article, statins have been shown to be not effective in lowering CAC scores; therefore, it seems prudent to look for other measures that might benefit women. We had too few women treated with antidepressants to draw any conclusions as to the effects of antidepressant medication on CAC progression so that the issue remains an open research question. Because of the small number, we could not look at subgroups of different types of antidepressantmedications.We agreewith Pizzi et al that a clinical trial remains to be conducted to evaluate the effects of antidepressants, especially selective seratonin reuptake inhibitors in women with any CAC. The Study of Women's Health Across the Nation (SWAN) has grant support from the National Institutes of Health (NIH, DHHS), through the National Institute on Aging (NIA), the National Institute of Nursing Research (NINR) and the NIH Office of Research on Women’s Health (ORWH) (Grants NR004061; AG012505, AG012535, AG012531, AG012539, AG012546, AG012553, AG012554, AG012495). The content of this letter is solely the responsibility of the authors and does not necessarily represent the official views of the NIA, NINR, ORWH or the NIH.

Background Major depression and depressive symptoms are associated with cardiovascular disease (CVD), but the impact of depression on early atherogenesis is less well known, particularly in women and minorities. This study examined whether depressive symptoms are associated with progression of coronary artery calcification (CAC) among women at midlife. Methods The SWAN is a longitudinal, multisite study assessing health and psychologic factors in midlife women. An ancillary study (SWAN Heart) evaluated subclinical atherosclerosis in women who reported no history of CVD or diabetes. In 346 women, CAC was measured twice by electron beam computed tomography, an average of 2.3 years apart. Progression, defined as an increase by ≥10 Agatston units, was analyzed using relative risk (RR) regression. Depressive symptoms were assessed with the Center for Epidemiologic Studies Depression (CES-D) Scale. Results Progression of CAC was observed in 67 women (19.1%). Each 1-SD-higher CES-D score at baseline related to a 25% increased risk of CAC progression (RR 1.25, 95% CI 1.06-1.47, P = .007), adjusting for age, time between scans, ethnicity, education, menopausal status, and known CVD risk factors. This risk was similar to the risk induced by body mass index (RR 1.31, 95% CI 1.11-1.54, P = .001) and systolic blood pressure (RR 1.28, 95% CI 1.06-1.55, P = .01). Conclusions Depressive symptoms were independently associated with progression of CAC in this cohort of midlife women. Depressive symptoms may represent a risk factor that is potentially modifiable for early prevention of CVD in women.

BACKGROUND AND METHODS Septic shock in humans is characterized by hypotension, low systemic vascular resistance, and high cardiac output. We hypothesized that circulating vasodilatory substances are, in part, responsible for this low systemic vascular resistance. To investigate this possibility, we exposed isolated rat aortic rings to sera from patients with septic shock and to sera from dogs made septic by intraperitoneal implantation of infected clots. Isolated rings from rat thoracic aortas were mounted on hooks in chambers filled with modified Krebs' buffer and bubbled with 95% oxygen/5% CO2. After documentation of functional endothelium, the rings were precontracted with norepinephrine. Serum was then added and ring tension measured continuously over the next 20 mins. RESULTS Sera from normal humans increased ring tension by 6% (60 +/- 39 [SEM] mg tension/mg ring). Sera from nine patients with septic shock decreased tension by 30% (350 +/- 42 mg tension/mg ring; p less than .001). In response to sera from control dogs, tension increased by 16% (122 +/- 37 mg tension/mg ring). In contrast, septic dog sera caused tension to decrease by 36% (278 +/- 38 mg tension/mg ring;p less than .001). Vasodilation was unaffected when the septic patient and dog sera were dialyzed to remove molecules less than 10,000 molecular weight. Chemical deendothelialization with sodium deoxycholate also did not affect the vasodilatory response to septic patient or dog sera. CONCLUSIONS Septic sera can relax rat aortic smooth muscle. Dialyzing to exclude the effects of small molecules and removing the endothelium did not eliminate this vasodilatory response. These data suggest the presence in septic serum of circulating substances capable of relaxing vascular smooth muscle that may play an important role in the pathogenesis of the cardiovascular abnormalities in septic shock.