Decongestion Models and Metrics in Acute Heart Failure: ESCAPE Data in the Age of the Implantable Cardiac Pressure Monitor.

The United States Food and Drug Administration restricts the use of implantable cardiac pressure monitors to patients with New York Heart Association (NYHA) class III heart failure (HF). We investigated whether single-pressure monitoring could predict survival in HF patients as part of a model constructed using data from the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) trial. We validated survival models in 204 patients, using all-cause 180-day mortality. Two levels of model complexity were tested: 1) a simplified 1-pressure model based on pulmonary artery mean pressure ([PAM]1P) (information obtainable from an implanted intracardiac monitor alone), and 2) a pair of 5-variable risk score models based on right atrial pressure (RAP) + pulmonary capillary wedge pressure (PCWP) ([RAP+PCWP]5V) and on RAP + PAM ([RAP+PAM]5V). The more complex models used 5 dichotomous variables: a congestion index above a certain threshold value, baseline systolic blood pressure of <100 mmHg, baseline blood urea nitrogen level of ≥ 34 mg/dL, need for cardiopulmonary resuscitation or mechanical ventilation, and posttreatment NYHA class IV status. The congestion index was defined as posttreatment RAP+PCWP or posttreatment RAP+PAM, with congestion thresholds of 34 and 42 mmHg, respectively (median pulmonary catheter indwelling time, 1.9 d). The 5-variable models predicted survival with areas under the curve of 0.868 for the (RAP+PCWP)5V model and 0.827 for the (RAP+PAM)5V model, whereas the 1-pressure model predicted survival with an area under the curve of 0.718. We conclude that decongestion as determined by hemodynamic assessment predicts survival in HF patients and that it may be the final pathway for treatment benefit despite improvements in pharmacologic intervention since the ESCAPE trial.

Usefulness of the Sum of Pulmonary Capillary Wedge Pressure and Right Atrial Pressure as a Congestion Index that Prognosticates Heart Failure Survival (from the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness Trial).

In the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial, use of a pulmonary artery catheter did not significantly affect advanced heart failure outcomes. However, the success of achieving the targeted hemodynamic goals of pulmonary capillary wedge pressure (PCWP) of 15 mm Hg and right atrial pressure (RAP) of 8 mm Hg and the association of these goals with clinical outcomes were not addressed. Furthermore, goals with 2 independent variables, PCWP and RAP, left room for uncertainties. We assessed the ability of a single hemodynamic target to achieve a threshold sum of PCWP and RAP as a predictor of all-cause mortality, death-or-transplantation (DT), or death-or-rehospitalization (DR) at 6 months in the pulmonary artery catheter-guided treatment arm of ESCAPE (n = 206). Patients with a posttreatment PCWP + RAP of <30 mm Hg had characteristics similar to those of the population who achieved the ESCAPE hemodynamic goals. This group had 8.7% mortality, 13.0% DT, and 58.7% DR at 6 months. The contrasting cohort with PCWP + RAP of ≥30 mm Hg had 45.3% mortality, 54.7% DT, and 84.9% DR at 6 months, with greater relative risk (RR) of death (RR 5.76), DT (RR 4.92), and DR (RR 1.80) and higher prevalence of jugular venous pulsation, edema, hepatomegaly, and ascites at admission and discharge. In conclusion, PCWP + RAP of 30 mm Hg posttreatment, obtained early in the index hospitalization, may represent as a simple congestion index that has prognostic value for heart failure survival and readmission rates at 6 months and as a warning signal for more aggressive intervention, thus warranting further validation.

Central venous pressure and pulmonary capillary wedge pressure: fresh clinical perspectives from a new model of discordant and concordant heart failure.

Heart-failure phenotypes include pulmonary and systemic venous congestion. Traditional heart-failure classification systems include the Forrester hemodynamic subsets, which use 2 indices: pulmonary capillary wedge pressure (PCWP) and cardiac index. We hypothesized that changes in PCWP and central venous pressure (CVP), and in the phenotypes of heart failure, might be better evaluated by cardiovascular modeling. Therefore, we developed a lumped-parameter cardiovascular model and analyzed forms of heart failure in which the right and left ventricles failed disproportionately (discordant ventricular failure) versus equally (concordant failure). At least 10 modeling analyses were carried out to the equilibrium state. Acute discordant pump failure was characterized by a "passive" volume movement, with fluid accumulation and pressure elevation in the circuit upstream of the failed pump. In biventricular failure, less volume was mobilized. These findings negate the prevalent teaching that pulmonary congestion in left ventricular failure results primarily from the "backing up" of elevated left ventricular filling pressure. They also reveal a limitation of the Forrester classification: that PCWP and cardiac index are not independent indices of circulation. Herein, we propose a system for classifying heart-failure phenotypes on the basis of discordant or concordant heart failure. A surrogate marker, PCWP-CVP separation, in a simplified situation without complex valvular or pulmonary disease, shows that discordant left and right ventricular failures are characterized by differences of ≥ 4 and ≤ 0 mmHg, respectively. We validated the proposed model and classification system by using published data on patients with acute and chronic heart failure.

Modeling left ventricular diastolic dysfunction: classification and key indicators.

BACKGROUND: Mathematical modeling can be employed to overcome the practical difficulty of isolating the mechanisms responsible for clinical heart failure in the setting of normal left ventricular ejection fraction (HFNEF). In a human cardiovascular respiratory system (H-CRS) model we introduce three cases of left ventricular diastolic dysfunction (LVDD): (1) impaired left ventricular active relaxation (IR-type); (2) increased passive stiffness (restrictive or R-type); and (3) the combination of both (pseudo-normal or PN-type), to produce HFNEF. The effects of increasing systolic contractility are also considered. Model results showing ensuing heart failure and mechanisms involved are reported. METHODS: We employ our previously described H-CRS model with modified pulmonary compliances to better mimic normal pulmonary blood distribution. IR-type is modeled by changing the activation function of the left ventricle (LV), and R-type by increasing diastolic stiffness of the LV wall and septum. A 5th-order Cash-Karp Runge-Kutta numerical integration method solves the model differential equations. RESULTS: IR-type and R-type decrease LV stroke volume, cardiac output, ejection fraction (EF), and mean systemic arterial pressure. Heart rate, pulmonary pressures, pulmonary volumes, and pulmonary and systemic arterial-venous O2 and CO2 differences increase. IR-type decreases, but R-type increases the mitral E/A ratio. PN-type produces the well-described, pseudo-normal mitral inflow pattern. All three types of LVDD reduce right ventricular (RV) and LV EF, but the latter remains normal or near normal. Simulations show reduced EF is partly restored by an accompanying increase in systolic stiffness, a compensatory mechanism that may lead clinicians to miss the presence of HF if they only consider LVEF and other indices of LV function. Simulations using the H-CRS model indicate that changes in RV function might well be diagnostic. This study also highlights the importance of septal mechanics in LVDD. CONCLUSION: The model demonstrates that abnormal LV diastolic performance alone can result in decreased LV and RV systolic performance, not previously appreciated, and contribute to the clinical syndrome of HF. Furthermore, alterations of RV diastolic performance are present and may be a hallmark of LV diastolic parameter changes that can be used for better clinical recognition of LV diastolic heart disease.

Modeling study of the failing heart and its interaction with an implantable rotary blood pump.

The effectiveness of clinical diagnosis and treatment of heart failure is a direct function of clinical signs that can be measured in a patient within cost and safety constraints. Large-scale mathematical modeling can be a key tool in revealing important, measurable clinical signs of heart failure, furthering medical understanding and development of treatment. In the first part of this study we have created two models of left heart failure--diastolic and systolic, using our human cardiovascular-respiratory system (H-CRS) model, and we present a comparison of the two types with emphasis on novel and differentiating clinical signs, such as tricuspid flow and septal motion. In the event of compromised left ventricular performance, mechanical left ventricular assist devices (LVAD) are often implanted to augment or completely replace the pumping action of the left ventricle (LV). One such type is the implantable rotary blood pump (iRBP). Several design issues related to the iRBP are difficult to study experimentally due to procedure complexity and limitations in animal models of heart failure [2]. Therefore, modeling has become a key tool in iRBP development. In the second part of this study, we have introduced an iRBP model based on [1]-[2] in the systolic failing heart to study the interactions. We consider optimal motor settings for different levels of LV assistance, the effects of the iRBP on the right heart, septum, and pulmonary circulation. Our model results align with those reported in [1]-[2]. Improvement in cardiac output, pulmonary congestion, and heart work are seen with the iRBP. We observe lowered septal assistance to RV and LV ejection with increasing pump speeds, elevating right ventricular (RV) work, reducing LVET, and causing ventricular mechanical dyssynchrony in ejection. These results suggest right heart compromise via the septum's reduced role with the introduction of an iRBP. This work emphasizes the critical role of modeling in heart failure and treatment studies.

Using a human cardiovascular-respiratory model to characterize cardiac tamponade and pulsus paradoxus.

BACKGROUND: Cardiac tamponade is a condition whereby fluid accumulation in the pericardial sac surrounding the heart causes elevation and equilibration of pericardial and cardiac chamber pressures, reduced cardiac output, changes in hemodynamics, partial chamber collapse, pulsus paradoxus, and arterio-venous acid-base disparity. Our large-scale model of the human cardiovascular-respiratory system (H-CRS) is employed to study mechanisms underlying cardiac tamponade and pulsus paradoxus. The model integrates hemodynamics, whole-body gas exchange, and autonomic nervous system control to simulate pressure, volume, and blood flow. METHODS: We integrate a new pericardial model into our previously developed H-CRS model based on a fit to patient pressure data. Virtual experiments are designed to simulate pericardial effusion and study mechanisms of pulsus paradoxus, focusing particularly on the role of the interventricular septum. Model differential equations programmed in C are solved using a 5th-order Runge-Kutta numerical integration scheme. MATLAB is employed for waveform analysis. RESULTS: The H-CRS model simulates hemodynamic and respiratory changes associated with tamponade clinically. Our model predicts effects of effusion-generated pericardial constraint on chamber and septal mechanics, such as altered right atrial filling, delayed leftward septal motion, and prolonged left ventricular pre-ejection period, causing atrioventricular interaction and ventricular desynchronization. We demonstrate pericardial constraint to markedly accentuate normal ventricular interactions associated with respiratory effort, which we show to be the distinct mechanisms of pulsus paradoxus, namely, series and parallel ventricular interaction. Series ventricular interaction represents respiratory variation in right ventricular stroke volume carried over to the left ventricle via the pulmonary vasculature, whereas parallel interaction (via the septum and pericardium) is a result of competition for fixed filling space. We find that simulating active septal contraction is important in modeling ventricular interaction. The model predicts increased arterio-venous CO2 due to hypoperfusion, and we explore implications of respiratory pattern in tamponade. CONCLUSION: Our modeling study of cardiac tamponade dissects the roles played by septal motion, atrioventricular and right-left ventricular interactions, pulmonary blood pooling, and the depth of respiration. The study fully describes the physiological basis of pulsus paradoxus. Our detailed analysis provides biophysically-based insights helpful for future experimental and clinical study of cardiac tamponade and related pericardial diseases.

Impact of alpha 1-adrenergic antagonist use for benign prostatic hypertrophy on outcomes in patients with heart failure.

Previous clinical trials have shown that alpha(1)-adrenergic antagonists are not effective in subjects with heart failure (HF) and might increase HF rates when used for hypertension. However, alpha(1)-adrenergic antagonists may be prescribed to subjects with HF who have symptomatic benign prostatic hyperplasia. We sought to determine any association between alpha(1)-adrenergic antagonist use, commonly prescribed for benign prostatic hyperplasia, and the clinical outcomes of subjects with HF receiving contemporary therapy. An existing database of 388 subjects with decompensated HF admissions from 2002 to 2004 at the Veterans Affairs Hospital was analyzed according to the use of alpha(1)-adrenergic antagonists at discharge. Covariate-adjusted Cox proportional hazard models were used to examine any association with future admissions for decompensated HF and total mortality. Alpha-1-adrenergic antagonist therapy was prescribed in 25% of our HF population, predominantly for benign prostatic hyperplasia, and was not associated with significant increases in the combined risk of all-cause mortality and rehospitalization for HF (hazard ratio 1.24, 95% confidence interval 0.93 to 1.65, p = 0.14), HF hospitalization (hazard ratio 1.20, 95% confidence interval 0.85 to 1.70, p = 0.31), or all-cause mortality (hazard ratio 1.10, 95% confidence interval 0.78 to 1.56, p = 0.57). In patients not receiving beta-blocker therapy, alpha(1)-adrenergic antagonist therapy was significantly associated with increased HF hospitalizations (hazard ratio 1.94, 95% confidence interval 1.14 to 3.32, p = 0.015). In conclusion, in patients with chronic HF, the use of alpha(1)-adrenergic antagonists was significantly associated with more HF hospitalizations when prescribed without concomitant beta blockade. Thus, background beta-blocker therapy appears to be protective against the potential harmful effects of alpha(1)-adrenergic antagonist therapy in patients with HF.

Herpes zoster and its cardiovascular complications in the elderly--another look at a dormant virus.

Herpes zoster (shingles) is a reactivation of latent Varicella-zoster virus (VZV). We present a case of pleuropericarditis simulating acute myocardial infarction and another with complete heart block in the setting of acute/recent VZV reactivation. These cases are consistent with a modified concept: (1) the VZV dormancy is comprised of multiple foci of infections in the sensory and autonomic ganglia, and (2) the VZV reactivation could involve co-incident activations of two or more loci. Recognition of this possibility of cardiovascular complications of VZV should be helpful in the clinical management of the elderly, in the differential diagnosis of chest pain, ST elevation, and heart block etiology in the setting of acute or recent VZV reactivation.

Malignant pleural/pericardial effusion with tamponade and life-threatening reversible myocardial depression in a case of an initial presentation of lung adenocarcinoma.

We present a case of a middle-aged woman in cardiac tamponade. Following pericardiocentesis that removed 1,500 ml of hemorrhagic fluid, the patient exhibited cardiogenic shock; LVEF, at its nadir, on inotrope, was less than 20%. Ventricular function slowly improved, with inotropic support, to the normal range by the 25th day of hospitalization. Cardiac failure in malignancy has often been attributed to multi-system failure; this case showed a hereto unrecognized clinical phenomenon - 'malignancy-associated myopericarditis'. While the direct link of cause and effect cannot be made with certainty, the case should be instructive to other clinicians who encounter similar life-threatening presentations of cardiac decompensation in malignancy.