A second look with prone SPECT myocardial perfusion imaging reduces the need for angiography in patients at low risk for cardiac death or MI.

BACKGROUND: Correction for soft tissue signal attenuation can improve the diagnostic accuracy of single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI). The aim of this study was to correlate SPECT-MPI findings with clinical outcomes in patients who underwent stress imaging in the supine position, who also underwent "second look" stress imaging in the prone position. METHODS: Patients without perfusion abnormalities were considered Normal (N = 270). Those with apparent supine stress perfusion abnormalities which all resolved during prone imaging formed the Normal-Prone group (N = 309). Patients with matched perfusion abnormalities during both supine and prone stress imaging were considered Abnormal (N = 169). RESULTS: During follow-up (187 ± 96 days), utilization rates for invasive coronary angiography were similar for Normal vs Normal-Prone patients (3.5% vs 3.8%; P = NS), but were significantly higher in Abnormal patients (42.4%, P < .0001). Coronary revascularization occurred in 0.78%, 0.64%, and 17.7% of Normal, Normal-Prone, and Abnormal patients, respectively (P < .001). Cardiac death or myocardial infarction occurred in 2.2%, 2.3%, and 6.3% of Normal, Normal-Prone, and Abnormal patients, respectively (P = .02). CONCLUSIONS: Second look SPECT-MPI identifies patients at low risk for death or myocardial infarction, who infrequently require invasive coronary angiography.

Diastolic heart failure: the current understanding and approach for management with focus on intensive care unit patients.

Multiple recent epidemiologic studies have highlighted the importance of diastolic heart failure (DHF) as a public health problem. Approximately half of patients presenting with symptomatic heart failure (HF) have DHF and they suffer from morbidity and mortality comparable to those with systolic HF. Our understanding of the pathophysiology of DHF has evolved rapidly over the last decade, and the associated echo-Doppler findings that assist with its diagnosis are greatly refined. Recently, there has been increased recognition of the role of diastolic dysfunction and DHF in the care of critically ill patients, including those admitted to noncardiac units. The purpose of this review is to provide an up-to-date summary of the concepts of the pathophysiology of DHF. In addition, we provide an overview of the diagnostic approaches, prognostic identifiers, and associated comorbidities that make DHF more resistant to manage with a focus of the patients admitted to the intensive care unit. The current approach to managing patients with DHF is also reviewed.

The pulmonary artery catheter: a critical reappraisal.

Balloon floatation pulmonary artery catheters (PACs) have been used for hemodynamic monitoring in cardiac, medical, and surgical intensive care units since the 1970s. With the availability of newer noninvasive diagnostic modalities, particularly echocardiography, the frequency of diagnostic pulmonary artery catheterization has declined. In this review, the evolution of PACs, the results of nonrandomized and randomized studies in various clinical conditions, the uses and abuses of bedside hemodynamic monitoring, and current indications for pulmonary artery catheterization are discussed.

Coronary collateral circulation: its relevance.

The interest in coronary collateral circulation (CCC) as "natural bypasses" is growing, especially in patients in whom the extent of coronary atherosclerosis is too severe to allow for conventional revascularization. The anatomic foundation of CCC has been recognized for long time. Recently, reliable methods have become available for the assessment of the adequacy of collateral flow. However, the debate regarding the importance of CCC in the different clinical settings continues. In this article, we present the recent progress in the understanding of anatomy and physiology of the CCC and focus on the studies addressing their functional significance in acute, subacute, and chronic coronary artery disease. In addition, we provide a focused update on the essential role of collateral circulation in the management of coronary chronic total occlusions.

Pathophysiology of systolic and diastolic heart failure.

Systolic and diastolic heart failure are the 2 most common clinical subsets of chronic heart failure. Left ventricular "Starling" function is depressed in patients with systolic heart failure. In systolic heart failure, left ventricular mass is increased, which can be measured by transthoracic echocardiography. Cardiac magnetic resonance imaging is a more precise technique to measure left ventricular mass. Neurohormonal activation is a major pathophysiologic mechanism for ventricular remodeling and progression of heart failure in systolic heart failure.

Cytokine combination therapy with erythropoietin and granulocyte colony stimulating factor in a porcine model of acute myocardial infarction.

PURPOSE: Erythropoietin (EPO) and granulocyte colony stimulating factor (GCSF) have generated interest as novel therapies after myocardial infarction (MI), but the effect of combination therapy has not been studied in the large animal model. We investigated the impact of prolonged combination therapy with EPO and GCSF on cardiac function, infarct size, and vascular density after MI in a porcine model. METHODS: MI was induced in pigs by a 90 min balloon occlusion of the left anterior descending coronary artery. 16 animals were treated with EPO+GCSF, or saline (control group). Cardiac function was assessed by echocardiography and pressure-volume measurements at baseline, 1 and 6 weeks post-MI. Histopathology was performed 6 weeks post-MI. RESULTS: At week 6, EPO+GCSF therapy stabilized left ventricular ejection fraction, (41 ± 1% vs. 33 ± 1%, p < 0.01) and improved diastolic function compared to the control group. Histopathology revealed increased areas of viable myocardium and vascular density in the EPO+GCSF therapy, compared to the control. Despite these encouraging results, in a historical analysis comparing combination therapy with monotherapy with EPO or GCSF, there were no significant additive benefits in the LVEF and volumes overtime using the combination therapy. CONCLUSION: Our findings indicate that EPO+GCSF combination therapy promotes stabilization of cardiac function after acute MI. However, combination therapy does not seem to be superior to monotherapy with either EPO or GCSF.

Is detection of hibernating myocardium necessary in deciding revascularization in systolic heart failure?

Although the prognosis of systolic heart failure, also called heart failure with reduced ejection fraction, has improved with advances in therapy, the prognosis remains poor in patients who become refractory to such therapies. That cardiac transplantation improves the quality of life and survival of such patients has been established, but it is available to a very small number of patients. Thus, newer pharmacologic and nonpharmacologic therapies for patients with refractory systolic heart failure are being explored. Because chronic ischemic heart disease is the most common cause of systolic heart failure, potential exists for revascularization therapy. Although revascularization can be performed with low procedural mortality, improvement in left ventricular function, relief of symptoms, and long-term prognosis appear to be related to the presence and extent of viable ischemic hibernating myocardium. In conclusion, the detection of hibernating myocardium is highly desirable before revascularization treatment is undertaken.

Granulocyte colony stimulating factor in myocardial infarction with low ejection fraction.

BACKGROUND: We investigated the safety and efficacy of GCSF therapy in a porcine model of ischemia-reperfusion with left ventricle ejection fraction of <45% using a clinically relevant dosing and timing regimen. METHODS: MI was induced in pigs by a 90 min balloon occlusion of the left anterior descending coronary artery. Sixteen animals were randomized to either GCSF (IV bolus of 10 microg/kg at time of reperfusion, followed by SC injections of 5 microg/kg days 5-9 post-MI) or saline (control group). Inflammatory markers, bone marrow cell mobilization and LV function (echocardiography and pressure-volume measurements) were assessed at baseline, 1 and 6 weeks post-MI. Histopathology was performed 6 weeks post-MI. RESULTS: GCSF therapy was associated with a significant increase in white blood cell counts. At week 6, GCSF therapy resulted in less deterioration of LVEF compared to control (38+/-2% vs. 33+/-2%, p<0.02) and improved wall motion score index (p<0.05). Histopathology revealed increased vascular density (p<0.05) and a trend toward increased areas of viable myocardium compared to control (p=0.058). CONCLUSION: GCSF therapy prevents further deterioration of LV function in a porcine model of MI with lower EF (<45%). These results support future clinical trials with GCSF in selected patients with larger MI.

Prolonged therapy with erythropoietin is safe and prevents deterioration of left ventricular systolic function in a porcine model of myocardial infarction.

BACKGROUND: Erythropoietin (EPO) has generated interest as a novel therapy after myocardial infarction (MI), but the safety and efficacy of prolonged therapy have not been studied in a large animal model of reperfused MI. METHODS AND RESULTS: MI was induced in pigs by a 90-minute balloon occlusion of the left anterior descending coronary artery. Sixteen animals were randomized to either EPO or saline (control group). Inflammatory markers, bone marrow cell mobilization, and left ventricular function (by both echocardiography and pressure-volume measurements) were assessed at baseline, 1 and 6 weeks post-MI. EPO therapy was associated with a significant increase in hemoglobin and mononuclear counts. D-dimer and C-reactive protein levels did not differ between groups. At week 6, EPO therapy prevented further deterioration of left ventricular ejection fraction (39 +/- 2% vs. 33 +/- 1%, P < .01) and improved wall motion score index (P < .02). Histopathology revealed increased areas of viable myocardium, vascular density, and capillary-to-myocyte ratio in the EPO therapy compared with the control (all P < .05). CONCLUSION: Prolonged EPO therapy after MI in a large animal model is safe and leads to an increase in viable myocardium, increased vascular density, and prevents further deterioration of left ventricular function. These results support future clinical studies in post-MI patients.

Vincristine attenuates N-methyl-N'-nitro-N-nitrosoguanidine-induced poly-(ADP) ribose polymerase activity in cardiomyocytes.

The DNA-damaging agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) causes cardiomyocyte death as a result of energy loss from excessive activation of poly-(ADP) ribose polymerase-1 (PARP-1) resulting in depletion of its substrates nicotinamide adenine dinucleotide (NAD) and ATP. Previously we showed that the chemotherapeutic agent vincristine (VCR) is cardioprotective. Here we tested the hypothesis that VCR inhibits MNNG-induced PARP activation. Adult mouse cardiomyocytes were incubated with 100 micromol/L MNNG with or without concurrent VCR (20 micromol/L) for 2 to 4 hours. Cardiomyocyte survival was measured using the trypan blue exclusion assay. Western blots were used to measure signaling responses. MNNG-induced cardiomyocyte damage was time- and concentration-dependent. MNNG activated PARP-1 and depleted NAD and ATP. VCR completely protected cardiomyocytes from MNNG-induced cell damage and maintained intracellular levels of NAD and ATP. VCR increased phosphorylation of the prosurvival signals Akt, GSK-3beta, Erk1/2, and p70S6 kinase. VCR delayed PARP activation as evidenced by Western blot and by immunofluorescence staining of poly (ADP)-ribose, but without directly inhibiting PARP-1 itself. Known PARP-1 inhibitors also protected cardiomyocytes from MNNG-induced death. Repletion of ATP, NAD, pyruvate, and glutamine had effects similar to PARP-1 inhibitors. We conclude that VCR protects cardiomyocytes from MNNG toxicity by regulating PARP-1 activation, intracellular energy metabolism, and prosurvival signaling.

A comparison of echocardiography to invasive measurement in the evaluation of pulmonary arterial hypertension in a rat model.

Pulmonary arterial hypertension (PAH) is a life-threatening condition characterized by progressive elevation in pulmonary artery pressure (PAP) and total pulmonary vascular resistance (TPVR). Recent advances in imaging techniques have allowed the development of new echocardiographic parameters to evaluate disease progression. However, there are no reports comparing the diagnostic performance of these non-invasive parameters to each other and to invasive measurements. Therefore, we investigated the diagnostic yield of echocardiographically derived TPVR and Doppler parameters of PAP in screening and measuring the severity of PAH in a rat model. Serial echocardiographic and invasive measurements were performed at baseline, 21 and 35 days after monocrotaline-induction of PAH. The most challenging echocardiographic derived TPVR measurement had good correlation with the invasive measurement (r = 0.92, P < 0.001) but also more simple and novel parameters of TPVR were found to be useful although the non-invasive TPVR measurement was feasible in only 29% of the studies due to lack of sufficient tricuspid valve regurgitation. However, echocardiographic measures of PAP, pulmonary artery flow acceleration time (PAAT) and deceleration (PAD), were measurable in all animals, and correlated with invasive PAP (r = -0.74 and r = 0.75, P < 0.001 for both). Right ventricular thickness and area correlated with invasive PAP (r = 0.59 and r = 0.64, P < 0.001 for both). Observer variability of the invasive and non-invasive parameters was low except in tissue-Doppler derived isovolumetric relaxation time. These non-invasive parameters may be used to replace invasive measurements in detecting successful disease induction and to complement invasive data in the evaluation of PAH severity in a rat model.

Doxorubicin cardiomyopathy.

Established doxorubicin cardiomyopathy is a lethal disease. When congestive heart failure develops, mortality is approximately 50%. Extensive research has been done to understand the mechanism and pathophysiology of doxorubicin cardiomyopathy, and considerable knowledge and experience has been gained. Unfortunately, no effective treatment for established doxorubicin cardiomyopathy is presently available. Extensive research has been done and is being done to discover preventive treatments. However an effective and clinically applicable preventive treatment is yet to be discovered.

Hyponatremia in heart failure.

Hyponatremia is one of the newer and emerging risk factors for an adverse prognosis in chronic heart failure. Why decreased serum sodium is associated with worse prognosis remains unclear. It may reflect worsening heart failure and the deleterious effects of activation of neurohormones. The mechanism of hyponatremia in heart failure also remains unclear. A relatively greater degree of free-water retention compared to sodium retention is probably the major mechanism. The treatment of significant hyponatremia in heart failure is difficult. The conventional treatments such as fluid restriction, infusion of hypertonic saline, and aggressive diuretic therapies are not usually effective. Vasopressin receptor antagonists have been shown to enhance aquaresis and correct hyponatremia. However, long-term beneficial effects of such treatments in chronic heart failure have not been documented.

Left ventricular remodeling after myocardial infarction: characterization of a swine model on beta-blocker therapy.

Current guidelines recommend beta blockers for patients after myocardial infarction (MI). Novel therapies for heart failure should be tested in combination with this medication before entering clinical trials. In this methodologic study, we sought to describe the time course of systolic and diastolic parameters of cardiac performance over a 6-wk period in closed-chest model of swine MI treated with a beta blocker. Myocardial infarction in pigs (n = 10) was induced by 90-min balloon occlusion of the left anterior descending coronary artery. Echocardiography and pressure-volume data were collected before and at 1 and 6 wk after MI; histopathology was assessed at 6 wk. Left-ventricular (LV) volume increased significantly over 6 wk, with significant decreases in ejection fraction, wall motion index, stroke work, rate of pressure development (dP/dt(max)), preload recruitable stroke work, and mechanical efficiency. Impairment of diastolic function was manifested by a significant increase in the exponential beta coefficient of the LV end-diastolic pressure-volume relation and reduction of LV pressure decay. At 6 wk, histopathologic analysis showed that the size of the infarct area was 16.3% +/- 4.4%, and the LV mass and myocyte cross-sectional area in both the infarct border and remote zones were increased compared with those of noninfarcted pigs (n = 5). These findings suggest a dynamic pattern of remodeling over time in a closed-chest ischemia-reperfusion swine model of acute MI on beta-blocker therapy and may guide future studies.

Coronary hemodynamics in heart failure and effects of therapeutic interventions.

BACKGROUND: The abnormalities in coronary hemodynamics in systolic heart failure are frequent. Myocardial oxygen demand and consumption are increased and myocardial perfusion is also impaired, which may result in myocardial ischemia, necrosis, and apoptosis. This is potentially a contributing factor for progressive heart failure. METHODS AND RESULTS: Neurohormonal abnormalities such as activated renin-angiotensin-aldosterone system, increased adrenergic activity, hemodynamic abnormalities such as decreased left ventricular perfusion pressure, and increased left ventricular diastolic pressure are important mechanisms for myocardial ischemia. CONCLUSIONS: Different pharmacologic agents may exert different effects on coronary hemodynamics although changes in systemic hemodynamics may be similar. Some agents may enhance myocardial ischemia and others may decrease it. Thus, an understanding of changes in coronary hemodynamics may have therapeutic implications.

The Swan-Ganz catheters: past, present, and future. A viewpoint.

The Swan-Ganz balloon flotation catheter was introduced in 1970. It can be placed at the bedside within a few minutes even in critically ill patients. Although placement of these catheters is not difficult, some training and experience are required to avoid complications and for proper interpretation of the hemodynamic data that can be obtained by pulmonary artery catheterization. Because of the many advantages of balloon flotation catheters compared with conventional catheters, they have been used without a proper indication and frequently overused in critical care units, resulting in many complications, including mortality. The prospective randomized trials have reported that in the majority of clinical circumstances, the routine use of balloon flotation catheters is not indicated. These results are not surprising because balloon flotation catheters are diagnostic and not therapeutic tools. That we have learned a great deal about hemodynamics in critically ill patients with the use of balloon flotation catheters should not be ignored or forgotten. Furthermore, our clinical knowledge of hemodynamics has been made possible because of extensive experience gained from directly determined hemodynamics with the use of balloon flotation catheters. It should also be realized that despite the introduction and refinement of newer noninvasive imaging modalities, a number of clinical circumstances exist in which determination of hemodynamics with the use of a balloon flotation catheter is necessary and should be considered, but only by experienced physicians. With the proper use of Swan-Ganz catheters, our knowledge of hemodynamics has been enhanced considerably. Its abuse, particularly by relatively inexperienced operators, has resulted in serious complications, including death. Prospective randomized clinical trials have demonstrated that the routine use of Swan-Ganz catheters does not provide any benefit. However, use of the Swan-Ganz catheter is still indicated in many situations.