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Aims Invasive assessment of acute haemodynamic response to biventricular pacing has been proposed as a tool to determine individual response and to optimize the effects of CRT. However, the long-term results of this approach have been poorly studied. The present study relates acute haemodynamic effects of CRT to long-term outcome. Methods and results Forty-one patients were analysed in the present study. During temporary biventricular pacing before implantation, acute changes in LV pump function were assessed by pressure–volume loop measurements and related to long-term response after CRT. In the study population [30 (71%) men, NYHA class 2.9 ± 0.4, EF 28 ± 7%, QRS 150 ± 25 ms], baseline mean stroke work (SW) and dP/dtmax were 4.6 ± 2.6 L ×mmHg and 874 ± 259 mmHg/s, respectively. During biventricular pacing, mean SW and dP/dtmax increased significantly by 43 ± 39% (+ 2.2 ± 2.4 L × mmHg, P < 0.001) and 13 ± 18% (+ 96 ± 136 mmHg/s, P < 0.001), respectively. In long-term responders (n = 29, 71%) compared with non-responders (n = 12, 29%), the acute increase in SW was significantly higher (+57 ±33% vs. + 10 ±30%, P < 0.001), whereas the acute increase in dP/dtmax was not significantly different between responders and non-responders (+ 15 ±18% vs. 6 ±15%, P = 0.139). Receiver operating characteristic (ROC) curve analysis indicated that SW was superior to dP/dtmax, QRS duration and LV dyssynchrony in prediction of response to CRT. A cut-off value for SW of 20% yielded a sensitivity of 90% and specificity of 75% to predict reverse remodelling at 6 months. Conclusion Invasive assessment of acute haemodynamics is a reliable tool to determine individual response to CRT. An acute increase in SW predicts long-term response to CRT with a higher accuracy than an acute increase in dP/dtmax, baseline QRS duration, and degree of LV mechanical dyssynchrony.

We aimed to describe the logistics of a prehospital triage system for patients with acute chest pain in the region of Amsterdam, The Netherlands. Ambulance electrocardiograms (ECGs) were evaluated immediately in 1 of the percutaneous coronary intervention (PCI)-capable centers. Patients accepted for primary PCI (PPCI) were directly transferred to the catheterization laboratory. Two thousand three hundred fifty ECGs of 2,192 patients were transmitted to the region's intervention centers. Median duration of chest complaints before ambulance dispatch was 67 minutes; ambulance crews recorded the first ECG within 7 minutes after arrival. Actual transmission of the ECG took an additional (median) 10 minutes. Seven hundred eleven patients (32.4%) were transported to the catheter laboratory and were treated with PPCI. Time between first prehospital ECG and start of PPCI procedure was 66 minutes. The PPCI procedure started 36 minutes after ambulance arrival at the hospital. In conclusion, the results of this study compare favorably to other reported performances of prehospital triage systems of PPCI for ST-segment elevated myocardial infarction and demonstrate that the European Society of Cardiology and American Heart Association guidelines for treatment of patients with ST-segment elevated myocardial infarction can be met. (C) 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;106: 931-935)

During left ventricular (LV) torsion, the base rotates in an overall clockwise direction and the apex rotates in a counterclockwise direction when viewed from apex to base. LV torsion is followed by rapid untwisting, which contributes to ventricular filling. Because LV torsion is directly related to fiber orientation, it might depict subclinical abnormalities in heart function. Recently, ultrasound speckle tracking was introduced for quantification of LV torsion. This fast, widely available technique may contribute to a more rapid introduction of LV torsion as a clinical tool for detection of myocardial dysfunction. However, knowledge of the exact function and structure of the heart is fundamental for understanding the value of LV torsion. LV torsion has been investigated with different measurement methods during the past 2 decades, using cardiac magnetic resonance as the gold standard. The results obtained over the years are helpful for developing a standardized method to quantify LV torsion and have facilitated the interpretation and value of LV torsion before it can be used as a clinical tool.

Background— Excessive diastolic left ventricular stiffness is an important contributor to heart failure in patients with diabetes mellitus. Diabetes is presumed to increase stiffness through myocardial deposition of collagen and advanced glycation end products (AGEs). Cardiomyocyte resting tension also elevates stiffness, especially in heart failure with normal left ventricular ejection fraction (LVEF). The contribution to diastolic stiffness of fibrosis, AGEs, and cardiomyocyte resting tension was assessed in diabetic heart failure patients with normal or reduced LVEF. Methods and Results— Left ventricular endomyocardial biopsy samples were procured in 28 patients with normal LVEF and 36 patients with reduced LVEF, all without coronary artery disease. Sixteen patients with normal LVEF and 10 with reduced LVEF had diabetes mellitus. Biopsy samples were used for quantification of collagen and AGEs and for isolation of cardiomyocytes to measure resting tension. Diabetic heart failure patients had higher diastolic left ventricular stiffness irrespective of LVEF. Diabetes mellitus increased the myocardial collagen volume fraction only in patients with reduced LVEF (from 14.6±1.0% to 22.4±2.2%, P 2 , P =0.006). Diabetes increased myocardial AGE deposition in patients with reduced LVEF (from 8.8±2.5 to 24.1±3.8 score/mm 2 ; P =0.005) and less so in patients with normal LVEF (from 8.2±2.5 to 15.7±2.7 score/mm 2 , P =NS). Conclusions— Mechanisms responsible for the increased diastolic stiffness of the diabetic heart differ in heart failure with reduced and normal LVEF: Fibrosis and AGEs are more important when LVEF is reduced, whereas cardiomyocyte resting tension is more important when LVEF is normal.

AIMS: This study investigated the relationship between right ventricular (RV) structure and function and survival in idiopathic pulmonary arterial hypertension (IPAH).METHODS AND RESULTS: In 64 patients, cardiac magnetic resonance, right heart catheterization, and the six-minute walk test (6MWT) were performed at baseline and after 1-year follow-up. RV structure and function were analysed as predictors of mortality. During a mean follow-up of 32 months, 19 patients died. A low stroke volume (SV), RV dilatation, and impaired left ventricular (LV) filling independently predicted mortality. In addition, a further decrease in SV, progressive RV dilatation, and further decrease in LV end-diastolic volume (LVEDV) at 1-year follow-up were the strongest predictors of mortality. According to Kaplan-Meier survival curves, survival was lower in patients with an inframedian SV index or= 84 mL/m(2), and an inframedian LVEDVCONCLUSIONS: The RV contains prognostic information in IPAH. A large RV volume, low SV, and a reduced LV volume are strong independent predictors of mortality and treatment failure.

Background— To support the clinical distinction between systolic heart failure (SHF) and diastolic heart failure (DHF), left ventricular (LV) myocardial structure and function were compared in LV endomyocardial biopsy samples of patients with systolic and diastolic heart failure. Methods and Results— Patients hospitalized for worsening heart failure were classified as having SHF (n=22; LV ejection fraction (EF) 34±2%) or DHF (n=22; LVEF 62±2%). No patient had coronary artery disease or biopsy evidence of infiltrative or inflammatory myocardial disease. More DHF patients had a history of arterial hypertension and were obese. Biopsy samples were analyzed with histomorphometry and electron microscopy. Single cardiomyocytes were isolated from the samples, stretched to a sarcomere length of 2.2 μm to measure passive force (F passive ), and activated with calcium-containing solutions to measure total force. Cardiomyocyte diameter was higher in DHF (20.3±0.6 versus 15.1±0.4 μm, P P passive (7.1±0.6 versus 5.3±0.3 kN/m 2 ; P passive was larger ( P Conclusions— LV myocardial structure and function differ in SHF and DHF because of distinct cardiomyocyte abnormalities. These findings support the clinical separation of heart failure patients into SHF and DHF phenotypes.

Objective: In human heart failure β-adrenergic-mediated protein kinase A (PKA) activity is down-regulated, while protein kinase C (PKC) activity is up-regulated. PKC-mediated myofilament protein phosphorylation might be detrimental for contractile function in cardiomyopathy. This study was designed to reveal the effects of PKC on myofilament function in human myocardium under basal conditions and upon modulation of protein phosphorylation by PKA and phosphatases. Methods: Isometric force was measured at different [Ca 2+] in single permeabilized cardiomyocytes from non-failing and failing human left ventricular tissue. Basal phosphorylation of myofilament proteins and the influence of PKC, PKA, and phosphatase treatments were analyzed by one- and two-dimensional gel electrophoresis, Western immunoblotting, and ELISA. Results: Troponin I (TnI) phosphorylation at the PKA sites was decreased in failing compared to non-failing hearts and correlated well with myofilament Ca2+ sensitivity (pCa50). Incubation with the catalytic domain of PKC slightly decreased maximal force under basal conditions, but not following PKA and phosphatase pretreatments. PKC reduced Ca2+ sensitivity to a larger extent in failing (ΔpCa50 = 0.19 ± 0.03) than in non-failing (ΔpCa50 = 0.08 ± 0.01) cardiomyocytes. This shift was reduced, though still significant, when PKC was preceded by PKA, while PKA following PKC did not further decrease pCa 50. Protein analysis indicated that PKC phosphorylated PKA sites in human TnI and increased phosphorylation of troponin T, while myosin light chain phosphorylation remained unaltered. Conclusion: In human myocardium PKC-mediated myofilament protein phosphorylation only has a minor effect on maximal force development. The PKC-mediated decrease in Ca2+ sensitivity may serve to improve diastolic function in failing human myocardium in which PKA-mediated TnI phosphorylation is decreased.

Background— Heart failure with preserved left ventricular (LV) ejection fraction (EF) is increasingly recognized and usually referred to as diastolic heart failure (DHF). Its pathogenetic mechanism remains unclear, partly because of a lack of myocardial biopsy material. Endomyocardial biopsy samples obtained from DHF patients were therefore analyzed for collagen volume fraction (CVF) and sarcomeric protein composition and compared with control samples. Single cardiomyocytes were isolated from these biopsy samples to assess cellular contractile performance. Methods and Results— DHF patients (n=12) had an LVEF of 71±11%, an LV end-diastolic pressure (LVEDP) of 28±4 mm Hg, and no significant coronary artery stenoses. DHF patients had higher CVFs (7.5±4.0%, P 2+ ]. Compared with cardiomyocytes of controls, cardiomyocytes of DHF patients developed a similar total isometric force at maximal [Ca 2+ ], but their resting tension ( F passive ) in the absence of Ca 2+ was almost twice as high (6.6±3.0 versus 3.5±1.7 kN/m 2 , P F passive and CVF combined yielded stronger correlations with LVEDP than did either alone. Administration of protein kinase A (PKA) to DHF cardiomyocytes lowered F passive to control values. Conclusions— DHF patients had stiffer cardiomyocytes, as evident from a higher F passive at the same sarcomere length. Together with CVF, F passive determined in vivo diastolic LV dysfunction. Correction of this high F passive by PKA suggests that reduced phosphorylation of sarcomeric proteins is involved in DHF.

During cardiac filling, the relative contribution of distension of interstitial collagen, of distension of cytoskeletal proteins, and of low-grade diastolic cross-bridge cycling in the generation of diastolic left ventricular (LV) pressure remains unclear. In failing myocardium, interstitial collagen deposition and cross-linking are augmented. This increase in collagen deposition is accompanied by expression of a stiffer isoform of titin in the cardiomyocytes. Higher diastolic stiffness of failing myocardium is therefore not necessarily related to increased interstitial collagen content. Moreover, phosporylation of titin by protein kinase A and G, and inhibition of titin-actin interaction by cytosolic calcium allow for dynamic modulation of its diastolic tension generation and could account for acute shifts of myocardial distensibility. Acute shifts of myocardial distensibility, as occur in hypertrophy or in demand ischemia, have usually been attributed to a diastolic resurgence of cross-bridge interaction. In hypertrophied and failing myocardium, the recent demonstrations of diastolic calcium release from the ryanodine receptor, of deficient diastolic calcium removal from the cytosol, and of enhanced myofilamentary calcium sensitivity support residual diastolic cross-bridge interaction. In demand ischemia, the role of calcium overload in the reduction of diastolic LV distensibility is less clear because of correction of the reduced diastolic LV distensibility by quick stretches but not by a calcium desensitizer. Simultaneous imposition in animal models of multiple molecular changes involving interstitial, cytoskeletal, and myofilamentary proteins could elucidate their relative importance for myocardial stiffness and lead to selective correction of diastolic LV dysfunction as a novel mode of heart-failure therapy.

Purpose To assess the accuracy of several noninvasive MRI-based estimators of pulmonary artery pressure by comparing them with invasive pressure measurement. Materials and Methods We compared five MRI methods with invasive pressure measurement by catheterization, in one group of pulmonary hypertension (PH) patients. Doppler echocardiography was included as a reference method. Main inclusion criterion was a mean pulmonary artery pressure above 25 mmHg at catheterization. MRI velocity quantification was used to obtain pulmonary flow acceleration and ejection times, and pulse wave velocity. The ventricular mass index was also assessed on MRI. Two commercially available 1.5-T systems were used for this study. Results Data from 44 patients were analyzed. Correlation of acceleration time with mean pressure was: r = –0.21, P = 0.21, correlation of the acceleration/ejection time ratio with systolic pressure was: r = –0.26, P = 0.01. The ventricular mass index showed the best correlation with mean pressure, with r = 0.56, P < 0.001. Using the pulse wave velocity and the cross-sectional area of the pulmonary artery, the mean pressure could not be estimated accurately. Conclusion Accurate estimation of pulmonary artery pressure in PH patients was not feasible by the MRI estimators studied. These noninvasive methods cannot replace right heart catheterization at this moment. J. Magn. Reson. Imaging 2005;22:67–72. © 2005 Wiley-Liss, Inc.

Beneficial actions of nitric oxide (NO) in failing myocardium have frequently been overshadowed by poorly documented negative inotropic effects mainly derived from in vitro cardiac preparations. NO's beneficial actions include control of myocardial energetics and improvement of left ventricular (LV) diastolic distensibility. In isolated cardiomyocytes, administration of NO increases their diastolic cell length consistent with a rightward shift of the passive length-tension relation. This shift is explained by cGMP-induced phosphorylation of troponin I, which prevents calcium-independent diastolic cross-bridge cycling and concomitant diastolic stiffening of the myocardium. Similar improvements in diastolic stiffness have been observed in isolated guinea pig hearts, in pacing-induced heart failure dogs, and in patients with dilated cardiomyopathy or aortic stenosis and have been shown to result in higher LV preload reserve and stroke work. NO also controls myocardial energetics through its effects on mitochondrial respiration, oxygen consumption, and substrate utilization. The effects of NO on diastolic LV performance appear to be synergistic with its effects on myocardial energetics through prevention of myocardial energy wastage induced by LV contraction against late-systolic reflected arterial pressure waves and through prevention of diastolic LV stiffening, which is essential for the maintenance of adequate subendocardial coronary perfusion. A drop in these concerted actions of NO on diastolic LV distensibility and on myocardial energetics could well be instrumental for the relentless deterioration of failing myocardium.

Abnormalities of diastolic function are common to virtually all forms of cardiac failure. However, their underlying mechanisms, precise role in the generation and phenotypic expression of heart failure, and value as specific therapeutic targets remain poorly understood. A growing proportion of heart failure patients, particularly among the elderly, have apparently preserved systolic function, and this is fueling interest for better understanding and treating diastolic abnormalities. Much of the attention in clinical and experimental studies has focused on relaxation and filling abnormalities of the heart, whereas chamber stiffness has been less well studied, particularly in humans. Nonetheless, new insights from basic and clinical research are helping define the regulators of diastolic dysfunction and illuminate novel targets for treatment. This review puts these developments into perspective with the major aim of highlighting current knowledge gaps and controversies.

Objectives: To gain more knowledge of changes in main pulmonary artery flow and right ventricular mass and volumes in patients with pulmonary hypertension during epoprostenol therapy. Methods: Eleven patients (9 women) were evaluated before the start of therapy and every 4 months thereafter. Right and left ventricular volumes and masses were measured by cine MRI. Flow was measured with MRI velocity quantification. At the same times, 6-min walking tests were performed. Right-heart catheterizations were performed at baseline and after 1 year. Results: Right ventricular mass in the patient group was significantly higher from that in a control group of healthy volunteers (95 ± 26 g vs 42 ± 10 g, p < 0.05 [mean ± SD]), whereas the stroke volume was lower (34 ± 11 mL vs 81 ± 11 mL, p < 0.05). The greatest improvement in right ventricular stroke volume (to 41 ± 11 mL, p < 0.05) took place in the first 4 months. During the 1-year follow-up, right ventricular end-diastolic volume and mass did not change, and mean pulmonary artery pressure remained nearly stable at 55 mm Hg at baseline and 53 mm Hg after 1 year. Pulmonary vascular resistance decreased by 12.5% (p = 0.06). Conclusions: From these data we conclude that epoprostenol lowers pulmonary vascular resistance, leading to an increase in pulmonary artery flow. This increase in pulmonary artery flow corresponds well with the increase in 6-min walking distance and can be noninvasively monitored by MRI (flow quantification). Right ventricular dilatation and hypertrophy are not reversed by epoprostenol therapy, but do not progress either.

Background— A total of 40% to 50% of patients with ST-segment–elevation myocardial infarction develop microvascular injury (MVI) despite angiographically successful primary percutaneous coronary intervention (PCI). We investigated whether hyperemic microvascular resistance (HMR) immediately after angiographically successful PCI predicts MVI at cardiovascular magnetic resonance and reduced myocardial blood flow at positron emission tomography (PET). Methods and Results— Sixty patients with ST-segment–elevation myocardial infarction were included in this prospective study. Immediately after successful PCI, intracoronary pressure–flow measurements were performed and analyzed off-line to calculate HMR and indices derived from the pressure–velocity loops, including pressure at zero flow. Cardiovascular magnetic resonance and H 2 15 O PET imaging were performed 4 to 6 days after PCI. Using cardiovascular magnetic resonance, MVI was defined as a subendocardial recess of myocardium with low signal intensity within a gadolinium-enhanced area. Myocardial perfusion was quantified using H 2 15 O PET. Reference HMR values were obtained in 16 stable patients undergoing coronary angiography. Complete data sets were available in 48 patients of which 24 developed MVI. Adequate pressure–velocity loops were obtained in 29 patients. HMR in the culprit artery in patients with MVI was significantly higher than in patients without MVI (MVI, 3.33±1.50 mm Hg/cm per second versus no MVI, 2.41±1.26 mm Hg/cm per second; P =0.03). MVI was associated with higher pressure at zero flow (45.68±13.16 versus 32.01±14.98 mm Hg; P =0.015). Multivariable analysis showed HMR to independently predict MVI ( P =0.04). The optimal cutoff value for HMR was 2.5 mm Hg/cm per second. High HMR was associated with decreased myocardial blood flow on PET (myocardial perfusion reserve P =0.04). Conclusions— Doppler-flow–derived physiological indices of coronary resistance (HMR) and extravascular compression (pressure at zero flow) obtained immediately after successful primary PCI predict MVI and decreased PET myocardial blood flow. Clinical Trial Registration— URL: http://www.trialregister.nl . Unique identifier: NTR3164.

See article by Bronzwaer et al. [15] (pages 270–278) in this issue. The nitric oxide synthase (NOS) family of enzymes consists of three protein products from three distinct genes that catalyze the conversion of l-citrulline to l-arginine in the presence of NADPH and O2 yielding the diffusible free radical gas NO. The current viewpoint is that two of these genes NOS1 (nNOS) and NOS3 (eNOS) are constitutively expressed while NOS2 (iNOS) is readily inducible. In addition, the neuronal (nNOS) and endothelial (eNOS) proteins contain flexible calmodulin binding domains making these low-output enzymes sensitive to Ca2+ activation. Conversely, the inducible (iNOS) protein binds calmodulin tightly, making this enzyme Ca2+ insensitive. However, this protein is readily induced by numerous cytokines (IL-1β, TNFα, IFNγ, IL-6) as well as lipopolysaccharide (LPS) [1]. NOS1 and NOS3, by nature of their calcium sensitive, transient activity, mediate cell signaling events associated with NO. NOS2 is a high output enzyme (100–1000-fold greater activity than NOS1 and/or NOS3), immune inducible, calcium insensitive and is typically associated with the response to infection and inflammation [2]. In the normal mammalian heart, all three NOS gene products are expressed. Alterations in expression occur in response to a number of pathological stimuli. NOS1 is located in nerve terminals and may be involved in the synaptic transmission of norepinephrine during normal function [3]. Due to limited available data, the role for NOS1 in pathological settings has yet to be defined. NOS2 is located in endothelial cells, endocardial cells, and cardiomyocytes and seems to play a major role in normal immune function. Modulation of NOS2 expression has been implicated in numerous forms of cardiac pathophysiology, the general consensus being that high levels of NOS2 are associated with dysfunction. NOS3 is expressed in endocardium, coronary endothelium, and cardiomyocytes. … * Corresponding author. Tel.: +1-217-333-2506; fax: +1-217-244-1652 dgross{at}cvm.uiuc.edu

ECG-gated electrical impedance tomography (EIT) is a non-invasive imaging technique, developed to monitor blood volume changes. This study is the first in comparing this non-invasive technique in measuring stroke volume with established techniques. The objective of this study was to validate EIT variables derived from the EIT images with paired obtained stroke volume measurements by thermodilution and MRI. After right cardiac catheterization, EIT measurements were performed in 25 patients. Regression analysis was used to analyse the relation between the EIT results and stroke volume determined by thermodilution. From the regression line an equation was derived to estimate stroke volume (in ml) by EIT. A strong correlation was found between EIT and stroke volume measured by the thermodilution method (r = 0.86). In a group of 11 healthy subjects this equation was validated to MRI. The mean and standard deviation of the difference between EIT and MRI was 0.7 ml and 5.4 ml respectively. These data indicate that EIT is a valid and reproducible method for the assessment of stroke volume.

Study objectives: Electrical impedance tomography (EIT) offers the possibility to study blood volume changes within the right atrium during the cardiac cycle. The aim of this study was to determine the applicability of EIT in the assessment of right ventricular diastolic function in COPD. Design: By means of region of interest analysis, impedance changes within the right atrium during the cardiac cycle were plotted as a function of time. As a diastolic index of the right ventricle, the right atrium emptying volume (RAEV), defined as the ratio between the volume change during the rapid filling phase relative to the total ventricular filling volume, was calculated. In a first study, the validity of the EIT method was assessed by comparison of the RAEV measured by EIT and MRI in a group of eight patients with severe COPD and seven control subjects. A second study was undertaken to assess the relation between RAEV and pulmonary artery pressure in a group of 27 patients measured by right-sided heart catheterization. Results: The correlation coefficient between RAEV measured with MRI and EIT was 0.78. The difference between RAEV measured by MRI and EIT was 8.3 ± 15.7% (mean ± SD) for the control subjects and 3.5 ± 10.9% for the COPD patients. RAEV values measured by EIT and MRI were larger in the control group (47.1 ± 7.6%) compared with the patient group (38.1 ± 10.4%). There was a clear nonlinear relationship between RAEV and the pulmonary artery pressure (y=315 x- 0.64, r=0.83, p

Background The clinical significance of anomalously originating coronary arteries depends on their proximal course. Diagnosis of this course by conventional x-ray coronary angiography alone may be equivocal. We postulated that with fast magnetic resonance (MR) angiography, accurate detection of anomalous coronary arteries and unambiguous delineation of their proximal course is feasible. Methods and Results In a selected group of 38 patients, 19 of them having an anomalously originating coronary artery, a fast MR angiographic technique was used to study the proximal coronary anatomy. Blinded analysis of randomly ordered MR studies was performed independently by two observers. Both origin and proximal course of the coronary arteries were defined. Two cardiologists reviewed all x-ray coronary angiograms. After the separate analyses, a final consensus result was defined for each patient. In 37 patients, successful MR coronary angiography could be performed. Interobserver agreement for determining both origin and proximal course was 100%. An x-ray coronary angiogram was available in 36 patients. In 3 patients (all with an anomalous left main coronary artery originating from the right aortic sinus), there was disagreement about the proximal course between the results of MR and x-ray coronary angiography. Review of these cases demonstrated that MR angiography had unambiguously visualized the proximal coronary artery course, whereas the results of x-ray angiography had been equivocal. Thus, sensitivity and specificity for detecting anomalous coronary arteries and delineating their proximal course were 100%. Conclusions These data suggest that fast MR angiography is highly accurate in determining the origin and delineating the proximal course of anomalous coronary arteries, even in those cases in which x-ray coronary angiographic diagnosis is difficult or even erroneous.

Background— Prominent features of myocardial remodeling in heart failure with preserved ejection fraction (HFPEF) are high cardiomyocyte resting tension (F passive ) and cardiomyocyte hypertrophy. In experimental models, both reacted favorably to raised protein kinase G (PKG) activity. The present study assessed myocardial PKG activity, its downstream effects on cardiomyocyte F passive and cardiomyocyte diameter, and its upstream control by cyclic guanosine monophosphate (cGMP), nitrosative/oxidative stress, and brain natriuretic peptide (BNP). To discern altered control of myocardial remodeling by PKG, HFPEF was compared with aortic stenosis and HF with reduced EF (HFREF). Methods and Results— Patients with HFPEF (n=36), AS (n=67), and HFREF (n=43) were free of coronary artery disease. More HFPEF patients were obese ( P P passive was measured in cardiomyocytes before and after PKG administration. Myocardial homogenates were used for assessment of PKG activity, cGMP concentration, proBNP-108 expression, and nitrotyrosine expression, a measure of nitrosative/oxidative stress. Additional quantitative immunohistochemical analysis was performed for PKG activity and nitrotyrosine expression. Lower PKG activity in HFPEF than in aortic stenosis ( P P passive ( P P P passive in HFPEF was corrected by in vitro PKG administration. Conclusions— Low myocardial PKG activity in HFPEF was associated with raised cardiomyocyte F passive and was related to increased myocardial nitrosative/oxidative stress. The latter was probably induced by the high prevalence in HFPEF of metabolic comorbidities. Correction of myocardial PKG activity could be a target for specific HFPEF treatment.

Cardiac resynchronization therapy (CRT) decreases the morbidity and mortality in patients with end-stage heart failure. However, patient selection remains challenging, because a considerable 30% to 50% do not respond. Controversy exists on the cutoff values for the QRS duration and the optimal lead location. The present study relates these parameters on an individual basis to acute pump function improvement using invasively obtained pressure-volume loops. Fifty-seven patients with symptomatic end-stage heart failure were included in our temporary biventricular stimulation study and were grouped according to the QRS duration (QRS

BACKGROUND During the initial phase of an ischemic insult, left ventricular (LV) performance depends on the complex interaction between oxygen deprivation, vascular turgor, and accumulation of metabolites. In experimental preparations, low-flow ischemia decreases systolic shortening and increases diastolic LV distensibility, whereas pacing-induced ischemia or hypoxic perfusion produces smaller decreases in systolic shortening but decreases LV diastolic distensibility. The purpose of this study was to investigate the different effects of low-flow ischemia, pacing-induced ischemia, and hypoxemic perfusion on LV performance in humans. METHODS AND RESULTS In 20 patients with a significant stenosis in the left anterior descending coronary artery, micromanometer-tip LV pressure recordings (n = 20), LV angiography (n = 18), and coronary sinus blood sampling (n = 11) were obtained at rest and during the following conditions: pacing-induced ischemia (PI) (n = 11), low-flow ischemia of balloon coronary occlusion (CO) (n = 20), and hypoxemia induced by balloon coronary occlusion with hypoxemic perfusion distal to the occlusion (CO+P) (n = 11). LV stroke work index fell from 75 +/- 17 g.m at rest to 43 +/- 14 g.m at the end of CO (n = 18; P < .001). In addition, LV stroke work index was lower at the end of CO than during PI (50 +/- 11 vs 77 +/- 15 g.m; n = 11; P < .002) and was lower at the end of CO than at the end of CO+P (35 +/- 7 vs 46 +/- 9 g.m; n = 9; P < .02). LV end-diastolic pressure rose from 16 +/- 5 mm Hg at rest to 23 +/- 6 mm Hg at the end of CO (n = 20; P < .001). However, LV end-diastolic pressure was lower at the end of CO than during PI (20 +/- 5 vs 30 +/- 5 mm Hg; n = 11; P < .002) and was lower at the end of CO than at the end of CO+P (26 +/- 5 vs 34 +/- 7 mm Hg; n = 11; P < .01). LV end-diastolic volume index increased from 75 +/- 14 mL/m2 at rest to 79 +/- 15 mL/m2 at the end of CO (n = 18; P < .05). Left ventricular end-diastolic volume index increased to values similar to those for CO during PI (79 +/- 13 mL/m2; n = 11; P = NS) and at the end of CO+P (78 +/- 14 mL/m2; n = 9; P = NS). Higher values of LV end-diastolic pressure and unchanged values of LV end-diastolic volume index for PI and CO+P, compared with CO, suggested a lower end-diastolic LV distensibility during PI and during hypoxemia, as compared with low-flow ischemia. Upward shifts of individual diastolic LV pressure-volume curves during PI (9 of 11 patients) and at the end of CO+P (7 of 9 patients), compared with CO, were also consistent with lower LV diastolic distensibility during pacing-induced ischemia and during hypoxemia, compared with low-flow ischemia. Coronary sinus lactate, H+, and K+ levels increased after balloon deflation (CO and CO+P) and during pacing (PI). CONCLUSIONS Thus, during low-flow ischemia, LV systolic performance was lower and LV diastolic distensibility larger than during pacing-induced ischemia or hypoxemia. The variable response of the human myocardium to different types of ischemia was probably related to the degree of vascular turgor and accumulation of tissue metabolites.

Background: Stroke volume is probably the best hemodynamic parameter because it reflects therapeutic changes and contains prognostic information in pulmonary hypertension (PH). Stroke volume directly reflects right ventricular function in response to its load, without the correction of compensatory increased heart rate as is the case for cardiac output. For this reason, stroke volume, which can be measured noninvasively, is an important hemodynamic parameter to monitor during treatment. However, the extent of change in stroke volume that constitutes a clinically significant change is unknown. The aim of this study was to determine the minimal important difference (MID) in stroke volume in PH. Methods: One hundred eleven patients were evaluated at baseline and after 1 year of follow-up with a 6-min walk test (6MWT) and cardiac MRI. Using the anchor-based method with 6MWT as the anchor, and the distribution-based method, the MID of stroke volume change could be determined. Results: After 1 year of treatment, there was, on average, a significant increase in stroke volume and 6MWT. The change in stroke volume was related to the change in 6MWT. Using the anchor-based method, an MID of 10 mL in stroke volume was calculated. The distribution-based method resulted in an MID of 8 to 12 mL. Conclusions: Both methods showed that a 10-mL change in stroke volume during follow-up should be considered as clinically relevant. This value can be used to interpret changes in stroke volume during clinical follow-up in PH. © 2011 American College of Chest Physicians.

Objectives. The aim of this study was to analyse the rate of major adverse clinical events in patients with coronary artery disease and a fractional flow reserve (FFR) of ≥0.75 and deferred for coronary intervention in daily practice. Methods. From 1 January to 31 December 2006, FFR measurement was initiated in 122 patients (5%) out of 2444 patients referred for coronary angiography. In two patients FFR measurement failed and in one patient the FFR value could no longer be traced in the documents. Thus, 119 patients (84 men, 64 years, range 41-85) were included in the evaluation (145 lesions). Major adverse clinical events (death, myocardial infarction, percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG)) and the presence of angina were evaluated at follow-up. Furthermore a cost-effectiveness analysis was performed.Results. In 93 patients (76%) the FFR value was ≥0.75. Seventy of these 93 patients (76%) were treated with medication alone or underwent PCI for a different lesion (medical treatment group). Average duration of follow-up of all 119 patients was 22 months (range 4 days to 30 months). In the medical treatment group seven patients (10%) experienced a major adverse clinical event related to the FFR-evaluated lesion during follow-up. In this study population, the use of FFR measurement is cost-reducing provided that at least 65% of the patients in the medical treatment group has had a PCI with stent implantation when the use of FFR measurement is impossible. In this case, the decision to use PCI with stent implantation is purely based on the angiogram. Conclusions. In patients with a coronary stenosis based on visual assessment and an FFR of ≥0.75 deferral of PCI or CABG is safe in daily clinical practice and saves money. (Neth Heart J 2010;18:402-7.).

High diastolic stiffness of failing myocardium results from interstitial fibrosis and elevated resting tension ( F passive ) of cardiomyocytes. A shift in titin isoform expression from N2BA to N2B isoform, lower overall phosphorylation of titin, and a shift in titin phosphorylation from N2B to N2BA isoform can raise F passive of cardiomyocytes. In left ventricular biopsies of heart failure (HF) patients, aortic stenosis (AS) patients, and controls (CON), we therefore related F passive of isolated cardiomyocytes to expression of titin isoforms and to phosphorylation of titin and titin isoforms. Biopsies were procured by transvascular technique (44 HF, 3 CON), perioperatively (25 AS, 4 CON), or from explanted hearts (4 HF, 8 CON). None had coronary artery disease. Isolated, permeabilized cardiomyocytes were stretched to 2.2-μm sarcomere length to measure F passive . Expression and phosphorylation of titin isoforms were analyzed using gel electrophoresis with ProQ Diamond and SYPRO Ruby stains and reported as ratio of titin (N2BA/N2B) or of phosphorylated titin (P-N2BA/P-N2B) isoforms. F passive was higher in HF (6.1±0.4 kN/m 2 ) than in CON (2.3±0.3 kN/m 2 ; P 2 ; P P P F passive of human HF cardiomyocytes.

Left ventricular (LV) myocardial structure and function differ in heart failure (HF) with normal (N) and reduced (R) LV ejection fraction (EF). This difference could underlie an unequal outcome of trials with beta-blockers in heart failure with normal LVEF (HFNEF) and heart failure with reduced LVEF (HFREF) with mixed results observed in HFNEF and positive results in HFREF. To investigate whether beta-blockers have distinct myocardial effects in HFNEF and HFREF, myocardial structure, cardiomyocyte function, and myocardial protein composition were compared in HFNEF and HFREF patients without or with beta-blockers.Patients, free of coronary artery disease, were divided into beta-(HFNEF) (n = 16), beta+(HFNEF) (n = 16), beta-(HFREF) (n = 17), and beta+(HFREF) (n = 22) groups. Using LV endomyocardial biopsies, we assessed collagen volume fraction (CVF) and cardiomyocyte diameter (MyD) by histomorphometry, phosphorylation of myofilamentary proteins by ProQ-Diamond phosphostained 1D-gels, and expression of beta-adrenergic signalling and calcium handling proteins by western immunoblotting. Cardiomyocytes were also isolated from the biopsies to measure active force (F(active)), resting force (F(passive)), and calcium sensitivity (pCa(50)). Myocardial effects of beta-blocker therapy were either shared by HFNEF and HFREF, unique to HFNEF or unique to HFREF. Higher F(active), higher pCa(50), lower phosphorylation of troponin I and myosin-binding protein C, and lower beta(2) adrenergic receptor expression were shared. Higher F(passive), lower CVF, lower MyD, and lower expression of stimulatory G protein were unique to HFNEF and lower expression of inhibitory G protein was unique to HFREF.Myocardial effects unique to either HFNEF or HFREF could contribute to the dissimilar outcome of beta-blocker therapy in both HF phenotypes.

It remains uncertain if diastolic heart failure (DHF) is a distinct HF phenotype or a precursor stage of systolic HF (SHF). The unimodal distribution of left ventricular ejection fraction (LVEF) in HF, depressed LV long-axis shortening in DHF, and progression to eccentric LV remodeling in hypertension favor DHF and SHF as successive stages. These arguments are countered by the bimodal distribution of LVEF after correction for gender, by the preserved LV twist in DHF and by the low incidence of eccentric LV remodeling in hypertension. Clinical features, LV anatomy and histology, cardiomyocyte stiffness, myocardial effects of diabetes, and the response to HF therapy support DHF and SHF as distinct phenotypes. Comparison of the myocardial signal transduction cascades that drive LV remodeling in DHF and SHF may solve the controversy. This review analyzes arguments supporting DHF and SHF as successive stages or distinct phenotypes of the HF syndrome.

BACKGROUND Effects of pacing-induced and coronary occlusion myocardial ischemia on left ventricular (LV) function have been compared only in anesthetized dogs. Diastolic properties of the same LV anterior wall segment were therefore compared in 12 patients with single-vessel proximal left anterior descending coronary artery stenosis at rest, immediately after 7 +/- 1.2 minutes of pacing, and at the end of a 1-minute balloon occlusion of coronary angioplasty (CO). METHODS AND RESULTS Shifts of the diastolic LV pressure-length relation, derived from simultaneous tip-micromanometer LV pressure recordings and digital subtraction LV angiograms, were used as an index of regional diastolic LV distensibility of the anterior wall segment. Immediately after pacing, LV end-diastolic pressure rose from 13.5 +/- 3.5 to 23.8 +/- 7.0 mm Hg (p less than 0.01 versus at rest) without a significant change of the LV end-diastolic volume index (83.1 +/- 18.9 versus 88.4 +/- 16.5 ml/m2), percentage systolic shortening (%SS) of the ischemic segment fell from 40.1 +/- 10.6% to 25.2 +/- 8.6% (p less than 0.01), and the diastolic LV pressure-radial length (P-RL) plot of the ischemic segment was shifted upward by 7.1 +/- 5.0 mm Hg for portions of the plot that overlapped with the diastolic LV P-RL plot at rest. At the end of CO, LV end-diastolic pressure rose to 20.8 +/- 7.8 mm Hg (p less than 0.01 versus at rest) and the LV end-diastolic volume index rose to 95.6 +/- 16.3 ml/m2 (p less than 0.05 versus at rest, p less than 0.05 versus after pacing). Ejection fraction and %SS of the ischemic segment fell respectively from 76.6 +/- 6.8% to 46.6 +/- 11.4% (p less than 0.01 versus at rest, p less than 0.01 versus after pacing) and from 40.1 +/- 10.6% to 6.4 +/- 8.6% (p less than 0.01 versus at rest, p less than 0.01 versus after pacing). The diastolic LV P-RL plot of the ischemic segment was shifted upward by 3.1 +/- 2.3 mm Hg for portions of the plot that overlapped with the diastolic LV P-RL plot at rest. This upward shift at the end of CO was significantly smaller (p less than 0.05) than that immediately after pacing. At the end of CO, a correlation (p less than 0.03) was observed for the ischemic segment between %SS and upward shift of the diastolic LV P-RL plot. CONCLUSIONS The upward shift of the diastolic LV P-RL plot, which was used as an index of decreased regional diastolic LV distensibility, was larger immediately after pacing than at the end of CO. Persistent systolic shortening of ischemic myocardium seems to be a prerequisite for a decrease in diastolic distensibility of the ischemic segment because of the higher %SS of the ischemic segment immediately after pacing, and because of the correlation at the end of CO between the upward shift of the diastolic LV P-RL plot and %SS of the ischemic segment.

Coronary artery spasm has been known to induce ischaemia and ventricular arrhythmias. We present a case of recurrent ventricular fibrillation caused by spasm-associated transmural myocardial ischaemia. During an intra-coronary acetylcholine provocation test, severe coronary spasm could be induced. The patient was treated with a hybrid approach of medication and an implantable defibrillator.

The authors appreciated the thoughtful comment of Connelly et al on their study,1 which indeed did not imply that fibrosis was no determinant of diastolic left ventricular (LV) dysfunction in patients with heart failure and normal LV ejection fraction (HFNEF). A previous study from our group identified both collagen volume fraction (CVF) and cardiomyocyte resting tension to be …

Myocardial ischemia initially results in reversible regional disturbances of ventricular pump function, whereas most changes in regional function following myocardial infarction are irreversible. After acute reduction in coronary flow, both diastolic and systolic dysfunctions occur. If blood flow is not restored, myocardial necrosis results, and the wall motion abnormality becomes fixed.

Early detection of myocardial dysfunction in Fabry disease (FD) cardiomyopathy suggests the contribution of myofilament structural alterations. Six males with untreated FD cardiomyopathy submitted to cardiac studies, including tissue Doppler imaging and left ventricular endomyocardial biopsy. Active and resting tensions before and after treatment with protein kinase A (PKA) were determined in isolated Triton-permeabilized cardiomyocytes. Cardiomyocyte cross-sectional area, glycosphingolipid vacuole area, myofibrillolysis, and extent of fibrosis were also determined. Biopsies of mitral stenosis in patients with normal left ventricles served as controls. Active tension was four times lower in FD cardiomyocytes and correlated with extent of myofibriflolysis. Resting tension was six times higher in FD cardiomyocytes than in controls. PKA treatment decreased resting tension but did not affect active force. Protein analysis revealed troponin I and desmin degradation products. FD cardiomyocytes were significantly larger and filled with glycosphingolipids. Fibrosis was mildly increased compared with controls. Tissue Doppler imaging lengthening and shortening velocities were reduced in FD cardiomyocytes; compared with controls, correlating with resting and active tensions, respectively, but not with cardiomyocyte area, percentage of glycosphingolipids, or extent of fibrosis. in conclusion, myofilament degradation and dysfunction contribute to FD cardiomyopathy. Partial reversal of high resting tension after pharmacological PKA treatment of cardiomyocytes suggests potential benefits from enzyme replacement therapy and/or energy-releasing agents.

During the last decade, the effects of nitric oxide (NO) on contractile function of failing myocardium elicited a lot of interest and research activity. Because of initial reports of NO acutely reducing the extent and velocity of shortening of isolated cardiomyocytes, especially following β-adrenergic stimulation, and because of increased activity of inducible nitric oxide synthase (NOS2) in human cardiomyopathic myocardium, numerous reports and reviews have persistently and erroneously identified NO as deleterious for contractile function of failing myocardium.1 Shortly after these initial reports, a rosier picture of NO's functional myocardial effects emerged, highlighting NO's ability to improve left ventricular (LV) diastolic function. In the normal human heart, intracoronary administration of NO donors instantaneously hastens onset of LV relaxation and increases LV diastolic distensibility.2 These effects appear to be especially favourable in patients with dilated cardiomyopathy as they lower LV filling pressures and increase LV preload reserve. The mechanisms involved in these favourable lusitropic effects of NO differ between exogenous NO and NO produced by some of the nitric oxide synthases (NOSs) because of compartimentalization of the NOSs within the cardiomyocyte. Protein kinase G (PKG)-induced troponin I phosphorylation results in myofilamentary desensitization and thereby mediates lusitropic effects of exogenous NO and of NO produced by endothelial nitric oxide synthase (NOS3),2 whereas sarcoplasmic reticular (SR) phospholamban phosphorylation and an increase in calcium sequestration by the SR accounts for lusitropic effects of NO produced by neuronal nitric oxide synthase (NOS1).3 Tang and co-workers from the Cleveland Clinic reappraised the importance of myocardial NO bioavailability for LV diastolic function in patients with ischaemic and non-ischaemic dilated cardiomyopathy.4 In this study, low myocardial NO bioavailability, evident from high plasma levels of monomethylarginine (MMA), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) were strongly related to diastolic LV dysfunction or to N-terminal … *Corresponding author. Tel: +31 20 4448110, Fax: +31 20 4448255, Email: wj.paulus{at}vumc.nl

Objectives: This study was designed to investigate the influence of high dose intracoronary adenosine on persistent ST-segment elevation after primary percutaneous coronary intervention (PCI). Background: After successful PCI for acute myocardial infarction 40-50% of patients show persistent ST-segment elevation indicating suboptimal myocardial reperfusion. Adenosine has been studied to ameliorate reperfusion and is frequently used in a variety of doses, but there are no prospective studies to support its use for treatment of suboptimal reperfusion. Methods: We conducted a blinded, randomized, and placebo-controlled study with high dose intracoronary adenosine in 51 patients with 70%) STRes compared with placebo (33% versus 9%, P

AIMS: This study investigated whether right ventricular (RV) diastolic function is impaired in pulmonary hypertension (PH) patients, and whether it is related to RV mass and afterload. In addition, the effects of an acute reduction of RV afterload by the oral intake of sildenafil were studied. Finally, we assessed whether diastolic function is related to cardiac parameters of disease severity.METHODS AND RESULTS: Twenty-five PH patients and 11 control subjects were studied. Right-heart catheterization and N-terminal pro-brain natriuretic peptide (NT-proBNP) sampling were performed in patients. MRI measured RV ejection fraction, mass, and diastolic function. Isovolumic relaxation time (IVRT), normalized early peak filling rate (E), atrium-induced peak filling rate (A), and E/A ratio described diastolic function. Compared to control subjects, patients had prolonged mean (+/- SD) IVRT (133.5 +/- 53.2 vs 29.3 +/- 20.8 ms, respectively; p < 0.001), decreased E (3.0 +/- 1.6 vs 6.4 +/- 2.5 s(-1), respectively; p < 0.001) and E/A ratio (1.1 +/- 0.7 vs 5.3 +/- 4.9, respectively; p < 0.001), and increased A (3.0 +/- 1.4 vs 1.5 +/- 0.9 s(-1), respectively; p = 0.001). IVRT was related to RV mass (r(25) = 0.56; p = 0.005) and pulmonary vascular resistance (r(25) = 0.74; p < 0.0001). Sildenafil therapy reduced RV afterload and improved RV diastolic and systolic function. IVRT was correlated with NT-proBNP level (r = 0.70; p < 0.001), and was inversely related to cardiac index (r = -0.70; p < 0.001) and RV ejection fraction (r = -0.69; p < 0.001).CONCLUSION: In PH patients, RV diastolic dysfunction is related to RV mass and afterload. RV diastolic function improves by reducing afterload. The correlations between diastolic function and prognostic parameters showed that diastolic function is most impaired in patients with severe disease.

In pulmonary arterial hypertension (PAH) an increased pulmonary vascular resistance results in chronic pressure overload on the right ventricle and induces pathological right ventricular (RV) remodelling and RV failure. This causes limited exercise capacity, fatigue and increased mortality. Several treatment options have become available for PAH, and in patients given monotherapy, a second drug of a different class is given to improve symptoms and exercise capacity. Whether the addition of a second treatment reverses RV remodelling has not been described. In this study, the phosphodiesterase 5 inhibitor sildenafil was added to treatment with bosentan, an endothelin receptor antagonist. The objective of this study was to investigate whether the addition of sildenafil reverses RV remodelling and further improves RV function in patients with PAH treated with bosentan. In 15 patients with PAH receiving bosentan for one year, sildenafil was added for three months. Sildenafil was started at 50 mg twice daily and increased to 50 mg thrice daily after four weeks. At the start of the study and again after one year of bosentan, right-heart catheterisation with vasoreactivity testing, cardiac magnetic resonance (CMR) and 6 min walk test (6MWT) were performed. N-terminal pro-brain natriuretic peptide (NT-proBNP) was determined after one year of bosentan and after three months of combination therapy. After three months of combination therapy, the effects of the addition of sildenafil were evaluated with …

Left ventricular (LV) filling results from diastolic suction of the left ventricle and passive left atrial (LA) emptying at early diastole and LA contraction at end-diastole. Effects of aging on LA and LV geometric characteristics and function and its consequences for LV filling are incompletely understood. Insight into these effects may increase the understanding of diastolic function. Cardiac magnetic resonance imaging was used to study effects of aging on left atrioventricular coupling and LV filling. Forty healthy volunteers underwent cardiac magnetic resonance imaging and were subdivided into 2 age groups of 20 to 40 (younger group) and 40 to 65 years (older group). For the older group, LA volumes were larger (p

To the Editor: With great interest we read the recent work by Steendijk et al1 that investigated the effects of long-term cardiac resynchronization therapy (CRT) on hemodynamics as evaluated by pressure-volume loops. That study elegantly demonstrates that the previously observed favorable short-term hemodynamic effects of CRT are maintained over time. Among other findings, the authors report a significant increase in end-systolic elastance (Ees …

The aim of this study was to investigate the contribution of direct right-to-left ventricular interaction to left ventricular filling and stroke volume in 46 patients with pulmonary arterial hypertension (PAH) and 18 control subjects. Stroke volume, right and left ventricular volumes, left ventricular filling rate, and interventricular septum curvature were measured by magnetic resonance imaging and left atrial filling by transesophageal echocardiography. Stroke volume, left ventricular end-diastolic volume, and left ventricular peak filling rate were decreased in PAH patients compared with control subjects: 28 ± 13 vs. 41 ± 10 ml/m2( P < 0.001), 46 ± 14 vs. 61 ± 14 ml/m2( P < 0.001), and 216 ± 90 vs. 541 ± 248 ml/s ( P < 0.001), respectively. Among PAH patients, stroke volume did not correlate to right ventricular end-diastolic volume or mean pulmonary arterial pressure but did correlate to left ventricular end-diastolic volume ( r = 0.62, P < 0.001). Leftward interventricular septum curvature was correlated to left ventricular filling rate ( r = 0.64, P < 0.001) and left ventricular end-diastolic volume ( r = 0.65, P < 0.001). In contrast, left atrial filling was normal and not correlated to left ventricular end-diastolic volume. In PAH patients, ventricular interaction mediated by the interventricular septum impairs left ventricular filling, contributing to decreased stroke volume.

Recent experimental and clinical research solved some of the controversies surrounding the myocardial contractile effects of NO. These controversies were: (1) does NO exert a contractile effect at baseline? (2) is NO a positive or a negative inotrope? (3) Are the contractile effects of NO similar when NO is derived from NO-donors or from the different isoforms of NO synthases (NOS)? (4) Does NO exert the same effects in hypertrophied, failing or ischemic myocardium? Transgenic mice with cardioselective overexpression of NOS revealed NO to produce a small reduction in basal developed LV pressure and a LV relaxation-hastening effect mainly through myofilamentary desensitization. Similar findings had previously been reported during intracoronary infusions of NO-donors in isolated rodent hearts and in humans. The LV relaxation hastening effect was accompanied by increased diastolic LV distensibility, which augmented LV preload reserve especially in heart failure patients. This beneficial effect on diastolic LV function always overrode the small NO-induced attenuation in LV developed pressure in terms of overall LV performance. In most experimental and clinical conditions, contractile effects of NO were similar when NO was derived from NO-donors or produced by the different isoforms of NOS. Because expression of inducible NOS (NOS2) is frequently accompanied by elevated oxidative stress, NO produced by NOS2 can lead to peroxynitrite-induced contractile impairment as observed in ischemic or septic myocardium. Finally, shifts in isoforms or in concentrations of myofilaments can affect NO-mediated myofilamentary desensitization and alter the myocardial contractile effects of NO in hypertrophied or failing myocardium.

Coronary perforation caused by percutaneous transluminal coronary angioplasty (PTCA) occurs rarely and most often leads to communication to the pericardial space. We report a case where PTCA caused a coronary artery rupture and fistulization to the right ventricular outflow tract.

Background Although percutaneous coronary intervention (PCI) is becoming the standard therapy in ST-segment elevation myocardial infarction (STEMI), to date most patients, even in developed countries, are reperfused with intravenous thrombolysis or do not receive a reperfusion therapy at all. In the post-lysis period these patients are at high risk for recurrent ischemic events. Early identification of these patients is mandatory as this subgroup could possibly benefit from an angioplasty of the infarct-related artery. Since viability seems to be related to ischemic adverse events, we initiated a clinical trial to investigate the benefits of PCI with stenting of the infarct-related artery in patients with viability detected early after acute myocardial infarction. Methods The VIAMI-study is designed as a prospective, multicenter, randomized, controlled clinical trial. Patients who are hospitalized with an acute myocardial infarction and who did not have primary or rescue PCI, undergo viability testing by low-dose dobutamine echocardiography (LDDE) within 3 days of admission. Consequently, patients with demonstrated viability are randomized to an invasive or conservative strategy. In the invasive strategy patients undergo coronary angiography with the intention to perform PCI with stenting of the infarct-related coronary artery and concomitant use of abciximab. In the conservative group an ischemia-guided approach is adopted (standard optimal care). The primary end point is the composite of death from any cause, reinfarction and unstable angina during a follow-up period of three years. Conclusion The primary objective of the VIAMI-trial is to demonstrate that angioplasty of the infarct-related coronary artery with stenting and concomitant use of abciximab results in a clinically important risk reduction of future cardiac events in patients with viability in the infarct-area, detected early after myocardial infarction.

BACKGROUND: Although balloon angioplasty has assumed an important role in the management of refractory unstable angina (UA), that is, UA that does not respond to conventional therapy, it is limited by complications related to thrombosis and acute coronary occlusion. The complication rate is higher in patients with UA than in those whose condition is stable. Preprocedural use of abciximab, a monoclonal platelet glycoprotein IIb/IIIa receptor blocker, has been used effectively in patients with UA, but its acceptance may be limited by safety concerns and economic constraints. The current trial investigated a protocol for abciximab pretreatment in patients with UA awaiting transfer from referring hospitals to a site of intervention (the 'drip and ship' protocol). AIMS: This observational study was conducted to evaluate whether a prophylactic, preprocedural regimen of abciximab can be safely and effectively administered to UA patients in referring hospitals while awaiting coronary angioplasty at the interventional clinic. METHODS: From April 1996 to December 1998, 168 consecutive patients with refractory UA (Braunwald class II or III) received abciximab prospectively at the referring clinic before undergoing PTCA or stent implantation at the interventional clinic. The following cost-conscious protocol was used: a 0.25 mg/kg bolus of abciximab followed by 10 micro g/min intravenously for 16 hours, in addition to intravenous nitrates, heparin and aspirin therapy. Patients were then transferred to a facility with PTCA capability via high-speed ambulance transport. No specific alterations of routine-transfer protocol were needed. Platelet aggregation studies were conducted during abciximab infusion. All interventions were performed while abciximab was given. Procedural and clinical success and long-term outcomes also were assessed. RESULTS: The primary angiographic success rate (patients with post-PTCA diameter stenosis50%) was 98%, and the in-hospital clinical success rate (angiographic success without major complications) was 98%. No major bleeding complications occurred during the abciximab pretreatment period. Platelet aggregation findings in the study patients showed a stable inhibition of80% at the time of angioplasty. At 30-day follow-up, all patients were alive and 91% were free of major adverse events. Outcomes of balloon angioplasty and stenting were equally favorable, indicating no device-specific effect. Event-free survival at six months was 89% with a target vessel revascularization rate of 10%. CONCLUSION: Abciximab was administered safely and effectively to angioplasty patients with refractory UA awaiting transfer from a noninterventional setting to the site of angioplasty. These results extend the current knowledge base that has been established in randomized trials performed in interventional centers. The study protocol potentially could make abciximab therapy more feasible economically, and therefore more widely available to patients who are most likely to benefit from prophylactic administration.

The purpose of the study was to investigate interactions between myocardial nitric oxide synthase (NOS) and myocardial fibrosis, both of which determine left ventricular (LV) preload reserve in patients with nonischemic dilated cardiomyopathy (DCM). In previous animal experiments, chronic inhibition of NOS induced myocardial fibrosis and limited LV preload reserve. Twenty-eight DCM patients underwent LV catheterization, balloon caval occlusions (BCO; n = 8), intracoronary substance P infusion ( n = 8), and procurement of LV endomyocardial biopsies for determinations of collagen volume fraction (CVF), of gene expression of NOS2, NOS3, heme oxygenase (HO)-1, and TNF-α, and of NOS2 protein. CVF was unrelated to the intensity of NOS2, NOS3, HO-1, or TNF-α gene expression or of NOS2 protein expression. Preload recruitable LV stroke work (PR-LVSW) correlated directly with NOS2 gene expression ( P = 0.001) and inversely with CVF ( P = 0.04). High CVF (>10%) reduced baseline LVSW and PR-LVSW at each level of NOS2 gene expression. In DCM, myocardial fibrosis is unrelated to the intensity of myocardial gene expression of NOS, antioxidative enzymes (HO-1), or cytokines (TNF-α) and blunts NOS2-related recruitment of LV preload reserve.

OBJECTIVES: The purpose of this study was to assess the value of cardiovascular magnetic resonance (CMR)-determined graft flow and flow reserve in differentiating significant from non-significant vein graft disease. BACKGROUND: In patients after coronary artery bypass grafting (CABG), non-invasive testing may be helpful in the detection of recurrent graft disease. METHODS: Randomly selected patients (n = 21) scheduled for X-ray angiography because of recurrent chest complaints after CABG were included for evaluation of vein grafts (n = 40) by CMR. Three-dimensional contrast-enhanced CMR angiography was performed and followed by flow measurements at rest and during hyperemia in patent grafts only. Flow reserve was calculated when resting flow exceeded 20 ml/min. Analysis was based on four categories defined by X-ray angiography: occluded grafts (n = 3), grafts with stenosis >50% (n = 19), grafts with stenosis 50% and normal run-off (n = 10). RESULTS: The CMR angiography demonstrated occlusion of three grafts. In nine of the 37 patent grafts, basal blood flow was 20 ml/min (n = 28), flow reserve significantly differed between grafts without stenosis and grafts with significant stenosis or with diseased run-off (2.5 ± 0.7 vs. 1.8 ± 0.9, p = 0.04). An algorithm combining basal volume flow

The combination of quantitative coronary analysis and flow reserve measurements enables the clinician to determine whether a coronary artery stenosis is significant and therefore has to be treated. 2-D SPECT polar diagrams are made to get information on cardiac perfusion. However, no real 3-D comparison between the anatomical coronary angiography data and the perfusion information can be made. In this feasibility study a first approach is made to create fusion images in 3-D of angiograms and SPECT data. From biplane coronary arteriograms (CAGs), both left and right coronary arteries of five patients have been reconstructed as 3-D models. The reconstruction output was automatically converted into Virtual Reality Markup Language (VRML) scenes. The 2-D polar SPECT data were mapped onto a half-ellipsoid and added to the VRML scene. Registration of the three models was performed interactively using VRML and common Internet browsers.

Electrical impedance tomography (EIT) has been proposed as a method to monitor dynamic changes in the pulmonary vascular bed. In this study we examined the validity of EIT in the measurement of pulmonary vasodilatation in eight patients with primary and secondary pulmonary hypertension when given the vasodilating agent epoprostenol (Flolan®). Therefore, catheterization of the pulmonary artery was performed in the ICU and the cardiac output was measured by means of the Fick method. The pulmonary vascular resistance (PVR) and mean pulmonary arterial pressure (mPAP) were determined. Epoprostenol was given in increasing doses to test reversibility of pulmonary hypertension. The maximum test dose was 12 ng kg-1 min-1. During each step simultaneous EIT (DAS-01 P Portable Data Acquisition System, Sheffield, England) measurements were performed with the 16 electrodes equidistantly positioned in the third intercostal space. The maximal systolic impedance change, relative to end-diastole, ΔZperf, was chosen as a measure of pulmonary perfusion. The impedance change between baseline and highest tolerable epoprostenol concentration was compared with the change in PVR. The mean PVR (dyn s/cm5) decreased from 636 (±399) to 366 (±242); p < 0.01. ΔZperf (in arbitrary units) for the whole patient group increased from 901 (±295) x 10-3 to 1082 (±472) x 10-3 (p < 0.05). Only one patient showed a reduction in pulmonary artery pressure >20%, which is defined as significant vasodilatation. A strong relationship was found between the impedance changes and the change in PVR and mPAP in the patient with a significant vasodilatation on epoprostenol. From these results we conclude that EIT is a reliable method to measure blood volume changes due to pharmacologically induced vasodilatation in the pulmonary bed.

The purpose of the study was to investigate the potential of magnetic resonance imaging (MRI) to assess transmural differences in myocardial perfusion. Contrast-enhanced MRI was performed at rest and during hyperemia in a dog model and in 22 patients with single-vessel coronary artery disease. From MR signal intensity-versus-time curves, three perfusion parameters were derived: maximum myocardial contrast enhancement (MCE), slope, and inverse mean transit time (I/MlT)). In dogs, MCE correlated well (r = 0.87, p < 0.00001) with microsphere-assessed myocardial bloodjow. In the patients, the subendocardial MCE decreased during hyperemia (0.89 2 0.18 vs. 0.74 +- 0.15, p < 0.003) and was lower in subendocardium than in subepicardium (0.74 +: 0.15 vs. 0.84 2 0.21, p < 0.02). Parameters slope and I/MlT paralleled MCE. Contrast-enhanced MRI reflects the transmural redistribution of myocardial perjhsion during hyperemia. Perfusion abnormalities can be identiJ5ed most distinctly in subendocardial myocardium.

Background —Patients with heart failure have modified myocardial expression of nitric oxide synthase (NOS), as is evident from induction of calcium-insensitive NOS isoforms. The functional significance of this modified NOS gene expression for left ventricular (LV) contractile performance was investigated in patients with dilated nonischemic cardiomyopathy. Methods and Results —In patients with dilated, nonischemic cardiomyopathy, invasive measures of LV contractile performance were derived from LV microtip pressure recordings and angiograms and correlated with intensity of gene expression of inducible (NOS2) and constitutive (NOS3) NOS isoforms in simultaneously procured LV endomyocardial biopsies (n=20). LV endomyocardial expression of NOS2 was linearly correlated with LV stroke volume ( P =0.001; r =0.66), LV ejection fraction ( P =0.007; r =0.58), and LV stroke work ( P =0.003; r =0.62). In patients with elevated LV end-diastolic pressure (>16 mm Hg), a closer correlation was observed between endomyocardial expression of NOS2 and LV stroke volume ( P =0.001; r =0.74), LV ejection fraction ( P =0.0007; r =0.77), and LV stroke work ( r =0.82; P =0.0002). LV endomyocardial expression of NOS3 was linearly correlated with LV stroke volume ( P =0.01; r =0.53) and LV stroke work ( P =0.01; r =0.52). To establish the role of nitric oxide (NO) as a mediator of the observed correlations, substance P (which causes endothelial release of NO) was infused intracoronarily (n=12). In patients with elevated LV end-diastolic pressure, an intracoronary infusion of substance P increased LV stroke volume from 72±13 to 91±16 mL ( P =0.06) and LV stroke work from 67±11 to 90±15 g · m ( P =0.03) and shifted the LV end-diastolic pressure–volume relation to the right. Conclusions —In patients with dilated cardiomyopathy, an increase in endomyocardial NOS2 or NOS3 gene expression augments LV stroke volume and LV stroke work because of a NO-mediated rightward shift of the diastolic LV pressure-volume relation and a concomitant increase in LV preload reserve.

Early recognition of heart failure is important because early treatment reduces mortality and hospitalization rates. In screening for this disease, there is a need for a simple, safe, and cost-effective method to obtain cardiovascular variables. Therefore we developed a noninvasive impedance cardiographic method to predict the pulmonary capillary wedge pressure (PCWP) from the impedance cardiogram. The impedance cardiographic technique, though, was originally designed for stroke volume (SV) determination. The objectives of this study were to validate both variables by comparison with the paired, invasively obtained equivalents. PCWP, measured with a pulmonary artery catheter, was related to the O/C ratio from the impedance cardiogram. The O/C ratio was calculated as the amplitude of the impedance cardiogram during diastole (O) divided by the maximum height during systole (C). Stroke volume was also calculated from the impedance cardiogram according to the equation of Kubicek (SVIC) and compared with thermodilution (SVTD). Data analysis was performed in 24 stable patients who underwent diagnostic heart catheterization. Linear regression analysis showed that the O/C ratio was strongly related to the invasively measured PCWP over a range of 3 to 30 mm Hg (r = 0.92, standard error of the estimate, 3.2 mm Hg). Between SVIC and SVTD a moderate correlation was established (r = 0.69), but after exclusion of the data from patients with an aortic valve disorder (n = 5), the correlation increased considerably (r = 0.87). No significant differences between SVIC and SVTD were found (mean difference +/- 2 SD = 1.8 +/- 28.8 ml). These preliminary observations suggest that impedance cardiography can predict PCWP and measure SV over a wide range of clinically relevant values. The combined measurement of SV and PCWP by impedance cardiography might be a clinical useful tool in screening for heart failure.

Background Intracoronary ultrasound (ICUS) imaging is potentially suitable to identify lesions at high risk of restenosis after percutaneous transluminal coronary angioplasty (PTCA), but it has not been studied systematically. Methods and Results We recruited 200 patients in whom ICUS studies were performed after successful PTCA and related their ICUS parameters to 6-month follow-up quantitative coronary angiography. This was performed in 164 patients (82%), yielding 170 lesions for analysis. The overall incidence of a ≥50% diameter stenosis at follow-up (categorical restenosis) was 29.4%. Quantitative ICUS parameters were weakly but significantly related to follow-up minimal luminal diameter on quantitative coronary angiography (lumen area: R 2 =.36, P =.0001; vessel area: R 2 =.29, P =.0002; plaque area: R 2 =−.18, P =.021; percent obstruction: R 2 =−.15, P =.05), but categorical restenosis was not significantly related to these parameters ( P =.63, .77, .38, and .08, respectively). There were no significant predictors of restenosis in ICUS parameters of plaque morphology: eccentric versus concentric ( P =1.0), plaque type (hard, soft, or calcific, P =.98), or the number of calcified quadrants ( P =.41). There were no significant predictors of restenosis in two predefined types of vessel-wall disruptions: (1) rupture: presence ( P =.79), depth (partial versus complete, P =.85), or extent in quadrants ( P =.6), and (2) dissection: presence ( P =.31), depth ( P =.82), or extent ( P =.38). Conclusions Qualitative ICUS parameters after PTCA did not predict restenosis. A larger lumen and vessel area and a smaller plaque area by ICUS were associated with a larger angiographic minimal lumen diameter at follow-up, but these parameters were not significantly related to categorical restenosis.