Low myocardial protein kinase G activity in heart failure with preserved ejection fraction.

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<0.05) or had diabetes mellitus (P<0.05). Left ventricular myocardial biopsies were procured transvascularly in HFPEF and HFREF and perioperatively in aortic stenosis. F(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<0.01) or HFREF (P<0.001) was associated with higher cardiomyocyte F(passive) (P<0.001) and related to lower cGMP concentration (P<0.001) and higher nitrosative/oxidative stress (P<0.05). Higher F(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.

Hypophosphorylation of the Stiff N2B titin isoform raises cardiomyocyte resting tension in failing human myocardium.

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-microm 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<0.01) or in AS (2.2+/-0.2 kN/m(2); P<0.001). Titin isoform expression differed between HF (N2BA/N2B=0.73+/-0.06) and CON (N2BA/N2B=0.39+/-0.05; P<0.001) and was comparable in HF and AS (N2BA/N2B=0.59+/-0.06). Overall titin phosphorylation was also comparable in HF and AS, but relative phosphorylation of the stiff N2B titin isoform was significantly lower in HF (P-N2BA/P-N2B=0.77+/-0.05) than in AS (P-N2BA/P-N2B=0.54+/-0.05; P<0.01). Relative hypophosphorylation of the stiff N2B titin isoform is a novel mechanism responsible for raised F(passive) of human HF cardiomyocytes.

Distinct myocardial effects of beta-blocker therapy in heart failure with normal and reduced left ventricular ejection fraction.

AIMS: 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. METHODS AND RESULTS: 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. CONCLUSION: Myocardial effects unique to either HFNEF or HFREF could contribute to the dissimilar outcome of beta-blocker therapy in both HF phenotypes.

Diastolic stiffness of the failing diabetic heart: importance of fibrosis, advanced glycation end products, and myocyte resting tension.

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<0.001) and increased cardiomyocyte resting tension only in patients with normal LVEF (from 5.1+/-0.7 to 8.5+/-0.9 kN/m2, P=0.006). Diabetes increased myocardial AGE deposition in patients with reduced LVEF (from 8.8+/-2.5 to 24.1+/-3.8 score/mm2; P=0.005) and less so in patients with normal LVEF (from 8.2+/-2.5 to 15.7+/-2.7 score/mm2, 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.

Myofilament degradation and dysfunction of human cardiomyocytes in Fabry disease.

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 myofibrillolysis. 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.

Diastolic and systolic heart failure: different stages or distinct phenotypes of the heart failure syndrome?

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.

High dose adenosine for suboptimal myocardial reperfusion after primary PCI: A randomized placebo-controlled pilot study.

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% ST-segment resolution (STRes) after successful primary PCI. All patients were treated with stents and abciximab. RESULTS: Immediately after adenosine, significantly more patients showed optimal (>70%) STRes compared with placebo (33% versus 9%, P < 0.05). Mean STRes was higher after adenosine (35.4% versus 23.0%, P < 0.05). In addition, TIMI frame count was significant lower (15.7 versus 30.2, P < 0.005), Myocardial Blush Grade was higher (2.7 versus 2.0, P < 0.05) and resistance index was lower in the adenosine group (0.70 versus 1.31 mm Hg per ml/min, P < 0.005). CONCLUSIONS: Intracoronary adenosine accelerates recovery of microvascular perfusion in case of persistent ST segment elevation after primary PCI.

Recurrent ventricular fibrillation caused by coronary artery spasm leading to implantable cardioverter defibrillator implantation.

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.

Myocardial structure and function differ in systolic and diastolic heart 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 microm to measure passive force (Fpassive), 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 microm, P<0.001), but collagen volume fraction was equally elevated. Myofibrillar density was lower in SHF (36+/-2% versus 46+/-2%, P<0.001). Cardiomyocytes of DHF patients had higher Fpassive (7.1+/-0.6 versus 5.3+/-0.3 kN/m2; P<0.01), but their total force was comparable. After administration of protein kinase A to the cardiomyocytes, the drop in Fpassive was larger (P<0.01) in DHF than in SHF. 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.

Effects of aging on left atrioventricular coupling and left ventricular filling assessed using cardiac magnetic resonance imaging in healthy subjects.

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 <0.05) and LV volumes, including stroke volumes, were smaller (p <0.05), whereas ejection fraction remained constant. LA/LV volume ratios were larger (0.27 +/- 0.06 vs 0.19 +/- 0.03; p <0.001) and correlated with LV mass-volume ratio (r = 0.42, p <0.01). The older group also had lower LA passive emptying (15 +/- 3.0 vs 19 +/- 4.8 ml/m(2); p <0.05) and higher LA active emptying volumes (13 +/- 3.1 vs 11 +/- 3.9 ml/m(2); p <0.05). For both groups, conduit volume contributed most to LV filling, but was lower in the older group (21 +/- 5.1 vs 27 +/- 9.0 ml; p <0.05). In conclusion, changes in LA volume and function were age dependent and related to changes in LV mass-volume ratio. Conduit volume contributed most to LV filling and decreased with age, suggesting it to be an indicator of diastolic function.

Right ventricular diastolic dysfunction and the acute effects of sildenafil in pulmonary hypertension patients.

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.

Functional effects of protein kinase C-mediated myofilament phosphorylation in human myocardium.

OBJECTIVE: In human heart failure beta-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 Ca(2+) sensitivity (pCa(50)). Incubation with the catalytic domain of PKC slightly decreased maximal force under basal conditions, but not following PKA and phosphatase pretreatments. PKC reduced Ca(2+) sensitivity to a larger extent in failing (DeltapCa(50)=0.19+/-0.03) than in non-failing (DeltapCa(50)=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 Ca(2+) sensitivity may serve to improve diastolic function in failing human myocardium in which PKA-mediated TnI phosphorylation is decreased.

Cardiomyocyte stiffness in diastolic heart failure.

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<0.05) than did controls (n=8, 3.8+/-2.0%), and no conspicuous changes in sarcomeric protein composition were detected. Cardiomyocytes, mechanically isolated and treated with Triton X-100 to remove all membranes, were stretched to a sarcomere length of 2.2 microm and activated with solutions containing varying [Ca2+]. Compared with cardiomyocytes of controls, cardiomyocytes of DHF patients developed a similar total isometric force at maximal [Ca2+], but their resting tension (F(passive)) in the absence of Ca2+ was almost twice as high (6.6+/-3.0 versus 3.5+/-1.7 kN/m2, P<0.001). 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.

What mechanisms underlie diastolic dysfunction in heart failure?

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.

Assessment of coronary artery bypass graft disease using cardiovascular magnetic resonance determination of flow 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% with diseased graft run-off (n = 8), and 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, all demonstrating significant stenosis at X-ray angiography. In grafts with resting flow >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 <20 ml/min and graft flow reserve <2 had a sensitivity and specificity of 78% and 80% respectively for detecting grafts with significant stenosis or diseased run-off. CONCLUSIONS: This feasibility study showed that quantification of flow and flow reserve by CMR may serve as a non-invasive adjunct to differentiate between vein grafts without stenosis and grafts with significant stenosis or diseased run-off.

Endomyocardial nitric oxide synthase and the hemodynamic phenotypes of human dilated cardiomyopathy and of athlete's heart.

OBJECTIVE: In dilated cardiomyopathy and in athlete's heart, progressive LV dilatation is accompanied by rightward displacement of the diastolic LV pressure-volume relation. In dilated cardiomyopathy, an increase in diastolic LV stiffness can limit this rightward displacement thereby decreasing LV systolic performance. Because nitric oxide (NO) reduces diastolic LV stiffness, the present study relates diastolic LV stiffness and LV systolic performance to intensity of endomyocardial NO synthase (NOS) gene expression in dilated cardiomyopathy and in athlete's heart. METHODS: Microtip LV pressures, conductance-catheter or angiographic LV volumes, echocardiographic LV wall thicknesses and snap-frozen LV endomyocardial biopsies were obtained in 33 patients with dilated cardiomyopathy and in three professional cyclists referred for sustained ventricular tachycardia. Intensity of LV endomyocardial inducible NOS (NOS2) and constitutive NOS (NOS3) gene expression was determined using quantitative reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Dilated cardiomyopathy patients with higher diastolic LV stiffness-modulus and lower LV stroke work had lower NOS2 and NOS3 gene expression at any given level of LV end-diastolic wall stress. The intensity of NOS2 and NOS3 gene expression observed in athlete's heart was similar to dilated cardiomyopathy with low LV diastolic stiffness-modulus and preserved LV stroke work. CONCLUSIONS: High LV endomyocardial NOS gene expression is observed in athlete's heart and in dilated cardiomyopathy with low diastolic LV stiffness and preserved LV stroke work. Favourable effects on the hemodynamic phenotype of high LV endomyocardial NOS gene expression could result from a NO-mediated decrease in diastolic LV stiffness and a concomitant rise in LV preload reserve.

Doppler-derived intracoronary physiology indices predict the occurrence of microvascular injury and microvascular perfusion deficits after angiographically successful primary percutaneous coronary intervention.

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 H2 (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 H2 (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 <2.0, 3.18±1.42 mm Hg/cm per second versus myocardial perfusion reserve ≥2.0, 2.24±1.19 mm Hg/cm per second; 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.

Effects of epoprostenol on right ventricular hypertrophy and dilatation in pulmonary hypertension.

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.