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The therapeutic strategy for percutaneous coronary intervention (PCI) of a tapered lesion is still being developed. Herein, we describe a 67-year-old man with stable angina who underwent elective PCI of a tapered lesion. The coronary angiogram showed diffuse, severe stenosis in the tapered left anterior descending artery. A third-generation sirolimus-eluting stent (2.5 × 24-mm Ultimaster, Terumo, Tokyo, Japan) was deployed, and the distal side was selected as the reference. Postdilatation with a balloon diameter 2.0 mm larger than the stent was needed because of the tapered lesion. We performed postdilatation from the distal side to the proximal side of the stent with a noncompliant balloon (4.5 × 8-mm Powered Lacrosse2, Goodman, Aichi, Japan). The final angiogram showed that the total stent length was 6 mm longer than the original length. Therefore, physicians should be aware of longitudinal stent elongation of a tapered lesion during PCI to ensure appropriate treatment.

Background— Matrix metalloproteinases (MMPs) are activated in dilated failing hearts, and angiotensin-converting enzyme (ACE) inhibition prevents left ventricular (LV) dilatation. However, it remains unclear whether activation of MMPs precedes or is secondary to LV remodeling, and an effect of ACE inhibition on MMPs is unknown. Methods and Results— Dahl salt-sensitive rats fed a high-salt diet from 8 weeks served as the hypertensive heart failure (HF) model. LV echo, histological study, measurement of mRNA levels, and gelatin zymography were performed before (at 23 weeks) and after (at 26 weeks) the development of LV dilatation and pulmonary edema. The same procedures were conducted in the HF model rats treated with a subdepressor dose of ACE inhibitor (enalapril 5 mg · kg −1 · d −1 ) from 9 weeks. Rats fed on normal chow served as age-matched controls. In the untreated HF model rats, gene expression of MMP-2 and MMP-9 and tissue gelatinase activity were elevated at 23 weeks without LV dilatation. LV dilatation, LV systolic dysfunction, and pulmonary edema occurred at 26 weeks, with further enhancement of the expression and activity of MMPs. ACE inhibition prevented such geometrical and functional deterioration. The gene expression and activity of MMPs were suppressed by ACE inhibition at 23 weeks without a decrease in blood pressure, and the suppressive effects continued at 26 weeks. Conclusions— MMPs are likely to trigger and promote LV remodeling, and ACE inhibition directly exerts inhibitory effect on MMPs, leading to the prevention of LV remodeling and dysfunction.

Background. Chest pain, ST segment elevation and slow flow are recognized as the complications of percutaneous transluminal coronary rotational atherectomy (PTCRA). But the relation between these complications and microvascular dysfunction remains unknown. We assessed the impact of PTCRA on coronary microvascular function with myocardial contrast echocardiography (MCE).Methods. Consecutive 36 patients with stable effort angina underwent PTCRA using the continuous infusion of verapamil into the target vessel. MCE was performed with the intracoronary injection of sonicated microbubbles before, during or shortly after, and after PTCRA procedure. We measured baseline-subtracted peak intensity (256 gray scales) in the risk zone and in the normal zone, and calculated the ratio of the former to the latter (PI ratio). We divided the patients into two groups based on the presence or absence of ST elevation during PTCRA, group-A (n=20) = present and group-B (n=16) = absent.Results. Before PTCRA, there was no difference in PI ratio between two groups (A vs. B; 0.85±0.32 vs. 0.77±0.23). During or shortly after PTCRA, PI ratio in group-A was significantly lower than that in group-B (0.29±0.26 vs. 0.90±0.19, p

Left ventricular (LV) systolic function is better characterized by midwall mechanics in patients with LV hypertrophy than by endocardial LV function, and the midwall mechanics is an independent predictor of prognosis. However, a complex calculation is currently required to assess it, and it is not routinely assessable in clinical practice. Tissue Doppler imaging enables tracking of a point within the LV wall though a cardiac cycle; we tested our hypothesis that the tissue Doppler tracking technique provides an instantaneous and reliable evaluation of midwall mechanics.LV M-mode echocardiogram was recorded in 18 subjects with conventional echocardiography and with tissue Doppler imaging. The midwall shortening was calculated from the data obtained with conventional echocardiography for the comparison with that measured with the tissue Doppler tracking technique. The tissue Doppler-determined midwall shortening correlated well with conventionally calculated value (r=.84, P.0001), and their difference was small irrespective of absolute value of the midwall shortening.The midwall mechanics can be instantaneously and accurately evaluated with the tissue Doppler tracking technique.

Objective: Congestive heart failure with left ventricular (LV) diastolic dysfunction and preserved systolic function, i.e. diastolic heart failure (DHF), is often observed in hypertensive patients. Although angiotensin converting enzyme (ACE) inhibitors are widely used as antihypertensive therapy, there is a continued controversy about long-term effect of ACE inhibition on diastolic function. The current study was designed to elucidate a therapeutic effect of ACE inhibitor, temocapril, administration initiated after LV hypertrophy (LVH) and diastolic dysfunction are evident. Methods: Dahl salt sensitive rats fed on 8% NaCl diet from 7 weeks (hypertensive DHF model) were studied at 13 weeks ( n =6) or at 19 weeks following chronic administration of a subdepressor dose of temocapril (0.2 mg/kg/day, TEM(+), n =6) or placebo (TEM(−), n =7) from 13 weeks. Results: Compensatory LVH was associated with prolonged time constant of LV relaxation (Tau) at 13 weeks. In TEM(−), progression of LVH and fibrosis and elevation of LV end diastolic pressure were observed at 19 weeks. Administration of temocapril from 13 weeks prevented the further progression of LVH and fibrosis, attenuated increases in myocardial stiffness constant and Tau, and prevented the development of DHF. These effects were accompanied with the attenuation of decreases in sarcoplasmic reticulum calcium(2+)-ATPase 2a and phosphorylated phospholamban and of hypertrophic signalings’ upregulation. Conclusions: This study demonstrated that chronic administration of temocapril exerts a therapeutic effect on diastolic dysfunction and prevents the transition to DHF even if initiated after appearance of LVH and diastolic dysfunction.

Objective: Remodeling of extracellular matrix (ECM) is considered to contribute to progression of left ventricular (LV) remodeling and matrix metalloproteinases (MMPs) play crucial roles in regulation of ECM. Activation of MMPs is observed in systolic heart failure (SHF) and is suggested to be responsible for LV dilatation in SHF. Diastolic heart failure (DHF) that is not associated with LV dilatation is also accompanied with collagen accumulation; however, differences in ECM regulatory system, especially activation of MMPs, between SHF and DHF remain to be clarified. This study was conducted to clarify whether MMPs are activated even in DHF, and if so, to characterize the difference in activation of MMPs between SHF and DHF for identification of a target for the prevention of LV remodeling in SHF. Methods: To exclude effects of differences in underling cardiovascular diseases and genetic background on the comparison between DHF and SHF, we used Dahl salt-sensitive rats fed on high salt diet starting at 7 weeks of age as DHF model and at 8 weeks as SHF model, both of which our laboratory recently developed. Results: LV fibrosis progressed in the DHF and SHF model rats. MMP-2 was activated to the same degree in both rats. Activation of MMP-9 was enhanced in the DHF model rats, but the activity was more enhanced in the SHF rats. Film in situ zymography showed that enhanced gelatinolytic activity appeared only in the mid layer of the LV wall in the DHF rats and throughout the wall in the SHF rats. The distribution of gelatinolytic activity was consistent with that of expression of MMP-9 as assessed in immunohistochemical study. Conclusions: MMP-9 rather than MMP-2 may be involved in LV dilatation in SHF and be a specific target for the prevention of LV remodeling.

Objectives: Diastolic dysfunction that determines symptoms and prognosis in patients with systolic dysfunction causes heart failure even in the absence of systolic dysfunction. Our recent studies have suggested that myocardial stiffening is likely to play a crucial role in triggering deleterious cardiac disorder. This study investigated differential contribution of left ventricular (LV) hypertrophy and fibrosis to myocardial stiffening in the pressure-overloaded heart. Methods: Dahl-Iwai salt-sensitive rats fed on high-salt diet since 7 weeks transit to congestive heart failure at 20 weeks following development of hypertension, LV hypertrophy and fibrosis, and 20 such rats were divided into three groups: rats treated with angiotensin II type 1 receptor antagonist from 8 weeks ( n = 7), rats treated with calcineurin inhibitor from 8 weeks ( n = 6), and untreated rats ( n = 7). Results: Administration of angiotensin II type 1 receptor antagonist and calcineurin inhibitor did not affect blood pressure and allowed the development of compensatory hypertrophy. However, in contrast to the untreated rats, additive and excessive LV hypertrophy was not observed in either of the treated rats. The blockade of angiotensin II kept LV hydroxyproline content, a ratio of type I to type III collagen mRNA levels, collagen solubility and myocardial stiffness constant at the normal level; however, the calcineurin inhibition failed. Conclusions: Myocardial stiffening may be attributed to progressive collagen accumulation, collagen phenotype shift and enhanced collagen cross-linking, but not to either compensatory LV hypertrophy or LV hypertrophy that progresses from the compensatory stage.

Objectives Despite the clinical frequency of diastolic heart failure, its therapeutic strategy has not been established. Our recent study demonstrated activation of the endothelin (ET) system in a diastolic heart failure model with hypertension. Several studies have reported that ET type A (ETA) receptor antagonist improves systolic function and prevents systolic heart failure; however, its effects on diastolic heart failure are unknown. We investigated the effects of chronic administration of ETA receptor antagonist in diastolic heart failure. Design and methods Dahl-Iwai salt-sensitive rats fed on a high-salt diet from 7 weeks of age, in which congestive heart failure develops following hypertension without cardiac chamber dilatation or systolic dysfunction, were divided into groups with and without administration of a subdepressor dose of ETA receptor antagonist. Results Hypertension induced compensatory left ventricular (LV) hypertrophy at 13 weeks in six untreated rats. Persistent pressure overload developed progressive LV hypertrophy and fibrosis from 13 to 19 weeks, resulting in elevated LV filling pressure and increased lung weight. Chronic ETA receptor blockade did not restrain compensatory LV hypertrophy at 13 weeks; however, it attenuated LV hypertrophy and fibrosis thereafter (n = 6). These beneficial effects resulted in the maintenance of normal LV filling pressure without changes in LV end-diastolic diameter, indicating prevention of LV stiffening. Conclusions Chronic ETA receptor blockade is likely to exert beneficial effects in diastolic failure through attenuation of the progression of LV hypertrophy and fibrosis.

Ultrasonic radiofrequency (RF) signals returned from the myocardium may display complex behavior, including deterministic chaos, and such chaos may be a useful marker of the tissue properties that are not obtainable with myocardial integrated backscatter. Thus, RF signals were obtained from the myocardium by the transthoracic approach in seven healthy subjects and eight patients with dilated cardiomyopathy (DCM). They were analyzed by a time-delay embedding technique to construct a continuous 3-D trajectory. The attractor formed a thick ring-like structure consisting of a relatively empty, roughly circular, core region in all healthy subjects. In DCM patients, the ring-like structure is thinned with a distinct empty circular core region. When the relation between embedding dimension and averaged correlation dimension was compared, the correlation dimension reached a plateau at the value of 3.5 in healthy subjects, and at the value of 2.6 in DCM patients. In conclusion, chaotic behavior is prevalent in the RF signals for the healthy myocardium, and a decrease in such chaos may be indicative of the damaged myocardium in DCM patients. (E-mail:masuyama@medone.med.osaka-u.ac.jp)

OBJECTIVES We assessed the effects of long-term amlodipine administration in a diastolic heart failure (DHF) rat model with preserved systolic function as well as the relationship between changes in left ventricular (LV) myocardial stiffening and alterations in extracellular matrix. BACKGROUND Although the effect of long-term administration of amlodipine has been shown to be disappointing in patients with systolic failure, the effect is unknown in those with DHF. METHODS Dahl salt-sensitive rats fed a high-salt diet for seven weeks were divided into three groups: eight untreated rats (DHF group), eight rats given high-dose amlodipine (10 mg/kg/day; HDA group) and seven rats given low-dose amlodipine (1 mg/kg/day; LDA group). RESULTS High-dose administration of amlodipine decreased systolic blood pressure and controlled excessive hypertrophy, without a decrease in the collagen content, and prevented the elevation of LV end-diastolic pressure at 19 weeks. Low-dose administration of amlodipine with subdeppressive effects did not control either hypertrophy or fibrosis; however, it prevented myocardial stiffening and, hence, the elevation of LV end-diastolic pressure. The ratio of type I to type III collagen messenger ribonucleic acid levels was significantly lower in both the HDA and LDA groups than in the DHF group. CONCLUSIONS Long-term administration of amlodipine prevented the transition to DHF both at the depressor and subdepressor doses. Amlodipine did not decrease the collagen content, but attenuated myocardial stiffness, with inhibition of the phenotype shift from type III to type I collagen. Thus, amlodipine may exert beneficial effects through amelioration of collagen remodeling in the treatment of DHF.

OBJECTIVESWe assessed whether the intravenous administration of nicorandil, an adenosine triphosphate (ATP)-sensitive K+channel opener, exerts beneficial effect on microvascular function and functional and clinical outcomes in patients with acute myocardial infarction (AMI).BACKGROUNDExperimental studies documented that ATP-sensitive K+channel opener exerts cardioprotection after prolonged ischemia.METHODSWe randomly divided 81 patients with a first anterior AMI into two groups, nicorandil (n = 40) and control groups (n = 41). All patients received successful coronary angioplasty within 12 h after the symptom onset and underwent myocardial contrast echcardiography (MCE) with the intracoronary injection of sonicated microbubbles. In the nicorandil group, we injected 4 mg of nicorandil followed by the infusion at 6 mg/h for 24 h and by oral nicorandil (15 mg/day).RESULTSThe improvement in regional left ventricular function, wall motion score and regional wall motion was significantly better in the nicorandil group then in the control group. Intractable congestive heart failure, malignant ventricular arrhythmia and pericardial effusion were more frequently found in the control group than in the nicorandil group (15% vs. 37%, 5% vs. 20% and 8% vs. 37%, p < 0.05, respectively). The frequency of sizable MCE no reflow phenomenon was significantly lower in the nicorandil group than in the control group (15% vs. 33%, p < 0.05).CONCLUSIONSIntravenous nicorandil in conjunction with coronary angioplasty is associated with better functional and clinical outcomes compared to angioplasty alone in patients with an anterior AMI. Myocardial contrast echocardiography findings imply that an improvement in microvascular function with nicorandil may be attributable to this better outcome.

We examined whether angina pectoris (AP) occurring shortly before the onset of acute myocardial infarction (AMI) can render the right ventricle and the conducting tissue resistant to ischemia in 75 patients with an inferior wall AMI. Each patient had total occlusion in the proximal right coronary artery and underwent successful coronary angioplastyor =24 hours from the onset. We divided patients into 2 groups based on presence or absence of antecedent APor =24 hours before the system onset: group 1 (absent) = 57 patients; group 2 (present) = 18 patients. Collateral circulation was more frequently observed in group 2 than in group 1 (group 1 vs 2, 28% vs 61%, p0.01). Elevation in ST segmentor =1 mm in lead V4R, hemodynamic right ventricular dysfunction, and frequency of high-degree heart block were more frequent in group 1 than in group 2 (75% vs 44%, 79% vs 39%, 53% vs 11%, p0.05, respectively). Multivariate analysis demonstrated that antecedent AP is the only factor related to these complications. Thus, episodes of AP occurring shortly before onset may restrain development of ischemic damage of the right ventricle and conducting tissue, and are associated with better clinical and functional outcomes among patients with an inferior wall AMI.

Background —The aim of the present study was to characterize temporal changes in cyclic variation of ultrasonic integrated backscatter (IBS), which reflects intrinsic contractile performance, in patients with reperfused acute myocardial infarction (AMI) and to elucidate the clinical value of tissue characterization in predicting myocardial viability. Methods and Results —We recorded short-axis IBS images before and 3, 7, and 21 days after reperfusion in 26 patients with AMI and obtained the cyclic variation of IBS in the normal and infarct zones. When cyclic variation showed synchrony and asynchrony, we expressed its magnitude as positive and negative values, respectively, called the phase-corrected magnitude. We also measured average wall motion score (dyskinesis, 4; normal, 0) of the infarct segments. The phase-corrected magnitude was lower in the infarct zone than in the normal zone before reperfusion (0.3±2.5 versus 5.2±1.7 dB, P P Conclusions —In patients with AMI, cyclic variation of IBS is blunted during ischemia but recovers much faster after reperfusion than the improvement in wall motion. The greater phase-corrected magnitude at day 3 may be a predictor of better functional improvement.

The beat-to-beat variation of PR interval, which is thought to be a reflection of autonomic nervous system, is difficult to measure with accuracy because the variation is too subtle. However, R wave amplitude in the P wave triggered SAECG is easily attenuated in comparison to that in the R wave triggered SAECG, which might be due to PR interval fluctuation. To determine whether autonomic neuropathy could be detected by use of SAECG, two types of SAECGs triggered by P and R waves were recorded in 23 diabetics with autonomic neuropathy and 41 age matched controls. The peak voltage of filtered QRS complex was measured in the R wave and P wave triggered SAECGs. Percent attenuation of the filtered QRS voltage was calculated by dividing the difference between the voltages in the R wave and P wave triggered SAECGs by the voltage in R wave triggered SAECG. The percent attenuation of filtered QRS voltage was significantly smaller in diabetics with autonomic neuropathy than controls (4.6% +/- 4.9% vs 16.3% +/- 15.0%; P < 0.001). These results suggest that the degree of attenuation of filtered QRS voltage in the P wave triggered SAECG would be useful for the detection of autonomic neuropathy.

BACKGROUND An effect of aldosterone on ventricular fibrosis has been demonstrated in animals, but remains unclear in human patients. This study aimed to investigate (1) the relationship between left ventricular (LV) fibrosis and myocardial ultrasonic texture as assessed with myocardial radio-frequency (RF) signals analyzed from the viewpoint of their waveform with chaos theory in animals and (2) serial changes in myocardial ultrasonic texture following long-term aldosterone blockade in patients with LV hypertrophy. METHODS AND RESULTS In an animal study, Sprague-Dawley rats were divided into 2 groups with and without adriamycin administration, and the relationship between the RF signals and LV fibrosis was assessed. In a clinical study, effects of 12-month-administration of spironolactone were assessed in patients with LV hypertrophy. The animal study revealed that the correlation dimension (CD) calculated from the RF signals inversely correlated with the area of fibrosis. The clinical study demonstrated an increase in CD following 6-month administration of spironolactone. The changes in CD positively correlated with those in the serum carboxy-terminal telopeptide of collagen type I. CONCLUSION Myocardial RF signals analyzed with chaos theory reflect the severity of LV fibrosis. Aldosterone blockade may alter myocardial ultrasonic texture with regression of LV fibrosis, at least partly through enhanced collagen degradation.

Background Promoted myocardial stiffening has a crucial role in the transition to overt diastolic heart failure (DHF) in hypertensive hearts and is attributed to progressive ventricular fibrosis. Previous studies revealed the effects of an angiotensin II type 1 receptor blocker (ARB) and an angiotensin-converting enzyme inhibitor (ACEI) on the synthesis and degradation of collagens in the other phenotype of heart failure, systolic heart failure, which has a different pathophysiology; however, little is known about their effects in DHF. Objective To investigate effects of an ACEI and an ARB on the regulatory system of ventricular fibrosis in hypertensive DHF. Design and methods Dahl salt-sensitive rats fed a diet containing 8% NaCl from age 7 weeks (DHF model) were divided into three groups: six untreated rats, six rats treated with a subdepressor dose of an ARB, candesartan cilexetil (1 mg/kg per day), from age 8 weeks, and six rats treated with a subdepress or dose of an ACEI, temocapril hydrochloride (0.2 mg/kg per day), from age 8 weeks. Six Dahl salt-sensitive rats fed on normal chow served as controls. Data were collected when animals were aged 20 weeks. Results The administration of an ARB or an ACEI inhibited ventricular fibrosis to the same degree. The ACEI decreased the level of type I collagen mRNA, but the decrease was less than that induced by the ARB. The difference in collagen synthesis was probably cancelled out by that in degradation: both in-vitro and in-situ zymography showed that gelatinase activity was greater in the rats treated with the ACEI than in those treated with the ARB. Conclusions An ARB and an ACEI inhibited ventricular fibrosis through different mechanisms in hypertensive DHF.

Diastolic heart failure (DHF) has become a social burden; however, evidences leading to its therapeutic strategy are lacking. This study investigated effects of addition of angiotensin II type 1 receptor blocker (ARB) to angiotensin-converting enzyme inhibitor (ACEI) at advanced stage of DHF in hypertensive rats. Dahl salt-sensitive rats fed 8% NaCl diet from age 7 weeks served as DHF model, and those fed a normal chow served as control. The DHF model rats were arbitrarily assigned to 3 treatment regimens at age 17 weeks: ACEI (temocapril 0.4 mg/kg per day), combination of ACEI (temocapril 0.2 mg/kg per day) with ARB (olmesartan 0.3 mg/kg per day), or placebo. At age 17 weeks, this model represents progressive ventricular hypertrophy and fibrosis, relaxation abnormality, and myocardial stiffening. Data were collected at age 20 weeks. As compared with the monotherapy with ACEI, the addition of ARB induced more prominent suppression of ventricular hypertrophy and fibrosis, leading to suppression of myocardial stiffening, improvement of relaxation, and inhibition of hemodynamic deterioration. Such benefits were associated with greater decreases in reactive oxygen species (ROS) generation, macrophage infiltration, and gene expression of transforming growth factor (TGF)-β 1 and interleukin (IL)-1β, but not with changes in gene expression of monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-α. Thus, ARB added to ACEI provides more benefits as compared with ACEI alone in DHF when initiated at an advanced stage. The additive effects are likely provided through more prominent suppression of ROS generation and inflammatory changes without effects on expression of MCP-1 and TNF-α.

Aim Ventricular fibrosis is promoted by many effectors that chronically activate phospholipase D (PLD), and induces cardiac dysfunction and heart failure in cardiovascular diseases. Since ethanolamine is a product of PLD, we hypothesised that an administration of an analogue of ethanolamine, N -methylethanolamine (MEA), decreases PLD activity through a negative feedback mechanism, suppresses collagen accumulation, and thus prevents organ dysfunction. Methods and results In human fibroblasts 1-butanol inhibited collagen synthesis and enhanced collagenase production, but iso-butanol did not. These indicate crucial roles of PLD in collagen synthesis and degradation. In fibroblasts, MEA dose-dependently decreased PLD activity, inhibited collagen synthesis and enhanced collagenase production. In a hypertensive heart failure model using Dahl–Iwai salt-sensitive rats, PLD activity increased with progressive ventricular fibrosis, leading to myocardial stiffening and overt heart failure. Long-term administration of MEA did not significantly decrease blood pressure, however, but decreased PLD activity and collagen content with inhibited gene expression of collagens, leading to the prevention of myocardial stiffening and haemodynamic deterioration. MEA also attenuated ventricular hypertrophy, another detrimental structural alteration. Conclusion MEA may exert therapeutic effects on cardiac disorders due to ventricular fibrosis through suppression of PLD activity and modulation of the fibrosis pathway even without relief from mechanical stress.

Background Angiotensin II type 1 receptor (AT 1 R) blockade attenuates left ventricular relaxation abnormality and myocardial stiffening in a model of hypertensive diastolic heart failure, but the mechanisms remain unclear. Objective To test the hypothesis that such benefits are provided by modulation of the quantitative or qualitative changes, or both, in Ca 2+ regulatory proteins and extracellular matrix. Design and methods Dahl salt-sensitive rats fed a diet containing 8% sodium chloride from 7 weeks of age present pulmonary congestion as a result of diastolic dysfunction with preserved systolic function, around 20 weeks of age. In this study, animals of this model were divided into groups that received (n = 7) or did not receive (n = 6) a subdepressor dose of an AT 1 R antagonist (candesartan cilexetil) from 8 weeks of age. Results Long-term AT 1 R blockade prevented the development of diastolic heart failure through attenuation of left ventricular relaxation abnormality and myocardial stiffening without a reduction in blood pressure. Left ventricular relaxation abnormality was not associated with any change in the ratio of abundance of phospholamban to that of sarcoplasmic reticulum Ca 2+ -ATPase 2a protein, but was accompanied by a decrease in Ser 16 -phosphorylated phospholamban. The AT 1 R blockade inhibited this decrease. Attenuation in myocardial stiffening was associated with reduced tissue collagen content, attenuated collagen cross-linking, and suppressed gene expression of collagen type I rather than type III. Conclusions AT 1 R blockade prevented abnormal relaxation at least partly through functional alterations in Ca 2+ -handling proteins in a hypertensive model of diastolic heart failure. It attenuated myocardial stiffening through preventing a shift in the phenotype of collagen synthesized and the accumulation of cross-linked collagen. These beneficial effects of AT 1 R blockade in diastolic heartfailure are achieved without a reduction in blood pressure.

Objective Ventricular fibrosis plays a pivotal role in the development of diastolic heart failure and is a therapeutic target; however, the effects of pharmacological interventions on the extracellular matrix (ECM) regulatory system in diastolic heart failure remain to be clarified. Design and methods Dahl salt-sensitive rats fed on a diet containing 8% NaCI from age 7 weeks - a hypertensive diastolic heart failure model - were divided into untreated rats, rats treated with angiotensin II type 1 (AT1) receptor antagonist and those treated with endothelin type A (ETA) receptor antagonist. Results Ventricular fibrosis progressed in the untreated rats, with increases in mRNA levels of type I collagen, matrix metalloproteinase-2, -9 and -13, and tissue inhibitor of metalloproteinase-1 and -2. Both antagonists attenuated ventricular fibrosis to the same degree. AT1 receptor blockade decreased the type I collagen mRNA level more than ETA receptor blockade. ETA receptor blockade did not decrease the matrix metalloproteinase-2 mRNA level that was decreased by AT1 receptor blockade, and decreased the tissue inhibitor of metalloproteinase-2 mRNA level that was not affected by AT1 receptor blockade. These led to a higher ratio of matrix metalloproteinase-2 to tissue inhibitor of metalloproteinase-2 mRNA levels and a greater 72-kDa gelatinase activity in the rats treated with ETA receptor antagonist than in those treated with AT1 receptor antagonist, and may well cancel out the lesser decline in collagen synthesis, resulting in the equivalent attenuation of ventricular fibrosis. Conclusions AT1 receptor and ETA receptor antagonists provide their beneficial effects on the ECM through different modulation of its regulatory system.

Dobutamine stress echocardiography (DSE), myocardial contrast echocardiography (MCE), and ultrasonic tissue characterization with integrated backscatter are useful methods for assessing myocardial viability in acute myocardial infarction. In this study, we compared the potential of 3 methods for predicting myocardial viability in 38 patients with reperfused anterior wall acute myocardial infarction. We performed MCE shortly after coronary reperfusion with an intracoronary injection of microbubbles. We recorded 2-dimensional integrated backscatter images at rest and, then, performed low-dose (10 μg/kg/min) DSE 3 days later. In integrated backscatter images, we placed the region of interest in the midwall of the myocardial segment to reconstruct the cyclic variation of myocardial integrated backscatter. The myocardial segment was judged viable when it showed active contraction 3 months later. Among 74 segments analyzed, 34 were judged viable. Presence of contractile response during DSE predicted segmental viability with 91% sensitivity and 78% specificity. Intense and homogenous contrast enhancement with MCE predicted viability with 82% sensitivity and 73% specificity. The presence of synchronous contraction of cyclic variation predicted myocardial viability with 79% sensitivity and 83% specificity. There were no differences in sensitivity and specificity among the 3 methods. Thus, MCE and ultrasonic tissue characterization can predict myocardial viability as accurately as DSE in patients with acute myocardial infarction. The logistics of the methods may determine clinical application.

This study attempted to establish echocardiographic measurements of left ventricular (LV) mass and LV systolic and diastolic function, particularly in rats with hypertensive heart.M-mode LV echograms and Doppler mitral flow were obtained in Dahl salt-sensitive rats placed on 0.3% or 8% sodium chloride diet. Echo Doppler measurements were compared with catheterization and pathologic measurements in 54 rats for LV mass and in 45 rats for LV systolic and diastolic function.Echocardiographic measurement of LV mass correlated well with pathologic measurement (r = 0.94, P.01, n = 54, SEE = 0.08 mg), independent of LV size, aging, and therapeutic intervention. Endocardial fractional shortening (FS) correlated with LV peak + dP/dt (r = 0.56, n = 45, P.01), and the correlation was improved to r = 0.71 if 11 rats with marked LV hypertrophy were excluded. Midwall FS correlated well with LV peak + dP/dt (r = 0.72, n = 45, P.01) even if rats with extremely thickened ventricular wall were included. If midwall FS was lower than 14%, LV systolic dysfunction was very likely (sensitivity 67%, specificity 91%). Association of mitral E/A ratio of 2.0 or greater with deceleration time of shorter than 35 ms was an accurate indicator of elevated LV end-diastolic pressure (sensitivity 82%, specificity 86%) and increased lung weight because of congestive heart failure (sensitivity 89%, specificity 96%) in rats with hypertension.LV mass, LV systolic function, and LV end-diastolic pressure were assessable with echo Doppler in rats with hypertensive heart.

Variability of paradoxical jet flow in a case of hypertrophic cardiomyopathy with midventricular obstruction was examined. Propranolol decreased both peak diastolic paradoxical jet flow velocity and peak systolic velocity at the narrowing portion. Nitroglycerin decreased peak diastolic paradoxical jet flow velocity with an increase in peak systolic velocity at the narrowing portion. Thus the diastolic paradoxical jet flow is dynamic as well as the abnormal systolic flow; however, changes in these abnormal flow dynamics may not be necessarily in the same direction. Doppler echocardiography should be useful in assessing effects of interventions on the flow dynamics in patients with hypertrophic cardiomyopathy with midventricular obstruction.

OBJECTIVES The aim of our study was to explore evolving changes in a mitral flow velocity pattern (MFVP) and its hemodynamic and pathological correlates in hypertensive rats in an isolated diastolic heart failure model. BACKGROUND Development of left ventricular (LV) hypertrophy and concomitant diastolic dysfunction cause heart failure in hypertensive hearts even with normal systolic function; however, associated evolving change in MFVP is still unclear. METHODS Mitral flow velocity pattern was recorded every 2 weeks from 7 to 19 weeks in six hypertensive rats. Hemodynamic and pathological correlates of Doppler mitral flow indexes were examined as an additional part of the study using the hypertensive rats at the age of 13 weeks (compensatory stage, n = 7) and at 19 weeks (heart failure stage, n = 8). RESULTS Initial development of pressure overload LV hypertrophy resulted in a decrease in early diastolic filling wave (E), a reciprocal increase in the filling wave due to atrial contraction (A) and prolongation of deceleration time of E wave (relaxation abnormality pattern). These changes were associated with an increase in tau, an index of LV relaxation, but without a change in LV end-diastolic pressure. Transition to congestive heart failure caused an increase in E, a decrease in A and shortening of deceleration time. These changes were not associated with further increase in tau but with elevation of LV end-diastolic pressure, reflecting marked LV hypertrophy and myocardial fibrosis. CONCLUSIONS Development of pressure overload LV hypertrophy is associated with evolving changes in MFVP from normal to relaxation abnormality pattern and, in turn, to pseudonormalized to restrictive pattern. Analysis of MFVP may be useful to follow not only functional but also constitutional changes of the myocardium in hypertensive hearts.

Background —There is controversy regarding the contribution of calcineurin activation to the development of pressure-overload left ventricular (LV) hypertrophy and heart failure. The aim of this study was to explore whether the inhibition of calcineurin may prevent the transition to heart failure in hypertensive rats and, if so, to clarify in which developmental stage of LV hypertrophy calcineurin plays a key role. Methods and Results —Dahl salt-sensitive rats placed on an 8% NaCl diet from the age of 7 weeks (hypertensive rats) were randomized to no treatment (n=6) or treatment with the calcineurin inhibitor FK506 (1 mg · kg − 1 · d − 1 ) from 8 weeks (FKE, n=7) or from 17 weeks (FKL, n=7). Rats placed on a 0.3% NaCl diet were defined as control rats (n=6). The administration of FK506 from 8 weeks attenuated, although it did not block, LV hypertrophy observed in the untreated rats and prevented the transition to heart failure. The development of LV fibrosis, however, was not attenuated by the administration of FK506 from 8 weeks. The administration of FK506 from 17 weeks brought no benefit for cardiac remodeling or LV function and failed to prevent heart failure. Conclusions —Calcineurin inhibition, if started from the initial stage of pressure overload, attenuated the development of LV hypertrophy without any effect on LV fibrosis and prevented the transition to heart failure. The activation of calcineurin is involved in the development of LV hypertrophy but not of LV fibrosis, and this involvement may be crucial at the initial stage.

Objective: Although interest in diastolic heart failure is growing because of its clinical frequency, little is known about this type of heart failure. Our laboratory recently developed a diastolic heart failure model using Dahl salt-sensitive rat. In this model, gene expression of angiotensin-converting enzyme and endothelin (ET) system in the left ventricle was enhanced at heart failure stage without downregulation of angiotensin type 1a receptor mRNA level. However, the roles of these humoral systems in the transition to diastolic failure remain unclear. Methods: Subdepressor doses of angiotensin II type 1 (AT1) receptor and ET type A (ETA) receptor antagonists were administered in this model just after onset of hypertension, and their effects were investigated. Results: Neither AT1 nor ETA receptor blockade inhibited the early (13 weeks) compensatory left ventricular (LV) hypertrophy. This form of compensatory hypertrophy is associated with subnormal LV end-systolic stress, which was normalized by AT1 receptor blockade but not by ETA receptor blockade. Progression of LV hypertrophy and fibrosis and transition to heart failure (19 weeks) in the untreated rats were prevented by both antagonists, resulting in normalization of LV end-diastolic pressure and lung weight. AT1 receptor blockade, but not ETA receptor blockade, normalized time constant of LV relaxation. Enhanced gene expression for ET system in the left ventricle observed in the untreated rats was suppressed with AT1 receptor antagonist administration. ETA receptor blockade slightly but significantly elevated the AT1a receptor mRNA level as compared with the untreated rats. Conclusions: RAS and ET system contribute to the transition to diastolic heart failure through the development of excessive hypertrophy and ventricular fibrosis in hypertensive heart diseases, however, neither RAS nor ET system is mandatory for normal compensation for pressure overload. RAS apparently causes such diastolic effects at least partly through the ET system.

Coronary flow velocity pattern in patients with acute myocardial infarction demonstrating no-reflow phenomenon is characterized with early systolic retrograde flow and rapid deceleration of diastolic flow velocity. In this study, we investigated the early temporal changes in microvascular function in patients with the no-reflow phenomenon. Among 144 patients with a first acute myocardial infarction, 33 exhibited sizable no-reflow phenomenon after coronary reperfusion with myocardial contrast echocardiography. We assessed temporal changes in coronary flow velocity patterns with the Doppler guidewire. The early systolic retrograde flow was observedor = 10 seconds after reperfusion in 16 patients (group A) or later in 17 patients (331 +/- 327 seconds, group B). Diastolic deceleration rate was higher in group A than in group B at 1 minute after reperfusion. It gradually increased in group B and showed comparable value to group A 10 minutes later. Group A had longer elapsed time from symptom onset to reperfusion and a greater number of infarct Q waves before reperfusion than group B (14 +/- 13 vs 5 +/- 2 hours, p0.01; and 3 +/- 2 vs 2 +/- 1, p0.02). In contrast, the incidence of transient ST reelevation shortly after reperfusion was higher in group B (76% vs 25%, p0.01). Thus, the characteristic coronary flow velocity pattern is either established at the moment of coronary reperfusion or progresses thereafter in patients with no-reflow phenomenon. This suggests different mechanisms of developing ischemic microvascular injury.

Objectives. We assessed the acute effect of intracoronary injection of verapamil on microvascular function after primary percutaneous translumanal coronary angioplasty (PTCA) for acute myocardial infarction (AMI) with myocardial contrast echocardiography (MCE) in relation to functional outcomes.Background. Recent clinical studies have documented the potential of verapamil for possible increase in coronary blood flow after primary PTCA.Methods. Forty patients with a first AMI were randomly assigned to the verapamil group (n = 20) or the control group (n = 20). In the verapamil group, verapamil (0.5 mg) was injected into the infarct-related artery shortly after PTCA, followed by the oral administration. We performed MCE with an intracoronary injection of sonicated microbubbles before and after verapamil. To assess microvascular integrity, we determined the baseline-subtracted peak intensity in the risk area and the ratio of the no reflow zone plus the low reflow zone to the risk area (low reflow ratio). We determined the average wall motion score (dyskinesia/akinesia = 3; normal = 0) in the risk area on the day of AMI and a mean of 24 days later.Results. The low reflow zone was observed shortly after PTCA in 14 verapamil group patients, and the low reflow ratio decreased after verapamil (0.39 ± 0.23 vs. 0.29 ± 0.17 [mean ± SD], p < 0.05). Peak intensity significantly (p < 0.05) increased from 6 ± 5 to 12 ± 6 after verapamil. The reduction in wall motion score from the acute (day −1) to the late stage (day −24) was significantly greater in the verapamil group than in the control group (0.7 ± 0.8 vs. 0.2 ± 1.3, respectively, p < 0.05).Conclusions. Intracoronary administration of verapamil after primary PTCA can attenuate microvascular dysfunction and thereby augment myocardial blood flow in patients with AMI, leading to better functional outcome than with PTCA alone.

To clarify how the long-term β-blocker (β) therapy for the patients (pts) with dilated cardiomyopathy (DCM) improves the rate of freedom from cardiac death (RFCD), 57 DCM pts with β (metoprolol; 40–60 mg/day)(G-l, followup; 6–120 M) and 72 DCM pts without β (G-2, follow-up; 6–102 M) were followed up. The survival was confirmed by annual interview. The cause of death and the preterminal condition of the pts were obtained from family members, medical personnel or medical recordings. The RFCO was analyzed with Kaplan-Meier life table method. At entry, there were no significant differences in age, sex, blood pressure, heart rate, left ventricular end-diastolic dimension (64.0 ± 6.0 vs 63.5 ± 6.8 mm) and ejection fraction (40.7 ± 9.1 vs 42.3 ± 8.3%) measured by echocardiography, and the severity of ventricular arrhythmia by 24 hours Holter monitoring (according to the Lawn's grade) between G-l and G-2. During the follow-up period, non-cardiac death occurred in 2 pts in G-1 and in 3 pts in G-2. The annual RFCD were calculated as shown below; 1Y 2Y 3Y 4Y 5Y 6Y 7Y G-1 1.0 * 1.0 # 0.98 * 0.98 # 0.98 # 0.98 # 0.87 * G-1 0.91 0.86 0.84 0.84 0.72 0.62 0.62 * p l 0.05 # P l 0.01 vs G-2 The number of death from heart failure did not show significant difference between G-1 (3 of 57 pts) and G-2 (4 of 72 pts). On the other hand, sudden death has occurred more often in G-2 (10 of 72 pts) than in G-1 (1 of 57 pts) (p l 0.05), resulting in that the RFCD was significantly better in G-l than in G-2. These results indicate that the long-term β-blocker therapy for DCM might improve the rate of freedom from cardiac death due to prevention of sudden death rather than of death from heart failure.

In sick sinus syndrome (SSS), pathophysiological abnormalities have been shown not only in the sinus node but also in the atrial muscle, especially of the perinodal portion. To investigate whether the electrophysiological abnormalities of atrial muscle in SSS would induce the characteristic P wavepattern, especially in the initial portion of the P wave, we studied 37 patients with SSS and 67 age-comparable control patients. using the P wave-triggered signal-averaged electrocardiography. Sixteen of 37 SSS patients had paroxysmal atrial fibrillation (Paf). Signal-averaged electrocardiograms were recorded with a band-pass filter of 40–300 Hz and signals of 200 beats or more were averaged with the P wave-triggering technique. The P wave complexes of the three bipolar leads were combined into a spatial magnitude, and then the root mean square voltage for the initial 30 ms (EP30) and the last 20 m (LP20) of filtered P wave were measured. The duration (Ad) and root mean square voltage (RMS) of the total filtered P wave were also measured. Results SSS with Paf SSS without Pat Control EP30 (μV) 2.55 ± 1.17 * 2.16 ± 0.98 * 3.93 ± 1.23 LP20 (μV) 1.98 ± 0.40 # † 2.79 ± 1.04 3.35 ± 1.76 Ad (ms) 145.8 ± 16.1 * † 131.2 ± 14.1 $ 123.7 ± 11.7 RMS (μV) 6.20 ± 0.41 5.82 ± 0.82 6.20 ± 1.47 * p l 0.0001 # P l 0.005 $ p l 0.05 vs. Control † p l 0.01 vs SSS Without Pat The amplitude of initial portion of filtered P wave was significantly lower and the duration was longer in SSS patients with/without Paf than the controls, while there was no significant difference in the amplitude of the terminal portion between SSS patients without Paf and controls. The criteria of “EP30 ≤ 3.0 μV and Ad g 130 m” as defining “atrial early potential” gave a sensitivity of 76%, a specificity of 83% and a predictive accuracy of 81% for detection of patients with SSS. These results indicate that the low amplitude signals in the initial portion of filtered P wave were characteristic of SSS, so that the recognition of atrial early potential might be promising to identify patients with SSS.

Background: Aldosterone antagonists are considered as one of interventions that may provide additional benefits to standard therapy of congestive heart failure. Experimental studies have suggested that aldosterone inhibition provides benefits through effects on cardiac structure; however, the confirmation of these experimental results in patients has been difficult because of limited tools for assessment of LV structure. Recently, we have reported that analysis of ultrasonic radio-frequency (RF) signals obtained from myocardium may have a potential of detecting structural damage noninvasively. Methods and Results: To assess long-term effect of aldosterone inhibition on cardiac structure, myocardial RF signals were analyzed in 15 patients with LV hypertrophy (LV mass index>120g/m2) before and after 6 and 12 month-administration of spironolactone. There were no changes in LV end-diastolic diameter, ejection fraction and LV mass index throughout the study protocol. Attractors constructed from RF signals formed a thin ring-like structure consisting of a relatively empty, roughly circular core (quasi-periodic pattern) before the administration and changed to chaotic pattern 6 and 12 months after the administration. The mean value of correlation dimension (CD) calculated from the RF signals of all the subjects increased towards a normal level (2.6±0.1 vs. 3.0±0.2, p