Anti-inflammatory and pro-angiogenic effects of beta blockers in a canine model of chronic ischemic cardiomyopathy: comparison between carvedilol and metoprolol.

There is controversy regarding the superiority of carvedilol (C) over metoprolol (M) in congestive heart failure. We hypothesized that C is superior to M in chronic ischemic cardiomyopathy because of its better anti-inflammatory and pro-angiogenic effects. In order to test our hypothesis we used a chronic canine model of multivessel ischemic cardiomyopathy where myocardial microcatheters were placed from which interstitial fluid was collected over time to measure leukocyte count and cytokine levels. After development of left ventricular dysfunction, the animals were randomized into four groups: sham (n = 7), placebo (n = 8), M (n = 11), and C (n = 10), and followed for 3 months after treatment initiation. Tissue was examined for immunohistochemistry, oxidative stress, and capillary density. At 3 months both rest and stress wall thickening were better in C compared to the other groups. At the end of 3 months of treatment end-systolic wall stress also decreased the most in C. Similarly resting myocardial blood flow (MBF) improved the most in C as did the stress endocardial/epicardial MBF. Myocardial interstitial fluid showed greater attenuation of leukocytosis with C compared to M, which was associated with less fibrosis and oxidative stress. C also had higher IL-10 level and capillary density. In conclusion, in a chronic canine model of multivessel ischemic cardiomyopathy we found 3 months of C treatment resulted in better resting global and regional function as well as better regional function at stress compared to M. These changes were associated with higher myocardial levels of the anti-inflammatory cytokine IL-10 and less myocardial oxidative stress, leukocytosis, and fibrosis. Capillary density and MBF were almost normalized. Thus in the doses used in this study, C appears to be superior to M in a chronic canine model of ischemic cardiomyopathy from beneficial effects on inflammation and angiogenesis. Further studies are required for comparing additional doses of these drugs.

Monday preference in onset of takotsubo cardiomyopathy.

OBJECTIVE: Acute cardiovascular events show definite temporal patterns of occurrence. Takotsubo cardiomyopathy (TTC) has been recently shown to exhibit a seasonal (summer) and circadian (morning) temporal distribution. The aim of this study, based on the database of a multicenter Italian network, was to investigate the possible existence of a weekly pattern of onset of TTC. METHODS: The study included all cases of TTC admitted to the coronary care unit of 8 referral cardiac centers in Italy (five in Southern Italy and three in Northern Italy, respectively), belonging to the Takotsubo Italian Network (January 2002-December 2008). Day of admission was categorized into seven 1-day intervals according by week, and chronobiological analysis was performed by partial Fourier series. RESULTS: The database included 112 patients with TTC (92.9% females). The weekly distribution identified the highest number of cases on Monday and the lowest on Saturday. Chronobiologic analysis yielded a rhythmic pattern with a significant peak on Monday (P = .036). CONCLUSIONS: This study confirms a Monday preference for TTC occurrence on Monday, similar to that reported for acute myocardial infarction. Stress of starting weekly day life activities, could play a triggering role.

Transient left ventricular ballooning (tako-tsubo cardiomyopathy) soon after intravenous ergonovine injection following caesarean delivery.

Transient left ventricular ballooning also called tako-tsubo syndrome, is increasingly being recognized as cardiomyopathy mimicking the clinical scenario of an acute myocardial infarction. Generally, it is characterized by apical ballooning appearance of the left ventricle in the presence of normal coronary arteries on the angiogram. Recently, a variant form involving the midventricle with sparing of the apical and basal segments has been described. This syndrome is more prevalent in postmenopausal woman and usually preceded by extreme emotional and/or physical stress. We describe a case never reported before of transient left ventricular ballooning occurring during the early postpartum period after ergonovine injection rapidly evolving from a 'typical apical' ballooning into a 'midventricular' myocardial dysfunction.

Short-term electrogeometric atrial remodelling after percutaneous atrial septal defect closure.

BACKGROUND: Atrial arrhythmias are well known long-term complications of atrial septal defect (ASD), presumably due to chronic atrial enlargement and stretch. Surgical repair often fails to revert the arrhythmic risk despite atrial volumetric unloading, maybe as a consequence of atriotomic scar. Avoiding atrial incision, percutaneous ASD closure should result in atrial unloading and arrhythmic risk decrease. This study evaluated the atrial short-term electrogeometric effects of percutaneous ASD closure. METHODS: Fifteen asymptomatic patients (age 23 +/- 5 years) submitted to percutaneous closure of large ASD (QP/QS 2.4 +/- 0.3) using the Amplatzer Septal Occluder device (24 +/- 2 mm) underwent atrial echocardiographic (indexed right atrial size and left atrial size as well as right atrial/left atrial volume ratio) and electrocardiographic (P-wave duration and dispersion, PR conduction time and dispersion) evaluation at 1 and 6 months after ASD closure. RESULTS: After 6 months, the indexed right atrial volume and the right atrial/left atrial volume ratio had significantly decreased (from 39 +/- 5 to 20 +/- 2 ml/m2, P < 0.001 and from 2.0 +/- 0.2 to 1.0 +/- 0.1, P < 0.0001, respectively) as did the P-wave dispersion (from 32 +/- 2 to 28 +/- 1 ms, P = 0.03) despite a significant increase of both P-wave maximal (from 75 +/- 3 to 81 +/- 3 ms, P < 0.01) and minimal (from 42 +/- 3 to 53 +/- 3 ms, P < 0.005) duration. CONCLUSION: Percutaneous ASD closure causes a short-term positive atrial electrogeometric remodelling. The electrocardiographic predictors of atrial arrhythmias, however, tend to worsen early after device implantation despite a marked volumetric unloading, possibly due to a 'foreign body' effect of the occluding device. This might warrant a closer follow-up during the first few weeks after device implantation.

Intravenous contrast echocardiography after myocardial infarction: relationship among residual myocardial perfusion, contractile reserve and long-term remodelling.

OBJECTIVE: Previous studies have shown the potential role played by intracoronary myocardial contrast echocardiography (MCE) in predicting long-term remodelling and function after myocardial infarction (MI). Scanty data, however, are available on the role of intravenous MCE in this regard. The aim of this study was to assess the role of residual myocardial blood volume in the asynergic region in modulating ventricular volume changes over time post-MI. METHODS: Thirty-two consecutive patients with anterior MI were studied predischarge using low-dose dobutamine echocardiography (Dob) and intravenous triggered MCE. Videointensity plots were generated from the apical approach and fitted exponentially. Volumes were assessed at baseline, during Dob and at 8 months. RESULTS: Baseline volumes, which appeared related to the extent of the asynergic region (P < 0.01) but showed no relation with videointensity in that area, did not change at follow-up, although Dob had elicited significant contractile reserve. However, videointensity in the asynergic region showed a significant interaction (P = 0.044) with the change in diastolic volume over time, with patients with the highest videointensity reverting remodelling (n = 11, from 69 +/- 16 to 65 +/- 16 ml/m) as compared with the remaining population (n = 21, from 68 +/- 16 to 73 +/- 21 ml/m). This was not seen when Dob-derived parameters were used. Multivariate analysis ranked videointensity second (P = 0.066), after baseline stroke volume (P = 0.005), in predicting changes in volumes over time. CONCLUSIONS: Unlike inotropic reserve, residual myocardial blood volume in the dysfunctioning muscle, as assessed by predischarge quantitative intravenous MCE, has the potential to modulate remodelling in patients who suffered an anterior MI.

Assessment of ischemia-induced microvascular remodeling using contrast-enhanced ultrasound vascular anatomic mapping.

Our aim was to apply novel contrast-enhanced ultrasound (CEU) techniques to characterize remodeling in different vascular compartments during ischemia-mediated angiogenesis. Hind limb ischemia was produced by ligation of an external iliac artery in 60 rats, half of which were treated with intramuscular fibroblast growth factor (FGF)-2 (5 microg). The proximal adductor muscles of the ischemic and control hind limb were studied immediately after ligation and at days 4, 7, or 14. Low-power maximum intensity projection imaging was performed to assess large intramuscular vessels to the fourth branch order. CEU data were analyzed to measure capillary perfusion and functional noncapillary microvascular blood volume. Resting capillary perfusion was reduced by 30% after arterial ligation and recovered earlier in FGF-2-treated versus nontreated rats (day 4 vs. 14). Changes in perfusion were temporally related to expansion of noncapillary microvascular blood volume on CEU, which was associated with an arteriogenic response on histology. Expansion of and organization (fractal distribution) of large collateral vessels occurred gradually over 2 weeks and was slightly more rapid with FGF-2 treatment. We conclude that CEU can separately assess collateral development, more distal arteriogenesis, and secondary changes in capillary perfusion that occur differentially with ischemia and growth factor therapy.

Phasic changes in arterial blood volume is influenced by collateral blood flow: implications for the quantification of coronary stenosis at rest.

BACKGROUND: The systolic to diastolic arteriolar blood volume (aBV) ratio derived using myocardial contrast echocardiography (MCE) can identify the presence of coronary stenosis at rest. There are some patients with moderate to severe coronary stenosis who nonetheless exhibit a normal systolic to disatolic aBV ratio. AIM: To test the hypothesis that collateral blood flow influences the systolic to diastolic aBV ratio. MCE-defined phasic changes in aBV were recorded at baseline and up to 2 degrees of non-critical stenosis in 12 dogs. Measurements were made from MCE-defined collateralised and non-collateralised portions of the left anterior descending arterial bed. RESULTS: Increases in both systolic and diastolic aBV were noted in the non-collateralised region with increasing degrees of stenosis. Although these increases in the absolute values did not reach statistical significance, the systolic to diastolic aBV signal ratio in the non-collateralised bed increased significantly between stages (analysis of variance, p = 0.003). In comparison, in the collateralised bed neither the absolute systolic nor diastolic aBV signals changed with increasing degrees of stenosis. Consequently, the aBV signal ratio between systole and diastole also did not change in this bed. CONCLUSION: Phasic changes in aBV are influenced by the degree of collateral blood flow. Thus, if the region of interest is not placed in the centre of the vascular bed, the degree of stenosis may be underestimated by the systolic to diastolic aBV ratio. On the other hand, as extensive collateralisation may indicate excellent prognosis, this ratio may provide prognostic information independent of the coronary anatomy.

Anatomy and flow in normal and ischemic microvasculature based on a novel temporal fractal dimension analysis algorithm using contrast enhanced ultrasound.

Strategies for improvement of blood flow by promoting new vessel growth in ischemic tissue are being developed. Recently, contrast-enhanced ultrasound (CEU) imaging has been used to assess tissue perfusion in models of ischemia-related angiogenesis, growth-factor mediated angiogenesis, and tumor angiogenesis. In these studies, microvascular flow is measured in order to assess the total impact of adaptations at different vascular levels. High-resolution methods for imaging larger vessels have been developed in order to derive "angiograms" of arteries, veins, and medium to large microvessels. We describe a novel method of vascular bed (microvessel and arterial) characterization of vessel anatomy and flow simultaneously, using serial measurement of the fractal dimension (FD) of a temporal sequence of CEU images. This method is proposed as an experimental methodology to distinguish ischemic from nonischemic tissue. Moreover, an improved approach for extracting the FD unique to this application is introduced.

Cyclic variation in ultrasonic myocardial integrated backscatter is due to phasic changes in the number of patent myocardial microvessels.

OBJECTIVE: We tested the hypothesis that the cyclic variation in ultrasonic myocardial integrated backscatter (IBS) is due to cardiac contraction-induced changes in the number of patent myocardial microvessels. METHODS: We performed experiments in open-chest dogs in which we increased the number of patent myocardial microvessels without changing cardiac contraction. We achieved this either by direct intracoronary administration of adenosine (group 1; n = 10) or by producing a noncritical coronary stenosis (group 2; n = 7). RESULTS: At baseline, IBS was lowest in systole and highest in diastole. This cyclic variation in IBS was closely associated with the phasic changes in myocardial blood volume that were measured with myocardial contrast echocardiography. During adenosine administration, the diastolic IBS increased from -18.8 +/- 6.5 to -17.5 +/- 6.1 dB (P = .002), with an associated increase in the difference between the systolic and diastolic IBS from 3.8 +/- 1.1 to 4.6 +/- 1.0 dB (P = .009). After a noncritical stenosis was produced, diastolic IBS also increased from -26.6 +/- 8.3 to -25.2 +/- 7.3 dB (P = .001), with an associated increase in the difference between the systolic and diastolic IBS from 3.7 +/- 1.2 to 5.0 +/- 1.0 dB (P = .02). No change in IBS was noted in the bed that did not receive adenosine or the bed that had a stenosis. CONCLUSIONS: The variation in IBS during the cardiac cycle is closely associated with the phasic changes in myocardial blood volume seen during cardiac contraction. When the number of patent myocardial arterioles is increased via adenosine or placement of a noncritical stenosis, diastolic IBS increases with a concomitant increase in IBS cyclic variation. These results may have important clinical applications for the noninvasive diagnosis of noncritical coronary stenosis at rest.

Time-course of cardiac remodeling following transcatheter closure of atrial septal defect.

BACKGROUND: Right chamber dilatation and right-to-left volumetric unbalance are well-known cardiac consequences of atrial septal defect (ASD) shunt, accounting for most of its long-term complications. Thus, cardiac volumetric unloading is a major aim of ASD closure. Different from surgery, transcatheter option might be considered as an "unbiased" tool to evaluate the cardiac geometric remodeling following ASD closure. METHODS: Extent and time-course of cardiac geometric changes were assessed by echocardiography 24 h, 1 and 6 months after percutaneous closure of large ASD (mean diameter 17+/-6 mm, QP/QS 2.2+/-0.9) in 42 asymptomatic patients (age 22+/-18 years). RESULTS: Transcatheter closure was accomplished using the Amplatzer Septal Occluder device (mean 23+/-7 mm, median 24 mm), achieving a complete occlusion in all patients at the 6-month follow-up control. After ASD closure, right atrial (RA) volume reduced from 45+/-24 to 28+/-12 ml (-37.8%, p<0.001), while left atrial (LA) volume did not significantly change. Inlet and infundibulum right ventricular (RV) end-diastolic diameters reduced by 23+/-2% and 23+/-3%, respectively (p<0.001 for both measurements), although with a different time-course of changes. Finally, transverse left ventricular (LV) end-diastolic diameter increased from 39+/-7 to 44+/-5 mm (+11.4%, p<0.01). These geometric changes resulted in an RV/LV diameter ratio decrease by 34+/-3% (p<0.001). Nearly 90% of cardiac remodeling ensued within 1 month from shunt disappearance (50% within 24 h). CONCLUSIONS: Percutaneous ASD closure results in early and striking cardiac geometric changes that almost completely revert the right-to-left volumetric unbalance. Most of this geometric remodeling ensues within a few weeks from ASD closure.

Global and regional left ventricular function in patients undergoing transcatheter closure of secundum atrial septal defect.

This study sought to evaluate global and regional left ventricular (LV) function before and early after device closure of atrial septal defects (ASDs) in patients with normal pulmonary pressure. Global LV diastolic function was unaffected by ASD closure. An improvement in global LV systolic function at rest resulted in an increase in stroke volume at rest. Nevertheless, total cardiac output did not change after the procedure, because of a decrease in heart rate at rest counterbalancing the increase in stroke volume. Thus, lateral and inferior LV regional systolic function were preserved after device implantation. Moreover, no changes in regional LV diastolic function were highlighted during the study.

Detection of peripheral vascular stenosis by assessing skeletal muscle flow reserve.

OBJECTIVES: We sought to determine whether the severity of peripheral arterial disease (PAD) can be assessed by measuring blood flow reserve in limb skeletal muscle with contrast-enhanced ultrasound (CEU). BACKGROUND: Noninvasive imaging of distal limb perfusion could improve management of patients with PAD by evaluating the impact of large and small vessel disease, and collateral flow. METHODS: In 12 dogs, blood flow in the quadriceps femoris was measured by CEU at rest and during either electrostimulated contractile exercise or adenosine infusion. Femoral artery blood flow was measured by Doppler ultrasound. Studies were performed in the absence and presence of either moderate or severe stenosis (pressure gradient of 10 to 20 mm Hg and >20 mm Hg, respectively). RESULTS: Resting femoral artery blood flow progressively decreased with stenosis severity, while resting skeletal muscle flow was reduced only with severe stenosis (52 +/- 21% of baseline, p < 0.05), indicating the presence of collateral flow. Skeletal muscle flow reserve during contractile exercise or adenosine decreased incrementally with increasing stenosis severity (p < 0.01). The stenotic pressure gradient correlated with skeletal muscle flow reserve for exercise and adenosine (r = 0.70 for both, p < 0.01). CONCLUSIONS: Contrast-enhanced ultrasound of limb skeletal muscle can be used to assess the severity of PAD by measuring muscle flow reserve during either contractile exercise or pharmacologic vasodilation. Unlike currently used methods, this technique may provide a measure of the physiologic effects of large- and small-vessel PAD, and the influence of collateral perfusion.

Analysis of right ventricular Doppler tissue imaging and load dependence in patients undergoing percutaneous closure of atrial septal defect.

In patients with volume overload due to atrial septal defect (ASD) and Doppler tissue imaging E'/A' <1 at baseline, right ventricular (RV) myocardial velocities show load independence after closure with a device. Conversely, in patients with ASD with basal E'/A' >1, regional velocities are load-dependent and positively correlate with RV dimension. Because RV Doppler tissue imaging velocities are still in the normal range 1 month after ASD closure, cardiac function does not seem to be affected by the presence of the occluder device.

Early electrical and geometric changes after percutaneous closure of large atrial septal defect.

Cardiac arrhythmias and right chamber enlargement are well known long-term sequelae of atrial septal defect (ASD). Surgical ASD closure relieves patient symptoms but often fails to revert cardiac volume overload findings. Transcatheter ASD closure might be an attractive alternative to surgery, also because of the possibility to study the amount and time-course of the electro-geometric modifications following shunt disappearance. Between March 2000 and December 2002, 24 patients (age 22.7 +16.8 years) underwent percutaneous closure of large ASD (stretched diameter >20 mm and/or QP/QS ratio >1.5:1). ASD closure was performed with the Amplatzer Septal Occluder device (mean 25 +/- 7 mm), achieving a complete occlusion in all patients at 1 month. In 6 patients, right ventricular (RV) monophasic action potential was recorded during the procedure. All patients underwent standard 12-lead electrocardiography and transthoracic echocardiography before and at 24 hours and 1 month after ASD closure. After the procedure, monophasic action potential length increased from 359 +/- 27 to 372 +/- 27 ms (p <0.0001). At 1 month, QT dispersion decreased from 54 +/- 25 to 41 +/- 17 ms (p <0.05), RV diastolic diameter decreased from 42 +/- 6 to 34 +/- 5 mm (p <0.00001), and left ventricular (LV) diastolic diameter increased from 39 +/- 5 to 44 +/- 5 mm (p <0.0001), resulting in a decrease in the RV/LV ratio from 1.11 +/- 0.22 to 0.79 +/- 0.11 (-28.8%, p <0.00001). Electrocardiographic changes, as well as the amount and time-course of RV overload relief, did not significantly differ between pediatric (<16 years of age; n = 11) and adult patients (n = 13). In conclusion, regardless of age at procedure, percutaneous ASD closure results in early striking electrical and geometric cardiac changes that may be beneficial during long-term follow-up.