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Background: Diastolic dysfunction in hypertrophic cardiomyopathy (HCM) is accompanied by augmented left ventricular (LV) end-diastolic pressure, above all in the presence of LV outflow tract (LVOT) obstruction. Increased back-pressure may augment right ventricular (RV) afterload and induce an oxidative metabolic imbalance between the 2 ventricles. The aim was to study right-to-left ventricular oxidative metabolism in HCM and the effects of alcohol septal ablation (ASA)., Methods and Results: Twenty-one HCM patients were enrolled. Eleven healthy subjects served as a control group. Subjects underwent 2-dimensional echocardiography to assess LVOT gradient, left atrial size, and diastolic function. [(11)C]Acetate positron-emission tomography (PET) was performed to determine RVk(2) and LVk(2), as a noninvasive index of oxidative metabolism. Seven HCM patients with LVOT obstruction, scheduled to undergo ASA, were also studied 6 months after the procedure. RVk(2) was higher in HCM patients than i control subjects (0.081 ± 0.021 min(-1) vs. 0.061 ± 0.017 min(-1); P = .05), whereas LVk(2) was similar between groups. Consequently, RVk(2)/LVk(2) was increased in the patients (0.85 ± 0.19 vs 0.59 ± 0.13; P = .004). In patients with obstructive HCM, ASA reduced RVk(2) (0.085 ± 0.021 min(-1) to 0.072 ± 0.022 min(-1); P = .001). Inasmuch as LVk(2) remained unaffected by the procedure, RVk(2)/LVk(2) was decreased after ASA (0.66 ± 0.18; P = .03). The absolute change in LVOT gradient was related to the absolute change in RVk(2) (r = 0.77; P = .044)., Conclusions: In HCM patients, RV oxygen consumption is increased in relation to the LV. ASA reduces RV oxygen consumption in HCM patients with LVOT obstruction, suggesting that increased LV loading conditions and diastolic dysfunction play a predominant role in augmenting RV workload in these patients., (Copyright © 2011 Elsevier Inc. All rights reserved.)

This study investigated the effects of alcohol septal ablation (ASA) on microcirculatory function and myocardial energetics in patients with hypertrophic cardiomyopathy (HCM) and left ventricular outflow tract (LVOT) obstruction. In 15 HCM patients who underwent ASA, echocardiography was performed before and 6 mo after the procedure to assess the LVOT gradient (LVOTG). Additionally, [(15)O]water PET was performed to obtain resting myocardial blood flow (MBF) and coronary vasodilator reserve (CVR). Changes in LV mass (LVM) and volumes were assessed by cardiovascular magnetic resonance imaging. Myocardial oxygen consumption (MVo(2)) was evaluated by [(11)C]acetate PET in a subset of seven patients to calculate myocardial external efficiency (MEE). After ASA, peak LVOTG decreased from 41 ± 32 to 23 ± 19 mmHg (P = 0.04), as well as LVM (215 ± 74 to 169 ± 63 g; P < 0.001). MBF remained unchanged (0.94 ± 0.23 to 0.98 ± 0.15 ml·min(-1)·g(-1); P = 0.45), whereas CVR increased (2.55 ± 1.23 to 3.05 ± 1.24; P = 0.05). Preoperatively, the endo-to-epicardial MBF ratio was lower during hyperemia compared with rest (0.80 ± 0.18 vs. 1.18 ± 0.15; P < 0.001). After ASA, the endo-to-epicardial hyperemic (h)MBF ratio increased to 1.03 ± 0.26 (P = 0.02). ΔCVR was correlated to ΔLVOTG (r = -0.82; P < 0.001) and ΔLVM (r = -0.54; P = 0.04). MEE increased from 15 ± 6 to 20 ± 9% (P = 0.04). Coronary microvascular dysfunction in obstructive HCM is at least in part reversible by relief of LVOT obstruction. After ASA, hMBF and CVR increased predominantly in the subendocardium. The improvement in CVR was closely correlated to the absolute reduction in peak LVOTG, suggesting a pronounced effect of LV loading conditions on microvascular function of the subendocardium. Furthermore, ASA has favorable effects on myocardial energetics.

Purpose: Next to hypertrophy, hypertrophic cardiomyopathy (HCM) is characterized by alterations in myocardial energetics. A small number of studies have shown that myocardial external efficiency (MEE), defined by external work (EW) in relation to myocardial oxidative metabolism (MVO(2)), is reduced. The present study was conducted to identify determinants of MEE in patients with HCM by use of dynamic positron emission tomography (PET) and cardiovascular magnetic resonance imaging (CMR)., Methods: Twenty patients with HCM (12 men, mean age: 55.2 + or - 13.9 years) and 11 healthy controls (7 men, mean age: 48.1 + or - 10 years) were studied with [(11)C]acetate PET to assess MVO(2). CMR was performed to determine left ventricular (LV) volumes and mass (LVM). Univariate and multivariate analyses were employed to determine independent predictors of myocardial efficiency., Results: Between study groups, MVO(2) (controls: 0.12 + or - 0.04 ml x min(-1) x g(-1), HCM: 0.13 + or - 0.05 ml x min(-1) x g(-1), p = 0.64) and EW (controls: 9,139 + or - 2,484 mmHg x ml, HCM: 9,368 + or - 2,907 mmHg x ml, p = 0.83) were comparable, whereas LVM was significantly higher (controls: 99 + or - 21 g, HCM: 200 + or - 76 g, p < 0.001) and MEE was decreased in HCM patients (controls: 35 + or - 8%, HCM: 21 + or - 10%, p < 0.001). MEE was related to stroke volume (SV), LV outflow tract gradient, NH(2)-terminal pro-brain natriuretic peptide (NT-proBNP) and serum free fatty acid levels (all p < 0.05). Multivariate analysis revealed that SV (ss = 0.74, p < 0.001) and LVM (ss = -0.43, p = 0.013) were independently related to MEE., Conclusion: HCM is characterized by unaltered MVO(2), impaired EW generation per gram of myocardial tissue and subsequent deteriorated myocardial efficiency. Mechanical external efficiency could independently be predicted by SV and LVM.

Introduction: Some studies reported an increased incidence of premature ventricular complexes (PVCs) during triggered myocardial contrast echocardiography (MCE) using high-intensity ultrasound destruction. Whether PVCs are also induced by real time MCE using low emission power, is unknown. The aim of the study was to assess the occurrence of arrhythmias during real time adenosine MCE in healthy volunteers and patients with stable coronary artery disease (CAD)., Methods: Fifty healthy volunteers and 26 patients with stable CAD underwent real time MCE using Sonovue and power pulse inversion (ATL 5000) at rest and during adenosine stress. The occurrence of premature atrial complexes (PAC) and PVCs was analyzed before and during MCE using ECG-tracings from videotapes., Results: In healthy subjects, the occurrence of PVCs at baseline (0.04 +/- 0.23 PVCs/min) was similar at rest (0.04 +/- 0.23 PVCs/min, P = NS), and adenosine stress (0.03 +/- 0.14, P = NS). In CAD patients, the occurrence of PVCs at baseline was 0.30 +/- 0.76 PVC/min, compared to 0.29 +/- 0.74 at rest (P = NS), and 0.34 +/- 0.74 during adenosine stress (P = NS). The number of subjects demonstrating PVCs did not increase during MCE. The occurrence of PACs during MCE was not increased compared to baseline., Conclusion: Real time MCE using low emission power does not increase the occurrence of premature complexes in healthy volunteers or CAD patients.

Background: Experimental studies have shown that ultrasound contrast agents enhance the effectiveness of thrombolytic agents in the presence of ultrasound in vitro and in vivo. Recently, we have launched a clinical pilot study, called "Sonolysis", to study this effect in patients with ST-elevation myocardial infarction based on proximal lesions of the infarct-related artery., Methods/design: In our multicenter, randomized, placebo controlled clinical trial we will include patients between 18 and 80 years of age with their first ST-elevation myocardial infarction based on a proximal lesion of the infarct-related artery. After receiving a single bolus alteplase 50 mg IV (Actilyse(R) Boehringer Ingelheim GmbH), a loading dose of aspirin 500 mg, and heparin 5000 IU in the ambulance according to the prehospital thrombolysis protocol, patients, following oral informed consent, are randomized to undergo 15 minutes of pulsatile ultrasound with intravenous administration of ultrasound contrast agent or placebo without ultrasound. Afterwards coronary angiography and, if indicated, percutaneous coronary intervention will take place. A total of 60 patients will be enrolled in approximately 1 year.The primary endpoints are based on the coronary angiogram and consist of TIMI flow, corrected TIMI frame count, and myocardial blush grade. Follow-up includes 12-lead ECG, 2D-echocardiography, cardiac MRI, and enzyme markers to obtain our secondary endpoints, including the infarct size, wall motion abnormalities, and the global left ventricular function., Discussion: The Sonolysis study is the first multicenter, randomized, placebo controlled clinical trial investigating the therapeutic application of ultrasound and microbubbles in acute ST-elevation myocardial infarction patients. A positive finding may stimulate further research and technical innovations to implement the treatment in the ambulance and maybe obtain even more patency at an earlier stage., Trial Registration: Trialregister NTR161.

We hypothesized that relief of obstruction in patients with hypertrophic cardiomyopathy (HC) by percutaneous transluminal septal myocardial ablation (PTSMA) improves microvascular dysfunction by relief of extravascular compression. Microvascular dysfunction in obstructive HC is related to extravascular compression by increased left ventricular (LV) mass and LV end-diastolic pressure. The study included 14 patients with obstructive HC (mean age 55+/-12 years, 11 men) who underwent successful PTSMA and 14 healthy volunteers (mean age 31+/-4 years, 11 men). LV hemodynamics (by Doppler echocardiography) and intramyocardial flow dynamics (by adenosine myocardial contrast echocardiography) were evaluated in healthy volunteers and before and 6 months after PTSMA in patients with HC. LV end-diastolic pressure was estimated from the ratio of transmitral early LV filling velocity to early diastolic mitral annular velocity. PTSMA reduced the invasively measured LV outflow tract gradient (119+/-35 vs 17+/-16 mm Hg, p<0.0001) and LV end-diastolic pressure (23+/-3 vs 16+/-2 mm Hg, p<0.001). Six months after PTSMA, myocardial flow reserve improved (2.73+/-0.56 vs 3.21+/-0.49, p<0.001), but did not normalize compared with healthy controls (vs 3.95+/-0.77, p<0.001). Also, septal hyperemic endo-to-epi myocardial blood flow ratio improved (0.70+/-0.11 vs 0.92+/-0.07, p<0.001). Changes in LV end-diastolic pressure, LV mass index, and LV outflow tract peak systolic gradient correlated well with changes in hyperemic perfusion (all p<0.05). In conclusion, microvascular dysfunction improves after PTSMA due to relief of extravascular compression forces.

Ultrasound (US) contrast agents have gained wide interest in gene therapy as many researchers reported increased membrane permeability and transfection efficiency by sonoporation in the presence of US contrast agents. We recently demonstrated an increase in cell membrane permeability for Ca2+ in rat cardiomyoblast (H9c2) cells insonified in the presence of microbubbles. In the present study, we specifically investigated whether US-exposed microbubbles have an effect on the cell membrane potential and whether Ca2+-dependent potassium (BK(Ca)) channels are involved. We particularly focused on local events where the microbubble was in contact with the cell membrane. H9c2 cells were cultured on US transparent membranes. US exposure consisted of bursts with a frequency of 1 MHz with a peak-to-peak pressure of 0.1 or 0.5 MPa. Pulse repetition frequency was set to 20 Hz, with a duty cycle of 0.2%. Cells were insonified during 30 s in the presence of Sonovue(trade mark) microbubbles. The membrane potential was monitored during US exposure using the fluorescent dye di-4-aminonaphtylethenylpyridinium (di-4-ANEPPS). The experiments were repeated in the presence of iberiotoxin (100 nM), a specific inhibitor of BK(Ca) channels. Surprisingly, despite the previously reported Ca(2+) influx, we found patches of hyperpolarization of the cell membrane, as reflected by local increases in di-4-ANEPPS mean intensity of fluorescence (MIF) to 118.6 +/- 2.5% (p < 0.001, n = 267) at 0.1 MPa and 125.7 +/- 5.9% (p < 0.001, n = 161) at 0.5 MPa at t = 74 s, respectively, compared with "no US" (100.3 +/- 3.4%, n = 52). This hyperpolarization was caused by the activation of BK(Ca) channels, as iberiotoxin completely prevented hyperpolarization. (MIF(t74) = 100.6 +/- 1.4%; p < 0.001, n = 267) and 0.5 MPa (MIF(t74) = 88.8 +/- 2.0%; p< 0.001, n = 193), compared with 0.1 and 0.5 MPa microbubbles without iberiotoxin. In conclusion, US-exposed microbubbles elicit a Ca2+ influx, which leads to activation of BK(Ca) channels and a subsequent, local hyperpolarization of the cell membrane. This local hyperpolarization of the cell membrane may facilitate uptake of macromolecules through endocytosis and macropinocytosis. (E-mail: ljm.juffermans@vumc.nl).

Background: A left bundle branch block (LBBB) affects both global left ventricular (LV) function and mechanical dyssynchrony. The aim was to evaluate global LV function and mechanical dyssynchrony with real-time 3D echocardiography (RT3DE), in asymptomatic LBBB patients, healthy volunteers and patients with symptomatic heart failure (HF) and a LBBB. Furthermore, the relation between presence or absence of symptoms of HF and mechanical dyssynchrony was investigated., Methods: RT3DE was performed in 61 consecutive patients: 16 healthy volunteers, 22 patients with an asymptomatic LBBB and 23 patients with symptomatic HF and a LBBB. Global LV function and the systolic dyssynchrony index (SDI) were measured., Results: In healthy volunteers, mean LV ejection fraction was 54 +/- 5%, in asymptomatic LBBB patients 50 +/- 9%, and in HF patients 29 +/- 9%. SDI was 5.6 +/- 3.6%, 7.3 +/- 3.2% and 12.8 +/- 4.8% for healthy volunteers, asymptomatic LBBB patients and HF patients respectively. SDI differed significantly between HF patients and both other groups. A cut-off value for SDI for presence of symptoms of HF was 10.8%., Conclusion: Asymptomatic LBBB patients have more depressed global LV function than healthy volunteers have; patients with symptoms of HF and a LBBB have severe global LV dysfunction. Asymptomatic LBBB patients have an intermediate mechanical dyssynchrony; HF patients with a LBBB have the most severe mechanical dyssynchrony. A substantial amount of mechanical dyssynchrony might be accompanied by the presence of symptoms of HF.

Objectives: To assess mechanisms of myocardial perfusion impairment in patients with hypertrophic cardiomyopathy (HCM)., Methods: Fourteen patients with obstructive HCM (mean (SD) age 53 (10) years, 11 men) underwent intravenous adenosine myocardial contrast echocardiography (MCE), positron emission tomography (PET) and cardiac catheterisation. Fourteen healthy volunteers (mean age 31 (4) years, 11 men) served as controls. Relative myocardial blood volume (rBV), exchange flow velocity (beta), myocardial blood flow (MBF), MBF reserve (MFR) and endocardial-to-subepicardial (endo-to-epi) MBF ratio were measured from the steady state and contrast replenishment time-intensity curves., Results: Patients with HCM had lower rest MBF (for LVRPP-corrected)--mean (SD) (0.92 (0.12) vs 1.13 (0.25) ml/min/g, p<0.01)--and hyperaemic MBF--(2.56 (0.49) vs 4.34 (0.78) ml/min/g, p<0.01) than controls. Resting rBV was lower in patients with HCM (0.094 (0.016) vs 0.138 (0.014) ml/ml), and during hyperaemia (0.104 (0.018) ml/ml vs 0.185 (0.024) ml/ml) (all p<0.001) than in controls. beta tended to be higher in HCM at rest (9.4 (4.6) vs 7.7 (4.2) ml/min) and during hyperaemia (25.8 (6.4) vs 23.1 (6.2) ml/min) than in controls. Septal endo-to-epi MBF decreased during hyperaemia (0.86 (0.15) to 0.64 (0.18), p<0.01). rBV was inversely correlated with left ventricular (LV) mass index (p<0.05). Both hyperaemic and endo-to-epi MBF were inversely correlated with LV end-diastolic pressure, LV mass index, and LV outflow tract pressure gradient (all p<0.05). MCE-derived MBF correlated well with PET at rest (r = 0.84) and hyperaemia (r = 0.87) (all p<0.001)., Conclusions: In patients with HCM, LV end-diastolic pressure, LV outflow tract pressure gradient, and LV mass index are independent predictors of rBV and hyperaemic MBF.

Cardiac involvement is very common in patients with systemic lupus erythematosus since 30 to 50% of all patients suffer from some sort of heart disease (Lahita, Textbook of rheumatology, 1997). Pericarditis is the most common form of involvement and occurs in 19 to 48% of patients (Lahita, Textbook of rheumatology, 1997). Pleural and/or pericardial pain can occur in any phase of the disease; however, pericardial effusion leading to cardiac tamponade is rare (Lahita, Textbook of rheumatology, 1997; Lee et al., Journal of Korean Medical Science 12(1):75-77, 1997). We report such a case, illustrated by echocardiography.

Objectives: The purpose of this study was to evaluate whether structural left ventricular (LV) abnormalities can be observed in hypertrophic cardiomyopathy (HCM) mutation carriers who have not yet developed echocardiographic signs of hypertrophy by using cardiac magnetic resonance imaging (CMR)., Background: Hypertrophic cardiomyopathy is caused by mutations of genes encoding for sarcomeric proteins. Myocyte disarray and interstitial fibrosis precede the development of regional hypertrophy in HCM mutation carriers (carriers). No macroscopic LV structural abnormalities have been observed in carriers without LV hypertrophy., Methods: A CMR, echocardiogram, and electrocardiogram (ECG) were performed in 16 carriers. Delayed contrast enhancement imaging was used with CMR to detect fibrosis. In 16 age- and gender-matched control subjects, CMR and ECG were performed and an echocardiogram was made when structural abnormalities were detected with CMR. All carriers had an LV wall thickness <13 mm in the year before the study, measured by echocardiography., Results: In 13 carriers (81%), crypts were discerned with CMR in the basal and mid inferoseptal LV wall, not detected by routine echocardiography and not observed in healthy volunteers. In 4 of the crypt-positive carriers, both the echocardiogram and ECG were normal. Two HCM carriers revealed regional hypertrophy of the inferoseptum not detected by echocardiography, and in both carriers, focal fibrosis was present., Conclusions: In carriers who have not yet developed frank hypertrophy, crypts can be detected with CMR in the inferoseptal LV wall, even when echocardiography and ECG are normal. The crypts might represent one of the early pathological alterations of myocardium in carriers that ultimately progress into manifest HCM.

Intravenous myocardial contrast echocardiography (MCE) is a recently developed technique for assessment of myocardial perfusion. Up to now, many studies have demonstrated that the sensitivity and specificity of qualitative assessment of myocardial perfusion by MCE in patients with acute and chronic ischemic heart disease are comparable with other techniques such as cardiac scintigraphy and dobutamine stress echocardiography. Furthermore, quantitative parameters of myocardial perfusion derived from MCE correlate well with the current clinical standard for this purpose, positron emission tomography. Myocardial contrast echocardiography provides a promising and valuable tool for assessment of myocardial perfusion. Although MCE has been primarily performed for medical research, its implementation in routine clinical care is evolving. This article is intended to give an overview of the current status of MCE.

In the present study, we addressed the interactions among ultrasound, microbubbles, and living cells as well as consequent arising bioeffects. We specifically investigated whether hydrogen peroxide (H(2)O(2)) is involved in transient permeabilization of cell membranes in vitro after ultrasound exposure at low diagnostic power, in the presence of stable oscillating microbubbles, by measuring the generation of H(2)O(2) and Ca(2+) influx. Ultrasound, in the absence or presence of SonoVue microbubbles, was applied to H9c2 cells at 1.8 MHz with a mechanical index (MI) of 0.1 or 0.5 during 10 s. This was repeated every minute, for a total of five times. The production of H(2)O(2) was measured intracellularly with CM-H(2)DCFDA. Cell membrane permeability was assessed by measuring real-time changes in intracellular Ca(2+) concentration with fluo-4 using live-cell fluorescence microscopy. Ultrasound, in the presence of microbubbles, caused a significant increase in intracellular H(2)O(2) at MI 0.1 of 50% and MI 0.5 of 110% compared with control (P < 0.001). Furthermore, we found increases in intracellular Ca(2+) levels at both MI 0.1 and MI 0.5 in the presence of microbubbles, which was not detected in the absence of extracellular Ca(2+). In addition, in the presence of catalase, Ca(2+) influx immediately following ultrasound exposure was completely blocked at MI 0.1 (P < 0.01) and reduced by 50% at MI 0.5 (P < 0.001). Finally, cell viability was not significantly affected, not even 24 h later. These results implicate a role for H(2)O(2) in transient permeabilization of cell membranes induced by ultrasound-exposed microbubbles.

Purpose: To prospectively evaluate, by using positron emission tomography (PET) and magnetic resonance (MR) imaging, the interrelationships between regional myocardial fibrosis, perfusion, and contractile function in patients with idiopathic dilated cardiomyopathy (DCM)., Materials and Methods: The study protocol was approved by the hospital ethics committee, and all subjects gave written informed consent. Sixteen patients with idiopathic DCM (mean age, 54 years +/- 11 [standard deviation]; nine men) and six healthy control subjects (mean age, 28 years +/- 2; five men) were examined with PET and MR tissue tagging. Oxygen 15-labeled water and carbon monoxide were used as tracers at PET to assess myocardial blood flow (MBF) and the perfusable tissue index (PTI), which is inversely related to fibrosis. MBF was determined at rest and during pharmacologically induced hyperemia. Maximum circumferential shortening (E(cc)) was determined with MR tissue tagging. Student t tests were performed for comparison of data sets, and linear regression was used to investigate the association between parameters., Results: Mean global hyperemic MBF (2.23 mL/min/mL +/- 0.73), E(cc) (-10.5% +/- 2.9), and PTI (0.95 +/- 0.10) were lower in the patients with DCM than in the control subjects (4.33 mL/min/mL +/- 0.85, -17.4% +/- 0.6, and 1.09 +/- 0.12, respectively; P < .05 for all). In the patients with DCM, regional PTI was related to E(cc) (r = -0.21, P = .009) but not to resting or hyperemic MBF. Furthermore, regional E(cc) was correlated to both resting (r = -0.28, P = .004) and hyperemic MBF (r = -0.29, P < .001). In addition, the ratio of left ventricular end-diastolic volume to mass, as a reflection of wall stress, was related to global hyperemic MBF (r = -0.52, P = .047) and to global E(cc) (r = 0.69, P = .003)., Conclusion: In idiopathic DCM, the extent of myocardial fibrosis is related to the impairment in contractile function, whereas fibrosis and perfusion do not seem to be interrelated. The degree of impairment of hyperemic myocardial perfusion is related to contractility and end-diastolic wall stress., (RSNA, 2006)

Background: Intravenous myocardial contrast echocardiography (ivMCE) has the potential to evaluate myocardial contraction and perfusion simultaneously. The purpose of this study was to assess quantification of myocardial blood flow (MBF) using ivMCE and to compare this with MBF as measured with positron emission tomography (PET)., Methods: A total of 16 healthy volunteers underwent ivMCE using power pulse inversion and contrast agent microbubbles at rest and during pharmacologically induced vasodilation. Microbubble destruction was achieved with a burst of high-energy ultrasound, followed by imaging of contrast replenishment with low-energy ultrasound. Regions of interest were drawn and time intensity curves were calculated that were fitted to a monoexponential function. An estimate of MBF (perfusion estime) was calculated as the product of the plateau value A and the exponential beta describing the replenishment curve. MBF was measured with PET using oxygen-15-labeled water at rest and during adenosine stress., Results: Significant correlations were found between MBF as measured with PET and perfusion estimate as measured with ivMCE in the left anterior descending coronary artery (r = 0.87, P < .01), right coronary artery (r = 0.66, P < .01), and left circumflex artery (r = 0.75, P < .01) territories. Heterogeneity, however, was significantly larger for ivMCE (coefficient of variation 32 +/- 15%) than for PET (9 +/- 6%) measurements (P < .01)., Conclusion: Perfusion parameters as measured with ivMCE correlated with PET-derived MBF, but associated heterogeneity was significantly larger. Currently, this heterogeneity precludes true quantification of MBF using ivMCE.

Paradoxical embolism is a rare cause of myocardial infarction. We present a case of a young man who was admitted to our hospital with an inferior myocardial infarction. Coronary arteriography showed a total distal occlusion of a posterolateral branch of the circumflex artery. Contrast-enhanced echocardiography showed a large atrial septal aneurysm with a patent foramen ovale and massive right-to-left shunting. No other sources of cardiac embolism could be identified. In this case, paradoxical embolism probably has resulted in myocardial infarction.

The introduction of ultrasound contrast agents has led to a marked improvement in diagnostic capabilities in echocardiography. As no serious adverse events were seen during the preclinical development phase, ultrasound contrast agents were thought to be safe. Recently, three fatal and 19 severe, non-fatal adverse reactions were reported in a post marketing analysis of more than 150,000 studies of Sonovue, which has led to the addition of several contra-indications for the use of this ultrasound contrast agent. Although a strong relationship was established between the non-fatal cases and administration of Sonovue, a causal relationship between the fatal cases and the use of Sonovue is debatable. Therefore, the risk associated with the use of this ultrasound contrast agent should be judged carefully, taking into consideration the prevalence of adverse effects of other contrast media and diagnostic procedures used in cardiology.

Although gene therapy has great potential as a treatment for diseases, clinical trials are slowed down by the development of a safe and efficient gene delivery system. In this review, we will give an overview of the viral and nonviral vehicles used for drug and gene delivery, and the different nonviral delivery techniques, thereby focusing on delivery through ultrasound contrast agents. The development of ultrasound contrast agents containing encapsulated microbubbles has increased the possibilities not only for diagnostic imaging, but for therapy as well. Microbubbles have been shown to be able to carry drugs and genes, and destruction of the bubbles by ultrasound will result in local release of their contents. Furthermore, ligands can be attached so that they can be targeted to a specific target tissue. The recent advances of microbubbles as vehicles for delivery of drugs and genes will be highlighted.

The development of ultrasound contrast agents, containing encapsulated microbubbles, has increased the possibilities for diagnostic imaging. Ultrasound contrast agents are currently used to enhance left ventricular opacification, increase Doppler signal intensity, and in myocardial perfusion imaging. Diagnostic imaging with contrast agents is performed with low acoustic pressure using non-linear reflection of ultrasound waves by microbubbles. Ultrasound causes bubble destruction, which lowers the threshold for cavitation, resulting in microstreaming and increased permeability of cell membranes. Interestingly, this mechanism can be used for delivery of drugs or genes into tissue. Microbubbles have been shown to be capable of carrying drugs and genes, and destruction of the bubbles will result in local release of their contents. Recent studies demonstrated the potential of microbubbles and ultrasound in thrombolysis. In this article, we will review the recent advances of microbubbles as a vehicle for delivery of drugs and genes, and discuss possible therapeutic applications in thrombolysis.

Unlabelled: A varying degree of interstitial and perivascular fibrosis is a common finding in idiopathic dilated cardiomyopathy (DCM). The perfusable tissue index (PTI), obtained with PET, is a noninvasive tool for assessing myocardial fibrosis on a regional level. Measurements of the PTI in DCM, however, have not been performed yet. This study was undertaken to test the hypothesis that the PTI is reduced in patients with DCM., Methods: Fifteen patients with an advanced stage of DCM (New York Heart Association class III or IV and left ventricular ejection fraction [LVEF] < 35%) and 11 healthy control subjects were studied. PET was performed using H(2)(15)O and C(15)O to obtain the perfusable tissue fraction (PTF) and the anatomic tissue fraction (ATF), respectively., Results: The PTI (=PTF/ATF) was reduced in DCM compared with control subjects (0.91 +/- 0.12 vs. 1.12 +/- 0.10; P < 0.01). Heterogeneity of the PTI, expressed as the coefficient of variation, was increased in DCM versus that of healthy control subjects (0.18 +/- 0.07 vs. 0.13 +/- 0.06; P < 0.05). There was no correlation between the PTI and echocardiographically derived LVEF in both groups., Conclusion: The PTI was reduced in patients with an advanced stage of DCM. Interstitial and perivascular fibrosis may be responsible for this reduction. Furthermore, the degree of the PTI reduction was variable in DCM patients, both on a regional level and between patients. Noninvasive assessment of fibrosis with the PTI offers the opportunity to evaluate the effects of fibrosis on regional myocardial function, correlate fibrosis with prognosis, and monitor pharmaceutical intervention.