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A 42-year-old man presented after accidental drug overdose complicated by out-of-hospital cardiac arrest. The patient underwent cardiopulmonary resuscitation with successful return of spontaneous circulation and was admitted to the intensive care unit for postcardiac arrest care, which included targeted temperature management (TTM). Urine toxicology screen was positive for cocaine. Initial ECG showed normal sinus rhythm at 84 bpm with incomplete right bundle branch block (RBBB) (figure 1A). During cooling to 33.7°C, ST-segment elevations were noted on the bedside monitor. Follow-up ECG showed sinus bradycardia at 44 bpm with incomplete RBBB, ST-elevations with superimposed J-waves and ‘saddleback appearance’, resembling type …

This study details the development, characterization and non-clinical efficacy of an ultrasound molecular imaging agent intended for molecular imaging of P-selectin in humans. A targeting ligand based on a recently discovered human selectin ligand was manufactured as fusion protein, and activity for human and mouse P- and E-selectin was evaluated by functional immunoassay. The targeting ligand was covalently conjugated to a lipophilic anchor inserted into a phospholipid microbubble shell. Three lots of the targeted microbubble drug product, TS-07-009, were produced, and assays for size distribution, zeta potential and morphology were established. The suitability of TS-07-009 as a molecular imaging agent was evaluated in vitro in a flow-based adhesion assay and in vivo using a canine model of transient myocardial ischemia. Selectivity for P-selectin over E-selectin was observed in both the human and murine systems. Contrast agent adhesion increased with P-selectin concentration in a dynamic adhesion assay. Significant contrast enhancement was observed on ultrasound imaging with TS-07-009 in post-ischemic canine myocardium at 30 or 90 min of re-perfusion. Negligible enhancement was observed in resting (no prior ischemia) hearts or with a control microbubble 90 min after ischemia. The microbubble contrast agent described here exhibits physiochemical properties and in vivo behavior suitable for development as a clinical imaging agent.

Background Effective orifice area (EOA) ≥0.2 cm 2 or regurgitant volume (Rvol) ≥30 mL predicts prognostic significance in functional mitral regurgitation (FMR). Both volumetric and proximal isovelocity surface area (PISA) methods enable calculation of these metrics. To determine their clinical value, we compared EOA and Rvol derived by volumetric and PISA quantitation upon outcome of patients with FMR. Methods and Results We examined the outcome of patients with left ventricular ejection fraction 2 ), Rvol (24.7 versus 16.9 mL), and regurgitant fraction (61 versus 37 %) respectively (all P value 2 or Rvol ≥30 mL had a worse outcome than those with EOA 2 or Rvol P =0.003 and 0.004) but not PISA quantitation (log rank P =0.984 and 0.544), respectively. Conclusions Volumetric and PISA methods yield different measurements of EOA and Rvol in FMR; volumetric values exhibit greater prognostic significance. The echo method of quantifying FMR may affect the management of this disorder.

Functional mitral regurgitation (FMR) is associated with a poor outcome in patients with reduced left ventricular ejection fraction (LVEF). Two recent studies of percutaneous mitral valvular repair therapy reported disparate results, likely due in part to variable risk among FMR patients. The aim of this study is to define echocardiographic factors of prognostic significance in FMR patients, and particularly to compare ischemic and nonischemic FMR. We followed three hundred sixteen consecutive patients (age 60 ± 14 years, men 70%) with FMR and LVEF ≤ 35% between January 2010 and December 2015 (mean follow-up 3.7 years). Patients were categorized into ischemic (39.6%) and nonischemic (60.4%). MR was graded according to the American Society of Echocardiography guidelines. Although echo findings were similar between ischemic and nonischemic patient, the incidence of death, heart transplantation (HT), or LVAD implantation was higher in ischemic than in nonischemic patients (Log rank p = 0.001). In age and gender adjusted multivariate (11 variables) Cox regression analysis, left atrium volume index (LAVI) was associated with death, HT, or LVAD with hazard ratio of 2.1 for patients with FMR (p = 0.003). LAVI greater than 48.7 mL/m2 predicts adverse outcome in both nonischemic and ischemic FMR (AUC 0.62, p

The stethoscope has long been at the center of patient care, as well as a symbol of the physician–patient relationship. While advancements in other diagnostic modalities have allowed for more efficient and accurate diagnosis, the stethoscope has evolved in parallel to address the needs of the modern era of medicine. These advancements include sound visualization, ambient noise reduction/cancellation, Bluetooth (Bluetooth SIG Inc, Kirkland, Wash) transmission, and computer algorithm diagnostic support. However, despite these advancements, the ever-changing climate of infection prevention, especially in the wake of the COVID-19 pandemic, has led many to question the stethoscope as a vector for infectious diseases. Stethoscopes have been reported to harbor bacteria with contamination levels comparable with a physician's hand. Although disinfection is recommended, stethoscope hygiene compliance remains low. In addition, disinfectants may not be completely effective in eliminating microorganisms. Despite these risks, the growing technological integration with the stethoscope continues to make it a highly valuable tool. Rather than casting our valuable tool and symbol of medicine aside, we must create and implement an effective method of stethoscope hygiene to keep patients safe.

Lipoprotein(a) [Lp(a)] is a genetically determined risk factor for calcific aortic valve stenosis (CAVS) for which transcatheter aortic valve replacement (TAVR) is increasingly utilized as treatment. We evaluated the effect of a program to increase testing of and define the prevalence of elevated Lp(a) among patients undergoing TAVR. Educational efforts and incorporation of a “check-box” Lp(a) order to the preoperative TAVR order set were instituted. Retrospective chart review was performed in 229 patients requiring TAVR between May 2013 and September 2018. Of these patients, 57% had an Lp(a) level measured; testing rates increased from 0% in 2013 to 96% in 2018. Lipoprotein(a) testing occurred in 11% of patients before and in 80% of patients after the “check-box” order set ( P < .001). The prevalence of elevated Lp(a) (≥30 mg/dL) was 35%; these patients had a higher incidence of coronary artery disease requiring revascularization compared with patients with normal Lp(a) (65% vs 47%; P = .047). Patients with Lp(a) ≥30 mg/dL also had higher incidence of paravalvular leak compared with those with normal Lp(a) (13% vs 4%; P = .04). This study defines the prevalence of elevated Lp(a) in advanced stages of CAVS and provides a practice pathway to assess procedural complications and long-term outcomes of TAVR in patients with elevated Lp(a) levels.

Lipoprotein(a; Lp[a]) and its associated oxidized phospholipids are causal, genetic risk factors for calcific aortic valve stenosis (CAVS). We determined the prevalence of Lp(a) measurement among 2710 patients with CAVS and 1369 control patients (∼50% of study group) without CAVS with an echocardiogram between January 2010 and February 2016 in an academic echocardiography laboratory. Lipoprotein(a) measurements were performed at a referral laboratory using an isoform-independent assay. The prevalence of any Lp(a) measurement was 4.6% (124 of the 2710) in patients with CAVS and 3.1% (42 of the 1369) in the control group ( P = .021). In patients with CAVS, mean (standard deviation) Lp(a) levels were 38 (54) mg/dL and median (interquartile range) Lp(a) levels were 14 (6-48) mg/dL. Of the 124 patients with CAVS having Lp(a) measurements, 83 (66.9%) had Lp(a)

Studies in persons of European descent have suggested that mitochondrial DNA (mtDNA) haplogroups influence antiretroviral therapy (ART) toxicity. We explored associations between mtDNA variants and changes in endothelial function and biomarkers among non-Hispanic white, ART-naive subjects starting ART. A5152s was a substudy of A5142, a randomized trial of initial class-sparing ART regimens that included efavirenz or lopinavir/ritonavir with nucleoside reverse transcriptase inhibitors (NRTIs), or both without NRTIs. Brachial artery flow-mediated dilation (FMD) and cardiovascular biomarker assessments were performed at baseline and at weeks 4 and 24. Ten haplogroup-defining mtDNA polymorphisms were determined. FMD and biomarker changes from baseline to week 24 by mtDNA variant were assessed using Wilcoxon rank-sum tests. Thirty-nine non-Hispanic white participants had DNA and 24-week data. The nonsynonymous m.10398A>G mtDNA polymorphism (N=8) was associated with higher median baseline adiponectin (5.0 vs. 4.2 μg/ml; p=0.003), greater absolute (−1.9 vs. −0.2 μg/ml) and relative (−33% vs. −3%) adiponectin decreases (p

Background: The LPA gene causes elevated lipoprotein(a) (Lp(a)) levels and causally mediates calcific aortic valve stenosis (AS). Elevated Lp(a) and its associated oxidized phospholipids (OxPL-apoB) predict the progression of pre-existing AS and need for aortic valve replacement and are targets of therapy. Methods: We determined the prevalence and the extent of Lp(a) elevation in patients with AS diagnosed by echocardiography performed at the University of California San Diego between 2010-2015. Severity of AS was classified as critical, severe, moderate, mild, or trace. Lp(a) levels were organized as Lp(a) 100 mg/dL. Results: 2,266 patients with AS were found, with 130 critical, 333 severe, 477 moderate, 1318 mild, and 8 cases of trace AS. Mean age was 75.0 and range 18-106 years. 51% of patients were male. Prevalence of any Lp(a) measurement was 159/2,266 patients (7.02%). The number (%) of patients with an Lp(a) level was: 1) critical (n=4, 3.1%), 2) severe (n=28, 8.4%), 3) moderate (n=56, 11.7%), 4) mild (n=71, 5.4%), and 5) trace (n=0). The extent of Lp(a) elevation within each AS category is in Table 1: 55/159 (34%), 35/159 (22%) and 19/159 (12%) of patients had Lp(a) >30 mg/dL, >50 mg/dL and >100 mg/dL, respectively. Conclusion: Lp(a) was measured in only 7.0% of patients with AS in an academic setting. Given the ongoing development of therapies to lower Lp(a) in patients with AS, educational efforts are needed to raise awareness of Lp(a) as a causal risk factor for AS.

Background Dyslipidemia is a frequent complication of antiretroviral therapy (ART) for patients with human immunodeficiency virus infection (HIV). The effects of ART on lipoproteins are less well-understood, and have not been investigated in a prospective study where assignment to ART is randomized. Objective To evaluate the effects of three class-sparing ART regimens on lipids and lipoproteins. Methods This was a substudy of a prospective, multicenter study of treatment-naive HIV-infected individuals randomly assigned to receive a regimen of nucleoside reverse transcriptase inhibitors (NRTIs) + the non-nucleoside reverse transcriptase inhibitor efavirenz, NRTIs + the protease inhibitor lopinavir/ritonavir, or a NRTI-sparing regimen of efavirenz + lopinavir/ritonavir. Lipoproteins were measured by nuclear magnetic resonance spectroscopy. Results Among the 82 participants, total and small low-density lipoprotein concentrations increased by a median of 152 nmol/L (interquartile range, −49 to +407 nmol/L; P P P KW P P = 0.022). High-density lipoproteins increased by a median of 6.0 nmol/L (interquartile range, 2.8–10.4 nmol/L; P P KW = 0.069). Changes were not related to changes in markers of insulin/glucose metabolism. Conclusions Total and small low-density lipoprotein concentrations increased, especially in the arms containing lopinavir/ritonavir, as did increases in total very-low-density lipoproteins. Adverse changes were especially prominent in the arm with efavirenz + lopinavir/ritonavir.

Objectives This study evaluated the effects of 3 class-sparing antiretroviral therapy (ART) regimens on endothelial function in human immunodeficiency virus (HIV)-infected subjects participating in a randomized trial. Background Endothelial dysfunction has been observed in patients receiving ART for HIV infection. Methods This was a prospective, multicenter study of treatment-naive subjects who were randomly assigned to receive a protease inhibitor-sparing regimen of nucleoside reverse transcriptase inhibitors (NRTIs) + efavirenz, a non-nucleoside reverse transcriptase inhibitor-sparing regimen of NRTIs + lopinavir/ritonavir, or a NRTI-sparing regimen of efavirenz + lopinavir/ritonavir. The NRTIs were lamivudine + stavudine, zidovudine, or tenofovir. Brachial artery flow-mediated dilation (FMD) was determined by B-mode ultrasound before starting on ART, then after 4 and 24 weeks. Results There were 82 subjects (median age 35 years, 91% men, 54% white). Baseline CD4 cell counts and plasma HIV ribonucleic acid (RNA) values were 245 cells/mm3 and 4.8 log10 copies/ml, respectively. At baseline, FMD was 3.68% (interquartile range [IQR] 1.98% to 5.51%). After 4 and 24 weeks of ART, plasma HIV RNA decreased by 2.1 and 3.0 log10 copies/ml, respectively. FMD increased by 0.74% (IQR −0.62% to +2.74%, p = 0.003) and 1.48% (IQR −0.20% to +4.30%, p 0.600). The decrease in plasma HIV RNA at 24 weeks was associated with greater FMD (rs = −0.30, p = 0.017). Conclusions Among treatment-naive individuals with HIV, 3 different ART regimens rapidly improved endothelial function. Benefits were similar for all ART regimens, appeared quickly, and persisted at 24 weeks.

Antiretroviral therapy (ART) in HIV-infected patients has been associated with an increased risk of cardiovascular disease. This study evaluates vascular endothelial dysfunction of the peripheral circulation in Brazilian HIV-infected subjects on ART or naive to ART compared to a control group matched for age and body mass index (BMI). We performed a cross-sectional comparative study to measure postischemic peak flow-mediated dilation (FMD) of the brachial artery and the response to glyceryl trinitrate (GTN) in HIV-infected patients and healthy controls in Salvador, Bahia, Brazil. Endothelial vasomotor function was evaluated by assessing brachial artery FMD. Forty-four HIV-infected individuals (33 ARV treated and 11 ART naive) were compared to 25 healthy controls matched for age and BMI. FMD % was significantly lower for the ART-experienced patients compared to the ART-naive patients and was also significantly different from controls (ART experienced 8.2 +/- 6.0% vs. 19.3 +/- 4.8% vs. 23.3 +/- 6.1%), respectively (p < 0.0001). The cholesterol, triglyceride, and ALT levels were significantly higher in the ART-experienced group compared to the ART-naive and control subjects (p < 0.028); however, linear regression analysis revealed a statistically significant association of endothelial dysfunction as a dependent variable only with ARV treatment in HIV-infected subjects (p = 0.03). The association of endothelial dysfunction with ARV therapy in HIV-infected patients was independent of protease inhibitor-containing regimens or dyslipidemia. This dysfunction may contribute to the risk for HIV-associated atherosclerosis.

Lipoprotein(a) [Lp(a)], comprised of apolipoprotein(a) [apo(a)] and a low-density lipoprotein-like particle, is a genetically determined, causal risk factor for cardiovascular disease and calcific aortic valve stenosis. Lp(a) is the major plasma lipoprotein carrier of oxidized phospholipids, is pro-inflammatory, inhibits plasminogen activation, and promotes smooth muscle cell proliferation, as defined mostly through in vitro studies. Although Lp(a) is not expressed in commonly studied laboratory animals, mouse and rabbit models transgenic for Lp(a) and apo(a) have been developed to address their pathogenicity in vivo. These models have provided significant insights into the pathophysiology of Lp(a), particularly in understanding the mechanisms of Lp(a) in mediating atherosclerosis. Studies in Lp(a)-transgenic mouse models have demonstrated that apo(a) is retained in atheromas and suggest that it promotes fatty streak formation. Furthermore, rabbit models have shown that Lp(a) promotes atherosclerosis and vascular calcification. However, many of these models have limitations. Mouse models need to be transgenic for both apo(a) and human apolipoprotein B-100 since apo(a) does not covalently associated with mouse apoB to form Lp(a). In established mouse and rabbit models of atherosclerosis, Lp(a) levels are low, generally < 20 mg/dL, which is considered to be within the normal range in humans. Furthermore, only one apo(a) isoform can be expressed in a given model whereas over 40 isoforms exist in humans. Mouse models should also ideally be studied in an LDL receptor negative background for atherosclerosis studies, as mice don't develop sufficiently elevated plasma cholesterol to study atherosclerosis in detail. With recent data that cardiovascular disease and calcific aortic valve stenosis is causally mediated by the LPA gene, development of optimized Lp(a)-transgenic animal models will provide an opportunity to further understand the mechanistic role of Lp(a) in atherosclerosis and aortic stenosis and provide a platform to test novel therapies for cardiovascular disease.

Objectives We examined whether delayed post-injection imaging of a new ultrasound contrast agent (BR-14) could produce prolonged opacification and hyperenhancement of myocardium subjected to coronary occlusion/reperfusion. Background We hypothesized that ultrasound exposure destroyed BR-14 and eliminated visualization of sustained myocardial opacification from retained microbubbles. Methods We studied eight open-chest dogs with 3 h of left anterior descending coronary artery (LAD) occlusion followed by 3 h of reperfusion. Myocardial contrast echocardiography (MCE) was performed before occlusion and 120 min after the onset of both occlusion and reperfusion. Ultrasound imaging was initiated 15 min after injection. Myocardial blood flow (MBF) was assessed by microspheres. Results Pre-occlusion images revealed uniform opacification of left ventricular myocardium greater than that of the cavity, with a mean intensity of the LAD bed of 8.66 ± 1.38 dB. During occlusion, MCE resulted in the appearance of a perfusion defect in the LAD risk area (intensity 2.08 ± 1.10 dB). After 120 min of reperfusion, the LAD risk-area myocardium manifested dense opacification of a higher intensity (“hot spot”) than baseline (13.7 vs. 8.7 dB), but with reduced MBF consistent with accumulation of a high concentration of microbubbles. Increased MCE intensity was associated with a greater myeloperoxidase score. Conclusions These data establish that contrast opacification by BR-14 may be selectively retained within the perfusion bed of a coronary artery subjected to occlusion/reperfusion. Such opacification exhibits defects with occlusion, manifests hyperenhanced intensity (hot spot) with reperfusion, is associated with the level of myeloperoxidase activity, and conforms to the area of myocardium subjected to altered flow.

Background —Although defects on intracoronary myocardial contrast echocardiography (MCE) indicate loss of viability after reperfusion, opacified segments may also exhibit persistent dyssynergy. Therefore, we related the intensity and texture of opacification produced by an intravenous contrast agent to histological findings to determine the characteristics of necrotic tissue by postreperfusion MCE. Methods and Results —MCE was performed by intravenous injection of 0.15 mL/kg QW7437 in 14 dogs who underwent 3-hour coronary occlusion followed by 3-hour reperfusion. At baseline and 3 hours after reperfusion, midventricular short-axis images were digitized and segmented. Infarction fraction (IF) for each segment was determined by triphenyltetrazolium chloride stain. Of 224 segments, 140 showed no or small infarction and served as a control group. Of 84 segments with significant infarction (IF>30%), 52 exhibited a defect on MCE, and 32 exhibited no defect. Echo texture was quantified by computing entropy based on the co-occurrence matrix analysis of gray-level pairs within each segment. Three hours after reperfusion, average and maximal entropies in the infarct segments without opacification defects were significantly higher than control levels. Histologically, the degree of intracapillary erythrocyte stasis was less in this group than in the infarcted segments with MCE defects with similar magnitude of tissue injuries. Conclusions —Opacification defects by MCE may be present or absent in myocardium with histologically confirmed infarction. The texture of MCE from opacified but infarcted myocardium differed significantly from control segments and may assist in determination of segmental viability after reperfusion.

Background —The present study (1) compared the ability of power Doppler imaging with that of gray-scale B-mode tissue imaging to opacify the myocardium and detect coronary stenosis by myocardial contrast echocardiography and (2) compared the response of video intensity (VI) to variable pulsing intervals for each modality. Methods and Results —Four grades of left anterior descending coronary artery (LAD) stenoses were created in 9 open-chest dogs. Stenoses reduced resting LAD flow by 25%, 50%, 75%, and 100% of baseline by flow probe. Myocardial contrast echocardiography was performed during varying ECG gated pulsing intervals (PIs) from 1:1 to 1:10. By gray-scale imaging, background-subtracted LAD bed VI was less than baseline VI at all PIs for the 100% reduced-flow state but not for any other flow state or interval. By power Doppler imaging, LAD bed VI was less than baseline VI at all intervals for 75% and 100% reduced-flow states but only 1:1 and 1:2 for 25% and 50% reduced-flow states, respectively. Correlation of VI and myocardial blood flow (determined by use of fluorescent microspheres) ratios from stenosed versus normal beds was stronger by power Doppler imaging. A transmural opacification gradient with stenosis was visualized and measured by power Doppler imaging, but it was insignificant by gray-scale imaging. The ratio of endocardial/epicardial flow determined by use of fluorescent microspheres was correlated with VI by power Doppler imaging at all PIs. Conclusions —Power Doppler imaging has advantages compared with gray-scale imaging in opacifying the myocardium and in detecting coronary stenosis and altered transmural distribution of myocardial perfusion from peak VI. Because VI differences from baseline at long PI vary for mild versus severe (75% and 100%, respectively) reduced-flow states, power Doppler imaging may provide a method to quantify coronary stenoses.

We present a case report of a ruptured sinus of Valsalva aneurysm (SVA) that presented as aortic insufficiency following bacterial endocarditits in a cardiac transplant patient. Cardiac computed tomographic angiography (CCTA) including volume rendered images predicted the appearance of the fistula entrance and defined spatial relationships facilitating the surgical approach. CCTA ability to define the coronary anatomy obviated the need for invasive coronary angiography. The use of this imaging modality especially with three-dimensional spatial visualization, and multiphase cine angiography can add significant value to the care of a patient with ruptured sinus of Valsalva.

To demonstrate the feasibility and quantify the intensity of right ventricular (RV) myocardial opacification by myocardial contrast echocardiography (MCE), we analyzed MCE produced by intravenous injection of 0.15 ml/kg of QW7437 in 8 closed-chest dogs. MCE could produce visual opacification of the RV wall similar in time course to that of the left ventricular wall, and the data supported the potential role of MCE in evaluating RV hypertrophy, contraction, and perfusion abnormalities.

Intermittent ultrasound transmission during contrast echocardiography, so-called transient response imaging (TRI), amplifies contrast intensity. This effect of TRI is attributed to decreased microbubble destruction by reduced exposure time to ultrasound energy. The present study examined the hypothesis that the signal amplification produced by TRI is related to the baseline intensity present in the image and the velocity of flow. We performed second harmonic (2.5/5.0 MHz) imaging during both continuous (frame rate 55 Hz) and electrocardiogram-triggered TRI mode. Contrast images produced by perfluorohexane microbubbles (AF0150) in a steady flow model were obtained every minute throughout the decay phase at transit velocities of 8.1, 6.2, 3.4, 1.9, and 0.7 cm/sec. The decay of videointensity over time could be fitted to a sigmoid curve for both imaging modes with r > 0.99 for individual velocities. The intensity with TRI was greater than that with continuous imaging (CI) at any time and velocity. The mean increase in intensity between modes throughout decay was 8.2 +/- 3.7, 12.8 +/- 4.2, 25.7 +/- 5.8, 49.5 +/- 8.0, and 64.0 +/- 14.4 gray levels for the respective velocity levels studied (p < 0.0001). Although varying with baseline intensity at early and late phases, the TRI amplification plateaued during middecay, and within the intensity range of 16 to 143 gray levels for CI and 67 to 186 gray levels for TRI, it showed no overlap among the different velocity levels. Thus the ability of TRI to enhance contrast opacification is much greater at low flow velocities, which has implications regarding the mechanism of TRI effect and preferential visualization of intramyocardial coronary arteries by this agent. Although this effect was influenced by the baseline intensity, it was relatively constant for each velocity level within an optimal intensity range during middecay, providing the basis for flow velocity measurement by contrast echo.

[Figure][1] [![Graphic][3] ][3] Apical 4-chamber view of the transthoracic echocardiogram demonstrating the apically displaced tricuspid valve leaflet. [![Graphic][4] ][4] Apical 4-chamber view of the transthoracic echocardiogram demonstrating the intertrabecular recesses of

Highly active antiretroviral therapy (HAART) has signi ficantly improved the prognosis of patients with HIV infection; however, the use of protease inhibitors has been associated with increased cardiovascular events and worsening of multiple coronary heart disease risk factors including dyslipidemia, insulin resistance, and endothelial dysfunction. Endothelial dysfunction may be caused by the infection itself, the immunologic responses due to the HIV virus, and also by the effects of HAART through their effects on both lipid and glucose metabolism. The study of endothelial function in HIV infection and its modifications by HAART is an exciting new field in clinical research, limited by multiple factors such as viral factors, immunologic conditions, and metabolic drug effects that could affect the interpretation of endothelial impairment. Further studies are still needed to understand the significance of endothelial dysfunction in the cardiovascular risk assessment of patients with HIV infection.

The HIV epidemic has dramatically changed the paradigm for the development of drug therapy in the last 15 years. The goal is now not only to provide an effective reduction of plasma viremia , but also to reconstitute the immune deficiency due to the progression of the disease. Significant problems with the metabolism of sugars and lipids lead to the appearance of well-documented disorders such as insulin resistance, abnormalities in lipid metabolism and lipodystrophy in those patients on prolonged therapy with antiretrovirals. The question of whether or not HAART-associated lipid disorders contribute to the premature development of coronary artery disease is of major importance for the HIV community. Endothelial injury is associated with disease-related biochemical abnormalities that are implicated in HIV pathogenesis. The exploration of endothelial function began in the early 1980s at the start of the epidemic. The study of endothelial function in HIV infection and its modifications by HAART is an exciting new field in clinical research; in this review the available information on cardiovascular diseases associated with HIV infection and its treatment are discussed.

In a pilot study of 27 patients, those who presented with chest pain underwent 2 dobutamine stress echocardiographic studies, 1 with high mechanical index harmonic imaging to analyze wall motion without contrast and 1 with real-time low mechanical index perfusion imaging with intravenous Optison to assess myocardial perfusion and wall motion. All patients then underwent quantitative coronary angiography. Two independent reviewers demonstrated an improvement in sensitivity when analyzing myocardial perfusion. In the 21 patients who had significant coronary stenoses, 14 had abnormal myocardial perfusion detected at peak stress and 7 had abnormal wall motion detected by standard dobutamine stress echocardiography. There was decreased specificity with perfusion imaging by 1 reviewer. The addition of real-time perfusion imaging after intravenous contrast during dobutamine stress echocardiography has the potential to improve detection of coronary artery disease.

The heart is frequently affected in patients with the acquired immune deficiency syndrome (AIDS). Although the introduction of potent antiretroviral therapy (ART) has produced a sharp decline in mortality and morbidity in HIV-infected patients, the use of ART is associated with the development of peripheral insulin resistance, dyslipidemia, and lipodystrophy. These abnormalities are also associated with coronary artery disease, and numerous reports of myo-cardial infarction in young HIV-infected patients have raised concerns of pre-mature coronary disease in this population. A comprehensive review of the epidemiology of coronary artery disease is given. In recent years, several non-invasive methods to detect early development of atherosclerosis have been evaluated. Two noninvasive techniques using ultrasound have emerged as valid methods to detect early development of atherosclerosis: intima-media thickness and endothelial dysfunction assessed by the measurement of flow-mediated brachial artery dilatation. Multicenter, randomized trials using either technique may provide more information about whether HIV infection alone, long-term HAART use, or both may increase the risks of or accelerate coronary disease in HIV-infected patients.

The heart is an organ frequently affected in patients with acquired immune deficiency syndrome (AIDS). Since the introduction of highly active antiretroviral therapy (HAART), a sharp decline in mortality and morbidity has been observed in human immunodeficiency virus (HIV)-infected patients. However, numerous reports of myocardial infarcts in young HIV-infected patients have raised concerns of premature coronary artery disease in this population. New risk factors for coronary heart disease such as increased insulin resistance, dyslipidemia, and lipodystrophy syndrome, which are associated with HAART, may accelerate underlying arteriosclerosis in HIV-infected patients. Data on the incidence of coronary heart disease are limited to case reports and retrospective studies. Results from ongoing, large, prospective studies will provide information on whether or not HAART may increase the incidence of myocardial infarcts and whether a drastic change in HIV therapy is warranted.

Objectives: Two multicenter studies were conducted to evaluate the safety and efficacy of SonoVue as a contrast agent for enhanced left ventricular endocardial border delineation (LVEBD), and to compare the efficacy of SonoVue and Albunex in adult patients with a suboptimal, nonenhanced echocardiogram. Background: The use of contrast to enhance echocardiographic assessment of LVEBD is well-established. SonoVue is a new microbubble contrast agent that contains sulfur hexafluoride. Methods: Patients were randomized to receive four injections of SonoVue (0.5, 1, 2, and 4 ml), or two injections of Albunex and two injections of hand-agitated saline (0.08 and 0.22 ml/kg). Echocardiographic images were evaluated at the study centers and by four blinded, offsite reviewers for degree of left ventricle opacification (LVO), duration of contrast enhancement, and LVEBD. Results: LVO scores were significantly higher for all doses of SonoVue. Patients with complete LVO ranged from 34%–87% for SonoVue and from 0%–16% for Albunex. The mean duration of useful contrast effect ranged from 0.8–4.1 minutes for SonoVue and < 15 seconds for Albunex. Mean increases in LVEBD scores ranged from 3.8–18.2 for SonoVue and 0.1–4.3 for Albunex. SonoVue (cumulative 7.5 ml dose) was well-tolerated, with a safety profile similar to that observed in the control group. Conclusions: SonoVue is superior to Albunex for improving visualization of endocardial borders in patients with suboptimal noncontrast echocardiograms. Optimal increases in LVEBD, LVO, and duration of useful contrast effect were observed at the 2.0 ml dose of SonoVue.

We performed myocardial contrast echocardography with power Doppler imaging during left anterior descending occlusion in 10 dogs, and found that video intensity and dyssynergy in lateral border zones of ischemic myocardium were present, but the video intensity was significantly lower than adjacent nonischemic zones. The results of this study demonstrate that levels of perfusion and contraction, which are intermediate between normal and central ischemic zones, are observed in the border zone with coronary occlusion by myocardial contrast echocardography, and may have implications in identifying myocardium that will be spared necrosis and in measuring ultimate infarct size.

Background: The electrophysiologic mechanisms of the persistence of atrial fibrillation (AF) after its initiation are not well understood. Therefore, the electrophysiologic charac teristics of the right atrium were evaluated in an acute, pacing-induced model of AF in the pig in order to identify parameters associated with persistence of AF. Methods and Results: AF was induced by rapid atrial pacing in 30 anesthetized, open- chest, juvenile pigs. Sustained (S) AF was defined as that lasting > 10 minutes, nonsustained (NS) AF 30 seconds, and no (N) AF Conclusions: Persistence of AF correlated with shorter ERP and wavelength, and greater dispersion of ERP and electrical remodeling. There was no correlation with CV.

Background —Stimulation of 5-HT 4 receptors increases atrial chronotropic and inotropic responses. Whether other electrophysiological effects are produced is unknown. In humans and swine, 5-HT 4 receptors are present only in atrium. Therefore, the effects of a novel 5-HT 4 receptor antagonist, RS-100302, and the partial agonist cisapride on atrial flutter and fibrillation induced in swine were studied to delineate the role of the 5-HT 4 receptor in modulating atrial electrophysiological properties and the antiarrhythmic potential of RS-100302. Methods and Results —In 17 anesthetized, open-chest, juvenile pigs, atrial flutter or fibrillation was induced by rapid right atrial pacing with or without a right atrial free wall crush injury, respectively. Atrial effective refractory period (ERP), conduction velocity, wavelength, and dispersion of refractoriness were determined during programmed stimulation via a 56-electrode mapping plaque sutured to the right atrial free wall. Ventricular electrophysiological parameters were also measured. All electrophysiological parameters were measured at baseline and after infusion of RS-100302 and cisapride. In the atrium, RS-100302 prolonged mean ERP (115±8 versus 146±7 ms, P P P P Conclusions —The electrophysiological profile of RS-100302 suggests that it may have atrial antiarrhythmic potential without producing ventricular proarrhythmic effects.

Background —The lack of a suitable noninvasive method for assessing right ventricular (RV) volume and function has been a major deficiency of two-dimensional (2D) echocardiography. The aim of our animal study was to test a new real-time three-dimensional (3D) echo imaging system for evaluating RV stroke volumes. Methods and Results —Three to 6 months before hemodynamic and 3D ultrasonic study, the pulmonary valve was excised from 6 sheep (31 to 59 kg) to induce RV volume overload. At the subsequent session, a total of 14 different steady-state hemodynamic conditions were studied. Electromagnetic (EM) flow probes were used for obtaining aortic and pulmonic flows. A unique phased-array volumetric 3D imaging system developed at the Duke University Center for Emerging Cardiovascular Technology was used for ultrasonic imaging. Real-time volumetric images of the RV were digitally stored, and RV stroke volumes were determined by use of parallel slices of the 3D RV data set and subtraction of end-systolic cavity volumes from end-diastolic cavity volumes. Multiple regression analyses showed a good correlation and agreement between the EM-obtained RV stroke volumes (range, 16 to 42 mL/beat) and those obtained by the new real-time 3D method ( r =0.80; mean difference, −2.7±6.4 mL/beat). Conclusions —The real-time 3D system provided good estimation of strictly quantified reference RV stroke volumes, suggesting an important application of this new 3D method.

The ability not only to record automated systolic and diastolic pressure, but also to derive measurements of the rate of pressure change during the cardiac cycle, would have great potential clinical value. A new method has been developed to obtain pressure measurements at 20-ms intervals by oscillometric cuff signal pattern recognition. Derivation of noninvasive pressure measurements is based on a T tube aorta and straight tube brachial artery, and assumes that the systolic phase of the suprasystolic cuff signal and the diastolic phase of the subdiastolic cuff signal most closely approximate systolic and diastolic aortic pressures, respectively. Arterial pressures obtained by this method were compared with simultaneous invasive measurements from the thoracic aorta in 36 patients. Good agreement was observed between noninvasive and invasive methods for systolic (146 +/- 4 vs 145 +/- 5 mm Hg), diastolic (80 +/- 2 vs 77 +/- 2 mm Hg), and mean (100 +/- 3 vs 100 +/- 3 mm Hg) arterial pressures, and correlation coefficients were r = 0.94, 0.91, and 0.95, respectively. To assess the validity of measurements of the rate of pressure change, oscillometric cuff signals from a subgroup of 14 patients were analyzed in detail for the peak positive pressure derivative (dP/dt(Max)), peak negative pressure derivative (dP/dt(Min)), and time interval between peak positive and peak negative pressure derivatives [t(pp)]. Results (mean +/- SEM) were: [table in text]. The incorporation of measurements of the rate of pressure change into a physical model of the brachial artery was used to derive vascular compliance. A significant correlation was observed between vascular compliance derived from the oscillometric signal and determinations by either thermodilution or Fick methods and noninvasive pressures (n = 20, r = 0.83, p0.001). Day-to-day variability for blood pressure and vascular compliance derived by the noninvasive method did not differ by4%, representing a reproducible measure of vascular structure and function. We conclude that the measurement of absolute pressure and rate of pressure change show good correlation with catheter data and that vascular compliance can be reliably assessed by this new method. The technology should provide a valuable noninvasive tool for the assessment of both cardiac function and vascular properties.

Contrast echocardiography has been applied since 1968, when the injection of agitated saline was observed to produce dense ultrasonic reflectances within cavities of the heart and great vessels [1, 2]. However, although intravenous contrast injections opacified the right-sided chambers, left-sided cardiac chambers were not affected due to filtering of the contrast by the lungs. The recognition that the disappearance of the contrast in the lungs was related to the propensity of very small microbubbles to dissolve in blood has led to the development of superior ultrasonic contrast agents with prolonged persistence times. These agents have proven capable of transiting the microcirculation of lungs and myocardium. In addition, instrumentation advances such as harmonic imaging have resulted in amplified signals from contrast compared with those from tissue [4, 5]. These advances have enabled myocardial opacification and vascular structure visualization.

Sustained rapid left ventricular (LV) pacing has been used to induce congestive heart failure, but whether regional myocardial perfusion contributes to the development of myocardial dysfunction is unknown. Therefore, we examined 4 pigs before and sequentially during sustained rapid LV pacing (225 bpm) from the at posterolateral epicardium. We performed myocardial contrast echocardiography (MCE) with left atrial injection of an investigational galactose contrast agent prior to pacing and daily for 4 days after onset of pacing. Pacemakers were inactivated for 60 min prior to data acquisition. The ratio of peak intensity after injection and baseline intensity of region of interest (peak intensity ratio) was measured at 8 segments (Fig) in the short axis view at the tip of papillary muscle using video intensitometry. Percent wall thickening (%WTh) in the interventricular septum (IVS) and posterolateral wall (PLW) were assessed by M-mode echo. Over the 4 days of pacing, the peak intensity ratio progressively decreased in the PLW [region 4 (p l 0.01), 5 (p l 0.001),6 (p l 0.05)] but did not decrease in other regions. Significant regional-specific changes were observed between region 4 vs 8 (p l 0.0002). and region 5 vs 8 (p l 0.0001). Similarly, %WTh in the PLW progressively decreased (p l 0.0001) but was unchanged in the IVS. Conclusion These data suggest that sustained rapid LV pacing produces regional myocardial dysfunction in the initial development of LV failure. Myocardial contrast echocardiography suggests that relative hypoperfusion may contribute to regional myocardial dysfunction in this model. Download : Download high-res image (107KB) Download : Download full-size image

The fact that contrast microbubbles suspended in blood resonate results in the ability to alter the frequency of sound energy reflected by these targets. Therefore, preferential recording of reflected energy at frequencies which are harmonics of the carrier frequency offers the potential to selectively enhance contrast signals. We tested the clinical value of this concept during standard transthoracic echocardiography in 5 pts with organic heart disease (CAD, cardiomyopathy, other). Echo imaging was performed in the apical 4chamber view using a prototype instrument engineered to perform imaging focused about 2.5 or 5.0 megaHertz. Contrast signals were produced by injecting 3000–4000 mg of SHU508 (Levovist) into the brachial vein. For each injection, images were obtained at both 2.5 MHz and its second harmonic. Pts tolerated the injections well without change in BP or heart rate. Contrast echoes were analyzed qualitatively (1 + weak and incomplete opacification, 2+ complete LV filling, 3+ dense and complete filling) and with videointensity measurements. All pts manifested 1+ opacification during regular imaging except for one who showed no LV contrast. With 2nd harmonic imaging all pts were judged to have 2+ signals. Analysis of the ratio of LV cavity to myocardial intensity (gray levels) revealed a ratio of 0.7 ± 0.09 with regular imaging and 5.0 ± 2 with 2nd harmonics. Thus, second harmonic imaging can substantially enhance the relative signal from microbubbles as compared to tissue in patients with cardiac disease. This selective contrast amplification enables more dense and complete opacification of the LV. Second harmonic imaging should prove of value in the clinical application of contrast echocardiography

QW3600 (EG) is a new perflourocarbon (dodecaflouropentane) ultrasonic contrast agent capable of producing myocardial opacification by IV injection. However, the doses required for myocardial visualization have sometimes been associated with transient hemodynamic changes. Therefore, we evaluated the ability of pretreatment with: (1) antihistamines and corticosteroids to eliminate hypersensitivity and thus reduce hemodynamic changes; and (2) administration of coronary vasodilators to enhance myocardial intensity. We performed 2–D echo in the short axis parasternal view in 10 closed chest ventilated dogs in whom LV, Ao and pulmonary artery catheters enabled direct assessment of hemodynamics. All animals were given benadryl 1 mg/kg and Solu-Mediol 1 mg/kg approximately one hour prior to the study. Subsequently, a 0.5 cc/kg EchoGen®injection was repeated. Contrast intensity was quantified by a 0.3 cm2region of interest positioned in the midventricular wall and peak videointensity (PVI) was measured in gray levels. Results *= p l 0.01 for EG vs DIP + EG. HR FA (S) FA (D) LV PA PVI BASE 145 ± 23 172 ± 14 120 ± 7 165 ± 12 122 ± 6 23 ± 18 EG 150 ± 24 163 ± 13 114 ± 7 159 ± 13 28 ± 10 69 ± 50 DIP 142 ± 19 171 ± 14 114 ± 15 162 ± 23 24 ± 3 33 ± 21 DIP + EG 145 ± 23 156 ± 31 99 ± 21 145 ± 32 32 ± 4 110 ± 41 Thus, combination of antihistamine-steriod pretreatment and dipyridamole vasodilation enables enhanced visualization of myocardial perfusion by reduced doses of EG without significant hemodynamic effects. This approach may be of value in achieving myocardial opacification in patients with EG without incurring side effects.

QW 3600 (EchoGen®) (EG) is a new ultrasonic contrast agent which produces intense LV cavity and even myocardial opacification following IV injection in animals. However, no data exists regarding the potential of this agent to be used in conjunction with stress echo in humans. Therefore, in 17 normals we compared the results of injecting equal volumes of normal saline and progressive doses of EG: 0.02 cc/kg (5 pts). 0.05cc/kg (4). and 0.1cc/kg (8) during stress echo performed to 85% of maximal heart rate. Echo was performed in apical 4 chamber view, and LV contrast opacification was assessed qualitatively (1 + weak and incomplete, 2+ complete cavity. 3+dense and complete) and by videodensitometry (0.3cm2) region of interest in mid cavity. All subjects tolerated the injections well without adverse events. No significant changes were observed in pulse oximetry, the ECG, or 25 laboratory studies. We analyzed the maximal change (Δ) in systolic (S) and diastolic (D) pressure (mmHg) and heart rate (HR) and peak videointensity (PVI) from baseline to post exertion following the injection of either saline or EG (Table, all p=NS for saline vs EG except PVI)DoseSalineEGΔHRΔSBPΔDBPPVIΔHRΔSBPΔDBPPVI0.0248431813424917280.0537351611434321420.13740191037441962LV opacification was absent with saline, was inconsistent at 0.02 and 0.05cc/kg doses, but was≥ 2+ in all but one 0.1cc/kg administration (mean 2.4). Peak LV videointensity after EG was 62 for 0.1cc/kg. Thus, EchoGen® is a new contrast agent which is well tolerated when used with stress echo in normals and results in complete LV opacification at a dose of 0.1cc/kg. EchoGen® should prove to be a useful adjunct to clinical stress echo.