Monocyte imaging after myocardial infarction with 19F MRI at 3 T: a pilot study in explanted porcine hearts.

AIM: Inflammation is a hallmark of cardiac healing after myocardial infarction and it determines subsequent cardiovascular morbidity and mortality. The aim of the present study was to explore whether inflammation imaging with two perfluorocarbon (PFC) nanoemulsions and fluorine magnetic resonance imaging ((19)F MRI) is feasible at 3.0 T with sufficient signal-to-noise ratio (SNR) using explanted hearts, an (19)F surface coil and dedicated MR sequences. METHODS AND RESULTS: Acute myocardial infarction (AMI) was induced by balloon angioplasty (50 min) of the distal left anterior descending artery in 12 pigs. One day thereafter, PFCs were injected intravenously to label circulating monocytes. Either emulsified perfluoro-15-crown-5 ether or already clinically applied perfluorooctyl bromide (PFOB) was applied. Four days after AMI and immediately after gadolinium administration, hearts were explanted and imaged with a 3.0 T Achieva MRI scanner. (19)F MRI could be acquired with an SNR of >15 using an in-plane resolution of 2 × 2 mm(2) within <20 min for both agents. Combined late gadolinium enhancement (LGE) and (19)F MRI revealed that (19)F signal was inhomogenously distributed across LGE myocardium reflecting patchy macrophage infiltration as confirmed by histology. In whole hearts, we found an apico-basal (19)F gradient within LGE-positive myocardium. The (19)F-positive volume was always smaller than LGE volume. Ex vivo experiments on isolated monocytes revealed that pig and human cells phagocytize PFCs even more avidly than mouse monocytes. CONCLUSION: This pilot study demonstrates that (19)F MRI at 3.0 T with clinically applicable PFOB is feasible, thus highlighting the potential of (19)F MRI to monitor the inflammatory response after AMI.

Ccr1 deficiency reduces inflammatory remodelling and preserves left ventricular function after myocardial infarction.

Myocardial necrosis triggers inflammatory changes and a complex cytokine cascade that are only incompletely understood. The chemokine receptor CCR1 mediates inflammatory recruitment in response to several ligands released by activated platelets and up-regulated after myocardial infarction (MI). Here, we assess the effect of CCR1 on remodelling after MI using Ccr1-deficient (Ccr1(-)(/-)) mice. MI was induced in Ccr1(-/-) or wild-type mice by proximal ligation of the left anterior descending (LAD). Mice were sacrificed and analysed at day 1, 4, 7, 14 and 21 after MI. While initial infarct areas and areas at risk did not differ between groups, infarct size increased to 20.6+/-8.4% of the left ventricle (LV) in wild-type mice by day 21 but remained at 11.2+/-1.2% of LV (P<0.05) in Ccr1(-/-) mice. This attenuation in infarct expansion was associated with preserved LV function, as analysed by isolated heart studies according to Langendorff. Left ventricular developed pressure was 84.5+/-19.8 mmHg in Ccr1(-/-) mice compared to 49.0+/-19.7 mmHg in wild-type mice (P<0.01) and coronary flow reserve was improved in Ccr1(-/-) mice. An altered post-infarct inflammatory pattern was observed in Ccr1(-/-) mice characterized by diminished neutrophil infiltration, accelerated monocyte/lymphocyte infiltration, decreased apoptosis, increased cell proliferation and earlier myofibroblast population in the infarcted tissue. In conclusion, functional impairment and structural remodelling after MI is reduced in the genetic absence of Ccr1 due to an abrogated early inflammatory recruitment of neutrophils and improved tissue healing, thus revealing a potential therapeutic target.

Sepsis and the heart.

Sepsis is generally viewed as a disease aggravated by an inappropriate immune response encountered in the afflicted individual. As an important organ system frequently compromised by sepsis and always affected by septic shock, the cardiovascular system and its dysfunction during sepsis have been studied in clinical and basic research for more than 5 decades. Although a number of mediators and pathways have been shown to be associated with myocardial depression in sepsis, the precise cause remains unclear to date. There is currently no evidence supporting global ischemia as an underlying cause of myocardial dysfunction in sepsis; however, in septic patients with coexistent and possibly undiagnosed coronary artery disease, regional myocardial ischemia or infarction secondary to coronary artery disease may certainly occur. A circulating myocardial depressant factor in septic shock has long been proposed, and potential candidates for a myocardial depressant factor include cytokines, prostanoids, and nitric oxide, among others. Endothelial activation and induction of the coagulatory system also contribute to the pathophysiology in sepsis. Prompt and adequate antibiotic therapy accompanied by surgical removal of the infectious focus, if indicated and feasible, is the mainstay and also the only strictly causal line of therapy. In the presence of severe sepsis and septic shock, supportive treatment in addition to causal therapy is mandatory. The purpose of this review is to delineate some characteristics of septic myocardial dysfunction, to assess the most commonly cited and reported underlying mechanisms of cardiac dysfunction in sepsis, and to briefly outline current therapeutic strategies and possible future approaches.

Myoglobin: A scavenger of bioactive NO.

The present study explored the role of myoglobin (Mb) in cardiac NO homeostasis and its functional relevance by employing isolated hearts of wild-type (WT) and myoglobin knockout mice. (1)H NMR spectroscopy was used to measure directly the conversion of oxygenated Mb (MbO(2)) to metmyoglobin (metMb) by reaction with NO. NO was applied intracoronarily (5 nM to 25 microM), or its endogenous production was stimulated with bradykinin (Bk; 10 nM to 2 microM). We found that infusion of authentic NO solutions dose-dependently (>/= 2.5 microM NO) increased metMb formation in WT hearts that was rapidly reversible on cessation of NO infusion. Likewise, Bk-induced release of NO was associated with significant metMb formation in the WT (>/=1 microM Bk). Hearts lacking Mb reacted more sensitively to infused NO in that vasodilatation and the cardiodepressant actions of NO were more pronounced. Similar results were obtained with Bk. The lower sensitivity of WT hearts to changes in NO concentration fits well with the hypothesis that in the presence of Mb, a continuous degradation of NO takes place by reaction of MbO(2) + NO to metMb + NO(3)(-), thereby effectively reducing cytosolic NO concentration. This breakdown protects myocytic cytochromes against transient rises in cytosolic NO. Regeneration of metMb by metMb reductase to Mb and subsequent association with O(2) leads to reformation of MbO(2) available for another NO degradation cycle. Our data indicate that this cycle is crucial in the breakdown of NO and substantially determines the dose-response curve of the NO effects on coronary blood flow and cardiac contractility.

Transthoracic echocardiography using second harmonic imaging: diagnostic alternative to transesophageal echocardiography for the detection of atrial right to left shunt in patients with cerebral embolic events.

OBJECTIVES: We sought to evaluate whether transthoracic contrast echocardiography using second harmonic imaging (SHI) is a diagnostic alternative to transesophageal contrast echocardiography (TEE) for the detection of atrial right to left shunt. BACKGROUND: Paradoxic embolism is considered to be the major cause of cerebral ischemic events in young patients. Contrast echocardiography using TEE has proven to be superior to transthoracic echocardiography (TTE) for the detection of atrial shunting, SHI is a new imaging modality that enhances the visualization of echocardiographic contrast agents. METHODS: We evaluated 111 patients with an ischemic cerebral embolic event for the presence of atrial right to left shunt using an intravenous (IV) contrast agent in combination with three different echocardiographic imaging modalities: 1) TTE using fundamental imaging (FI); 2) TTE using SHI; and 3) TEE. The severity of atrial shunting and the duration of contrast visibility within the left heart chambers were evaluated for each imaging modality. Image quality was assessed separately for each modality by semiquantitative scoring (0 = poor to 3 = excellent). Presence of atrial right to left shunt was defined as detection of contrast bubbles in the left atrium within the first three cardiac cycles after contrast appearance in the right atrium either spontaneously or after the Valsalva maneuver. RESULTS: A total of 57 patients showed evidence of atrial right to left shunt with either imaging modality. Fifty-one studies were positive with TEE, 52 studies were positive with SHI, and 32 were positive with FI (p<0.001 for FI vs. SHI and TEE). The severity of contrast passage was significantly larger using SHI (61.6+/-80.2 bubbles) compared to FI (53.7+/-69.6 bubbles; p<0.005 vs. SHI) but was not different compared to TEE (43.9+/-54.3 bubbles; p = NS vs. SHI). The duration of contrast visibility was significantly longer for SHI (17.4+/-12.4 s) compared to FI (13.1+/-9.7 s; p<0.001) and TEE (11.9+/-9.6 s; p<0.02). Mean image quality improved significantly from FI (1.5+/-0.8) to SHI (2.0+/-0.8; p<0.001 vs. FI) and TEE (2.5+/-0.7; p<0.001 vs. SHI). CONCLUSIONS: In combination with IV contrast injections, TEE and SHI have a comparable yield for the detection of atrial right to left shunt. Both modalities may miss patients with atrial shunting. In young patients with an unexplained cerebrovascular event and no clinical evidence of cardiac disease, a positive SHI study may obviate the need to perform a TEE study to search for cardiac sources of emboli.