Chapter 1: The Astrobiology Primer 3.0.

The Astrobiology Primer 3.0 (ABP3.0) is a concise introduction to the field of astrobiology for students and others who are new to the field of astrobiology. It provides an entry into the broader materials in this supplementary issue of Astrobiology and an overview of the investigations and driving hypotheses that make up this interdisciplinary field. The content of this chapter was adapted from the other 10 articles in this supplementary issue and thus represents the contribution of all the authors who worked on these introductory articles. The content of this chapter is not exhaustive and represents the topics that the authors found to be the most important and compelling in a dynamic and changing field.

Chapter 2: What Is Life?

The question "What is life?" has existed since the beginning of recorded history. However, the scientific and philosophical contexts of this question have changed and been refined as advancements in technology have revealed both fine details and broad connections in the network of life on Earth. Understanding the framework of the question "What is life?" is central to formulating other questions such as "Where else could life be?" and "How do we search for life elsewhere?" While many of these questions are addressed throughout the Astrobiology Primer 3.0, this chapter gives historical context for defining life, highlights conceptual characteristics shared by all life on Earth as well as key features used to describe it, discusses why it matters for astrobiology, and explores both challenges and opportunities for finding an informative operational definition.

Subtle structural differences of nucleotide analogs may impact SARS-CoV-2 RNA-dependent RNA polymerase and exoribonuclease activity.

The rapid spread and public health impact of the novel SARS-CoV-2 variants that cause COVID-19 continue to produce major global impacts and social distress. Several vaccines were developed in record time to prevent and limit the spread of the infection, thus playing a pivotal role in controlling the pandemic. Although the repurposing of available drugs attempts to provide therapies of immediate access against COVID-19, there is still a need for developing specific treatments for this disease. Remdesivir, molnupiravir and Paxlovid remain the only evidence-supported antiviral drugs to treat COVID-19 patients, and only in severe cases. To contribute on the search of potential Covid-19 therapeutic agents, we targeted the viral RNA-dependent RNA polymerase (RdRp) and the exoribonuclease (ExoN) following two strategies. First, we modeled and analyzed nucleoside analogs sofosbuvir, remdesivir, favipiravir, ribavirin, and molnupiravir at three key binding sites on the RdRp-ExoN complex. Second, we curated and virtually screened a database containing 517 nucleotide analogs in the same binding sites. Finally, we characterized key interactions and pharmacophoric features presumably involved in viral replication halting at multiple sites. Our results highlight structural modifications that might lead to more potent SARS-CoV-2 inhibitors against an expansive range of variants and provide a collection of nucleotide analogs useful for screening campaigns.

Structural Analysis of Monomeric RNA-Dependent Polymerases Revisited.

In the past few years, our understanding of the RNA virosphere has changed dramatically due to the growth and spurt of metagenomics, exponentially increasing the number of RNA viral sequences, and providing a better understanding of their range of potential hosts. As of today, the only conserved protein among RNA viruses appears to be the monomeric RNA-dependent RNA polymerase. This enzyme belongs to the right-hand DNA-and RNA polymerases, which also includes reverse transcriptases and eukaryotic replicative DNA polymerases. The ubiquity of this protein in RNA viruses makes it a unique evolutionary marker and an appealing broad-spectrum antiviral target. In this work pairwise structural comparisons of viral RdRps and RTs were performed, including tertiary structures that have been obtained in the last few years. The resulting phylogenetic tree shows that the RdRps from (+)ss- and dsRNA viruses might have been recruited several times throughout the evolution of mobile genetic elements. RTs also display multiple evolutionary routes. We have identified a structural core comprising the entire palm, a large moiety of the fingers and the N-terminal helices of the thumb domain, comprising over 300 conserved residues, including two regions that we have named the "knuckles" and the "hypothenar eminence". The conservation of an helix bundle in the region preceding the polymerase domain confirms that (-)ss and dsRNA Reoviruses' polymerases share a recent ancestor. Finally, the inclusion of DNA polymerases into our structural analyses suggests that monomeric RNA-dependent polymerases might have diverged from B-family polymerases.

Two short low complexity regions (LCRs) are hallmark sequences of the Delta SARS-CoV-2 variant spike protein.

Low complexity regions (LCRs) are protein sequences formed by a set of compositionally biased residues. LCRs are extremely abundant in cellular proteins and have also been reported in viruses, where they may partake in evasion of the host immune system. Analyses of 28,231 SARS-CoV-2 whole proteomes and of 261,051 spike protein sequences revealed the presence of four extremely conserved LCRs in the spike protein of several SARS-CoV-2 variants. With the exception of Iota, where it is absent, the Spike LCR-1 is present in the signal peptide of 80.57% of the Delta variant sequences, and in other variants of concern and interest. The Spike LCR-2 is highly prevalent (79.87%) in Iota. Two distinctive LCRs are present in the Delta spike protein. The Delta Spike LCR-3 is present in 99.19% of the analyzed sequences, and the Delta Spike LCR-4 in 98.3% of the same set of proteins. These two LCRs are located in the furin cleavage site and HR1 domain, respectively, and may be considered hallmark traits of the Delta variant. The presence of the medically-important point mutations P681R and D950N in these LCRs, combined with the ubiquity of these regions in the highly contagious Delta variant opens the possibility that they may play a role in its rapid spread.

Structural analysis of viral ExoN domains reveals polyphyletic hijacking events.

Nidoviruses and arenaviruses are the only known RNA viruses encoding a 3'-5' exonuclease domain (ExoN). The proofreading activity of the ExoN domain has played a key role in the growth of nidoviral genomes, while in arenaviruses this domain partakes in the suppression of the host innate immune signaling. Sequence and structural homology analyses suggest that these proteins have been hijacked from cellular hosts many times. Analysis of the available nidoviral ExoN sequences reveals a high conservation level comparable to that of the viral RNA-dependent RNA polymerases (RdRp), which are the most conserved viral proteins. Two highly preserved zinc fingers are present in all nidoviral exonucleases, while in the arenaviral protein only one zinc finger can be identified. This is in sharp contrast with the reported lack of zinc fingers in cellular ExoNs, and opens the possibility of therapeutic strategies in the struggle against COVID-19.

Sofosbuvir as a potential alternative to treat the SARS-CoV-2 epidemic.

As of today, there is no antiviral for the treatment of the SARS-CoV-2 infection, and the development of a vaccine might take several months or even years. The structural superposition of the hepatitis C virus polymerase bound to sofosbuvir, a nucleoside analog antiviral approved for hepatitis C virus infections, with the SARS-CoV polymerase shows that the residues that bind to the drug are present in the latter. Moreover, a multiple alignment of several SARS-CoV-2, SARS and MERS-related coronaviruses polymerases shows that these residues are conserved in all these viruses, opening the possibility to use sofosbuvir against these highly infectious pathogens.

A yellow flag on the horizon: The looming threat of yellow fever to North America.

OBJECTIVES: Yellow fever virus historically was a frequent threat to American and European coasts. Medical milestones such as the discovery of mosquitoes as vectors and subsequently an effective vaccine significantly reduced its incidence, in spite of which, thousands of cases of this deathly disease still occur regularly in Sub-Saharan Africa and the Amazonian basin in South America, which are usually not reported. An urban outbreak in Angola, consecutive years of increasing incidence near major Brazilian cities, and imported cases in China, South America and Europe, have brought this virus back to the global spotlight. The aim of this article is to underline that the preventive YFV measures, such as vaccination, need to be carefully revised in order to minimize the risks of new YFV outbreaks, especially in urban or immunologically vulnerable places. Furthermore, this article highlights the diverse factors that have favored the spread of other Aedes spp.-associated arboviral diseases like Dengue, Chikungunya and Zika, to northern latitudes causing epidemics in the United States and Europe, emphasizing the possibility that YFV might follow the path of these viruses unless enhanced surveillance and efficient control systems are urgently initiated.

Are RNA Viruses Candidate Agents for the Next Global Pandemic? A Review.

Pathogenic RNA viruses are potentially the most important group involved in zoonotic disease transmission, and they represent a challenge for global disease control. Their biological diversity and rapid adaptive rates have proved to be difficult to overcome and to anticipate by modern medical technology. Also, the anthropogenic change of natural ecosystems and the continuous population growth are driving increased rates of interspecies contacts and the interchange of pathogens that can develop into global pandemics. The combination of molecular, epidemiological, and ecological knowledge of RNA viruses is therefore essential towards the proper control of these emergent pathogens. This review outlines, throughout different levels of complexity, the problems posed by RNA viral diseases, covering some of the molecular mechanisms allowing them to adapt to new host species-and to novel pharmaceutical developments-up to the known ecological processes involved in zoonotic transmission.

Structural Analysis of Monomeric RNA-Dependent Polymerases: Evolutionary and Therapeutic Implications.

The crystal structures of monomeric RNA-dependent RNA polymerases and reverse transcriptases of more than 20 different viruses are available in the Protein Data Bank. They all share the characteristic right-hand shape of DNA- and RNA polymerases formed by the fingers, palm and thumb subdomains, and, in many cases, "fingertips" that extend from the fingers towards the thumb subdomain, giving the viral enzyme a closed right-hand appearance. Six conserved structural motifs that contain key residues for the proper functioning of the enzyme have been identified in all these RNA-dependent polymerases. These enzymes share a two divalent metal-ion mechanism of polymerization in which two conserved aspartate residues coordinate the interactions with the metal ions to catalyze the nucleotidyl transfer reaction. The recent availability of crystal structures of polymerases of the Orthomyxoviridae and Bunyaviridae families allowed us to make pairwise comparisons of the tertiary structures of polymerases belonging to the four main RNA viral groups, which has led to a phylogenetic tree in which single-stranded negative RNA viral polymerases have been included for the first time. This has also allowed us to use a homology-based structural prediction approach to develop a general three-dimensional model of the Ebola virus RNA-dependent RNA polymerase. Our model includes several of the conserved structural motifs and residues described in other viral RNA-dependent RNA polymerases that define the catalytic and highly conserved palm subdomain, as well as portions of the fingers and thumb subdomains. The results presented here help to understand the current use and apparent success of antivirals, i.e. Brincidofovir, Lamivudine and Favipiravir, originally aimed at other types of polymerases, to counteract the Ebola virus infection.

Evaluation of the endothelial function in hypertensive patients with 13N-ammonia PET.

BACKGROUND: Essential hypertension is one of the main risk factors for the development of coronary artery disease (CAD). Hypertension causes endothelial dysfunction which is considered an early sign for the development of CAD. Positron emission tomography is a non-invasive imaging technique that measures myocardial blood flow (MBF), allowing us to identify patients with endothelial dysfunction. METHODS AND RESULTS: 19 patients without comorbidities recently diagnosed hypertensive, as well as 21 healthy volunteers were studied. A three-phase (rest, cold pressor test, and adenosine-induced hyperemia) (13)N-ammonia PET was performed, and MBF was measured. Endothelial-Dependent Vasodilation Index, ΔMBF, and coronary flow reserve (CFR) were calculated for each patient. Hypertensive patients had a significantly higher systolic and diastolic blood pressures compared with the control group (134.6 ± 11.7/86.4 ± 10.6 mm Hg and 106.0 ± 11.8/71.4 ± 6.6 mm Hg, respectively, P < .001). The ENDEVI (1.28 ± 0.26 vs 1.79 ± 0.30, P < .001), the ΔMBF (0.81 ± 0.50 vs 0.25 ± 0.21, P < .001) and the CFR (2.18 ± 0.88 vs 3.17 ± 0.68, P = .001) were significantly lower in the hypertensive patients compared to the control group, 84% of the former group had endothelial dysfunction i.e., ENDEVI < 1.5 and 58% had vasomotor abnormalities, i.e., CFR < 2.5. CONCLUSIONS: In this study, we showed that recently diagnosed hypertensive patients have coronary endothelial dysfunction and vasomotor disturbances which are early signs for the development of CAD.

Automatic alignment of myocardial perfusion PET and 64-slice coronary CT angiography on hybrid PET/CT.

BACKGROUND: Hybrid PET/CT allows for acquisition of cardiac PET and coronary CT angiography (CCTA) in one session. However, PET and CCTA are acquired with differing breathing protocols and require software registration. We aimed to validate automatic correction for breathing misalignment between PET and CCTA acquired on hybrid scanner. METHODS: Single-session hybrid PET/CT studies of rest/stress (13)N-ammonia PET and CCTA in 32 consecutive patients were considered. Automated registration of PET left ventricular (LV) surfaces with CCTA volumes was evaluated by comparing with expert manual alignment by two observers. RESULTS: The average initial misalignments between the position of LV on PET and CCTA were 27.2 ± 11.8, 13.3 ± 11.5, and 14.3 ± 9.1 mm in x, y, and z axes on rest, and 26.3 ± 10.2, 11.1 ± 9.5, and 11.7 ± 7.1 mm in x, y, and z axes on stress, respectively. The automated PET-CCTA co-registration had 95% agreement as judged visually. Compared with expert manual alignment, the translation errors of the algorithm were 5.3 ± 2.8 mm (rest) and 6.0 ± 3.5 mm (stress). 3D visualization of combined coronary vessel anatomy and hypoperfusion from PET could be made without further manual adjustments. CONCLUSION: Software co-registration of CCTA and PET myocardial perfusion imaging on hybrid PET/CT scanners is necessary, but can be performed automatically, facilitating integrated 3D display on PET/CT.

Comparison of clinical tools for measurements of regional stress and rest myocardial blood flow assessed with 13N-ammonia PET/CT.

UNLABELLED: Several models for the quantitative analysis of myocardial blood flow (MBF) at stress and rest and myocardial flow reserve (MFR) with (13)N-ammonia myocardial perfusion PET have been implemented for clinical use. We aimed to compare quantitative results obtained from 3 software tools (QPET, syngo MBF, and PMOD), which perform PET MBF quantification with either a 2-compartment model (QPET and syngo MBF) or a 1-compartment model (PMOD). METHODS: We considered 33 adenosine stress and rest (13)N-ammonia studies (22 men and 11 women). Average age was 54.5 ± 15 y, and average body mass index was 26 ± 4.2. Eighteen patients had a very low likelihood of disease, with no chest pain, normal relative perfusion results, and normal function. All data were obtained on a PET/CT scanner in list mode with CT attenuation maps. Sixteen dynamic frames were reconstructed (twelve 10-s, two 30-s, one 1-min, and one 6-min frames). Global and regional stress and rest MBF and MFR values were obtained with each tool. Left ventricular contours and input function region were obtained automatically in system QPET and syngo MBF and manually in PMOD. RESULTS: The flow values and MFR values were highly correlated among the 3 packages (R(2) ranging from 0.88 to 0.92 for global values and from 0.78 to 0.94 for regional values. Mean reference MFR values were similar for QPET, syngo MBF, and PMOD (3.39 ± 1.22, 3.41 ± 0.76, and 3.66 ± 1.19, respectively) by 1-way ANOVA (P = 0.74). The lowest MFR in very low likelihood patients in any given vascular territory was 2.25 for QPET, 2.13 for syngo MBF, and 2.23 for PMOD. CONCLUSION: Different implementations of 1- and 2-compartment models demonstrate an excellent correlation in MFR for each vascular territory, with similar mean MFR values.

Coenzymes, viruses and the RNA world.

The results of a detailed bioinformatic search for ribonucleotidyl coenzyme biosynthetic sequences in DNA- and RNA viral genomes are presented. No RNA viral genome sequence available as of April 2011 appears to encode for sequences involved in coenzyme biosynthesis. In both single- and double-stranded DNA viruses a diverse array of coenzyme biosynthetic genes has been identified, but none of the viral genomes examined here encodes for a complete pathway. Although our conclusions may be constrained by the unexplored diversity of viral genomes and the biases in the construction of viral genome databases, our results do not support the possibility that RNA viruses are direct holdovers from an ancient RNA/protein world. Extrapolation of our results to evolutionary epochs prior to the emergence of DNA genomes suggest that during those early stages living entities may have depended on discontinuous genetic systems consisting of multiple small-size RNA sequences.

[The importance of multi-imaging diagnosis in cardiology]. / La importancia del diagnóstico multi-imagen en cardiología.

Cardiovascular imaging is one of the disciplines in cardiology with the most recent advances. This means that the teaching of Cardiology must evolve in the same way. In 2009, the American College of Cardiology published a statement, which points out that all of the cardiology residents must have basic training in every one of the cardiovascular imaging modalities available. Ischemic heart disease is the main cause of death in the world, including Mexico. Up to 43% of the patients that suffered a myocardial infarction and up to 31% of the patients with sudden cardiac death had an almost normal nuclear myocardial perfusion study in the year before the event, thus evidencing the importance of a multi-imaging approach. With the better understanding of the pathophysiological processes of coronary artery disease, new techniques have been developed that allows the detection of this disease almost from the beginning, through the detection of endothelial dysfunction by Positron Emission Tomography. Later on, when the patient develops diffuse atherosclerosis, we can rely on the use of de coronary calcium score and the detection of atherosclerotic plaques with coronary computed tomography angiography. To detect the presence of myocardial ischemia, two methods are widely used: echocardiography and nuclear medicine. Other options to identify myocardial ischemia are magnetic resonance imaging and computed tomography, due to the development of the "Dual Source" and "Flash" technologies. After an acute coronary event, cardiovascular imaging is useful for risk stratification and detection of myocardial viability, being the positron emission tomography the gold standard.

La importancia del diagnóstico multi-imagen en cardiología / The importance of multi-imaging diagnosis in cardiology

La imagen cardiovascular es una de las disciplinas que más ha evolucionado en el campo de la cardiología. Ante esto, la enseñanza de la cardiología debe moverse a la par. En 2009, el Colegio Americano de Cardiología decidió publicar una declaración en la que señala que: todos los residentes de cardiología deben llevar un entrenamiento básico en cada una de las técnicas de imagen cardiovascular disponibles. La cardiopatía isquémica es la principal causa de muerte en casi todo el mundo, incluido México. Hasta 43% de los pacientes que habían sufrido un infarto del miocardio y 31% de los pacientes con muerte súbita de origen cardiaco, tenían un estudio de perfusión por medicina nuclear prácticamente normal en el año previo al desenlace, poniendo en evidencia la importancia del abordaje por medio de distintos métodos de imagen. Con el mejor entendimiento de los procesos fisiopatológicos de la enfermedad arterial coronaria, se han desarrollado técnicas diagnósticas que nos permiten identificar esta patología prácticamente desde su inicio, a través de la detección de disfunción endotelial por medio de la tomografía por emisión de positrones. Más adelante, cuando los pacientes desarrollan ateroesclerosis manifiesta, contamos con herramientas como el score de calcio y la detección de las placas ateroscleróticas por medio de la tomografía computarizada. Para detectar la presencia de isquemia miocárdica contamos con dos métodos ampliamente utilizados: la ecocardiografía en estrés con dobutamina o dipiridamol y la medicina nuclear. Otras opciones para la identificación de isquemia son la resonancia magnética y la tomografía computada, gracias a la tecnología Dual Source y Flash. Posterior a un evento coronario, la imagen cardiovascular tiene como funciones la estratificación de riesgo y la detección de tejido miocárdico viable, siendo hoy en día el método de elección la tomografía por emisión de positrones.

Cardiovascular imaging is one of the disciplines in cardiology with the most recent advances. This means that the teaching of Cardiology must evolve in the same way. In 2009, the American College of Cardiology published a statement, which points out that all of the cardiology residents must have basic training in every one of the cardiovascular imaging modalities available. Ischemic heart disease is the main cause of death in the world, including Mexico. Up to 43% of the patients that suffered a myocardial infarction and up to 31% of the patients with sudden cardiac death had an almost normal nuclear myocardial perfusion study in the year before the event, thus evidencing the importance of a multi-imaging approach. With the better understanding of the pathophysiological processes of coronary artery disease, new techniques have been developed that allows the detection of this disease almost from the beginning, through the detection of endothelial dysfunction by Positron Emission Tomography. Later on, when the patient develops diffuse atherosclerosis, we can rely on the use of de coronary calcium score and the detection of atherosclerotic plaques with coronary computed tomography angiography. To detect the presence of myocardial ischemia, two methods are widely used: echocardiography and nuclear medicine. Other options to identify myocardial ischemia are magnetic resonance imaging and computed tomography, due to the development of the "Dual Source" and "Flash" technologies. After an acute coronary event, cardiovascular imaging is useful for risk stratification and detection of myocardial viability, being the positron emission tomography the gold standard.

Determinación de actividad inflamatoria en pacientes con arteritis de Takayasu mediante tomografía por emisión de positrones (PET) / PET evaluation of inflammatory process in Takayasu's arteritis

Objetivos: Determinar la aplicación que tiene la tomografía por emisión de positrones en el seguimiento de pacientes con arteritis de Takayasu con actividad inflamatoria y su correlación con los criterios clínicos establecidos. Métodos: Se incluyeron 35 pacientes con diagnóstico de arteritis de Takayasu. Se determinó velocidad de sedimentación globular, proteína C reactiva, biometría hemática, así como, fibrinógeno y se aplicaron los criterios clínicos de actividad. Se realizó tomografía por emisión de positrones basal de los pacientes positivos para actividad inflamatoria, todos recibieron tratamiento farmacológico. De forma aleatoria se incluyó a 10 pacientes que posterior al tratamiento durante seis meses se les realizó un nuevo estudio clínico y una tomografía por emisión de positrones para determinar actividad inflamatoria. Se compararon los criterios clínicos con tomografía por emisión de positrones tanto del estudio basal como el de seguimiento. Resultados: Los criterios clínicos tuvieron una sensibilidad de 63% y especificidad de 90% para demostrar actividad inflamatoria en forma basal. La sensibilidad de los criterios clínicos disminuyó posterior al tratamiento hasta 27%, en donde se observó que pacientes aparentemente inactivos por clínica, continuaban activos por tomografía por emisión de positrones. Discusión: Éste es el primer estudio que compara de manera prospectiva los hallazgos de tomografía por emisión de positrones antes y después del tratamiento para actividad inflamatoria en pacientes con arteritis de Takayasu. Los criterios clínicos carecen de sensibilidad para la detección de actividad inflamatoria en el seguimiento posterior al tratamiento. Conclusiones: El tomografía por emisión de positrones es una técnica de diagnóstico con una alta sensibilidad y especificidad para el diagnóstico y seguimiento de pacientes con arteritis de Takayasu y actividad inflamatoria.

Objective: To determine the application of PET in monitoring patients with Takayasu's arteritis (TA) with inflammatory activity (IA) and its correlation with established clinical criteria. Methods: 35 patients diagnosed with TA were enrolled. Determination of erythrocyte sedimentation rate, C-reactive protein, fibrinogen and a complete blood count was performed and clinical criteria of activity were applied. A baseline PET was performed in all patients. Those who were positive for IA received drug treatment. Among the group of active patients, ten were randomized to undergo another PET scan and clinical criteria determination to evaluate inflammatory activity after 6 months of treatment. We compared clinical criteria with PET capacity to determine IA. The results between the initial and final PET were finally compared. Results: Clinical criteria had a sensitivity of 63% and a specificity of 90% to show IA. Sensitivity decreased after 6 months of treatment to 27%. Discussion: This is the first prospective study that compares the findings of PET before and after treatment for IA in patients with TA. Clinical criteria lack sensitivity for the detection of IA in the follow-up after treatment. Conclusions: PET is a diagnostic technique with high sensitivity and specificity for the diagnosis and monitoring of patients with TA and inflammatory activity.

Endothelial dysfunction in systemic lupus erythematosus: evaluation with 13N-ammonia PET.

UNLABELLED: Systemic lupus erythematosus (SLE) affects multiple organs and systems, severely involving the cardiovascular system. The aim of this study was to evaluate the presence of endothelial dysfunction with (13)N-ammonia PET in asymptomatic SLE patients. METHODS: We enrolled 16 women with SLE and 16 healthy women. Myocardial blood flow (MBF) was quantified in a 64-slice PET/CT scanner at rest, during a cold pressor test (CPT), and during stress. Endothelium-dependent vasodilation index, %ΔMBF, and myocardial flow reserve (MFR) were calculated. RESULTS: There were 16 women in the SLE group (mean age ± SD, 31.4 ± 8.3 y) and 16 women in the healthy control group (31.5 ± 11.1 y). Mean endothelium-dependent vasodilatation index and %ΔMBF were significantly lower in SLE patients (1.18 ± 0.55 vs. 1.63 ± 0.65, P = 0.04, and 18 ± 55 vs. 63 ± 65, P = 0.04, respectively). MFR was also lower in the SLE group (2.41 ± 0.59 vs. 2.73 ± 0.77, P = 0.20). CONCLUSION: SLE patients who are free of active disease present abnormal coronary flow and endothelial dysfunction. It is necessary to develop and intensify treatment strategies directed to CAD in SLE patients.

Effect of ezetimibe-simvastatine over endothelial dysfunction in dyslipidemic patients: assessment by 13N-ammonia positron emission tomography.

BACKGROUND: Dyslipidemias constitute an independent risk factor for the development of atherogenesis and they also predispose to the development of endothelial dysfunction (ED). Using PET with (13)N-ammonia, it is possible to quantify myocardial blood flow (MBF) in mL/min/g and to quantitatively evaluate ED. With the use of lipid lowering therapy it is possible to reduce ED and increase the MBF and the endothelial-dependent vasodilation index (ENDEVI). In this study, we aimed to evaluate with (13)N-ammonia PET the benefic effects of the combined treatment ezetimibe/simvastatine on the endothelial function of dyslipidemic patients after 8 weeks of treatment. MATERIAL AND METHODS: Fourteen consecutive patients with dyslipidemia diagnosis and 17 healthy volunteers were studied with a three phase [rest, Cold Pressor Test (CPT), and adenosine-induced hyperemia] (13)N-ammonia PET for MBF quantification assessment. A second PET study was performed in the dyslipidemic group after 8 weeks of treatment with ezetimibe/simvastatine (10/40 mg). Myocardial flow reserve (MFR), ENDEVI, and %ΔMBF were calculated. RESULTS: Total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides concentrations were markedly altered in the dyslipidemic group and after 8 weeks of treatment these values improved. Dyslipidemic patients showed endothelial dysfunction when compared with the control group, (MFR 2.79 ± 0.94 vs 3.15 ± 0.48, P < 0.05 ; ENDEVI 1.28 ± 0.25 vs 1.53 ± 0.24, P < 0.05; and %ΔMBF 29.08 ± 24.62 vs 53 ± 24.60%, P < 0.05, respectively). After 8 weeks of treatment, we found a significant increase in all the endothelial function markers (MFR: 3.14 ± 0.86, P < 0.05, ENDEVI 1.65 ± 0.23, P < 0.05; %ΔMBF: 65.21 ± 23.43, P < 0.05). CONCLUSIONS: Dyslipidemic patients show endothelial dysfunction measured with (13)N-ammonia PET. Treatment with ezetimibe/simvastatine was effective improving the lipid profile as well as the endothelial function of these patients. PET may be a useful tool to monitor vascular reactivity and regression/progression of coronary atherosclerosis after pharmacologic interventions.

Functional impact of coronary stenosis observed on coronary computed tomography angiography: Comparison with ¹³N-ammonia PET.

BACKGROUND AND AIMS: We undertook this study to evaluate the functional impact of coronary abnormalities in patients with suspected coronary artery disease (CAD) by means of integrated positron emission tomography (PET) and coronary computed tomography angiography (CCTA) scan obtained on a hybrid state-of-the-art PET/CT scanner. METHODS: We studied 29 consecutive, patients with a clinically suspected intermediate risk for CAD, using a hybrid PET/CT 64 slice scanner. During a single scanning session, CCTA was performed for coronary anatomy evaluation, and a rest/adenosine stress (13)N-ammonia PET was performed for myocardial perfusion assessment in 3D mode with CT attenuation correction. RESULTS: Twenty four (82.7%) patients had atherosclerosis detected by CCTA; 15 patients had significant (≥50%) coronary stenoses and all 15 patients showed ischemia by PET; moreover, 10/15 patients had a Summed Stress Score >12.20/24 and 83.3% patients with atherosclerosis detected by CCTA showed ischemia by PET. Two of five patients with normal coronary arteries showed ischemia by PET. CCTA agreement in positive identification of PET ischemia was 91% and agreement in ruling out ischemia was 43%; PET agreement in detecting CCTA atherosclerosis was 83%, and agreement in ruling it out was 60%. CONCLUSIONS: We found a strong relation between significant coronary stenosis identified by CCTA and ischemia by PET. However, in cases with low-grade stenosis, PET scan can assess the functional significance of atherosclerotic abnormalities.