Remimazolam in Cardiac Anesthesia: Analysis of Recent Data.

Interest in remimazolam has surged in recent years, thanks to its advantageous pharmacologic profile. This ultra-short-acting benzodiazepine is noted for its rapid onset and termination of action, organ-independent elimination, availability of a reversal agent, and excellent hemodynamic stability. Although the use of remimazolam has been explored in various anesthesia settings and procedures, data on its application in cardiovascular anesthesia and catheterization laboratory procedures remain limited. This review evaluates the latest literature to assess remimazolam's role in cardiovascular anesthesia across different settings and procedures. The analysis shows that remimazolam offers anesthesia without significant hemodynamic instability and a reduced need for vasopressors, with an incidence of perioperative adverse events comparable to that of other agents. These findings are relevant for both the induction and maintenance of general anesthesia in catheterization laboratory procedures and general anesthesia in elective cardiac surgery. Although further research is needed to fully understand remimazolam's role in cardiovascular anesthesia, its favorable hemodynamic and safety profile suggests that it is a promising option for cardiac anesthesiologists in both the catheterization laboratory and the operating room.

Critical Role of Astrocyte NAD+ Glycohydrolase in Myelin Injury and Regeneration.

Western-style diets cause disruptions in myelinating cells and astrocytes within the mouse CNS. Increased CD38 expression is present in the cuprizone and experimental autoimmune encephalomyelitis models of demyelination and CD38 is the main nicotinamide adenine dinucleotide (NAD+)-depleting enzyme in the CNS. Altered NAD+ metabolism is linked to both high fat consumption and multiple sclerosis (MS). Here, we identify increased CD38 expression in the male mouse spinal cord following chronic high fat consumption, after focal toxin [lysolecithin (LL)]-mediated demyelinating injury, and in reactive astrocytes within active MS lesions. We demonstrate that CD38 catalytically inactive mice are substantially protected from high fat-induced NAD+ depletion, oligodendrocyte loss, oxidative damage, and astrogliosis. A CD38 inhibitor, 78c, increased NAD+ and attenuated neuroinflammatory changes induced by saturated fat applied to astrocyte cultures. Conditioned media from saturated fat-exposed astrocytes applied to oligodendrocyte cultures impaired myelin protein production, suggesting astrocyte-driven indirect mechanisms of oligodendrogliopathy. In cerebellar organotypic slice cultures subject to LL-demyelination, saturated fat impaired signs of remyelination effects that were mitigated by concomitant 78c treatment. Significantly, oral 78c increased counts of oligodendrocytes and remyelinated axons after focal LL-induced spinal cord demyelination. Using a RiboTag approach, we identified a unique in vivo brain astrocyte translatome profile induced by 78c-mediated CD38 inhibition in mice, including decreased expression of proinflammatory astrocyte markers and increased growth factors. Our findings suggest that a high-fat diet impairs oligodendrocyte survival and differentiation through astrocyte-linked mechanisms mediated by the NAD+ase CD38 and highlights CD38 inhibitors as potential therapeutic candidates to improve myelin regeneration.SIGNIFICANCE STATEMENT Myelin disturbances and oligodendrocyte loss can leave axons vulnerable, leading to permanent neurologic deficits. The results of this study suggest that metabolic disturbances, triggered by consumption of a diet high in fat, promote oligodendrogliopathy and impair myelin regeneration through astrocyte-linked indirect nicotinamide adenine dinucleotide (NAD+)-dependent mechanisms. We demonstrate that restoring NAD+ levels via genetic inactivation of CD38 can overcome these effects. Moreover, we show that therapeutic inactivation of CD38 can enhance myelin regeneration. Together, these findings point to a new metabolic targeting strategy positioned to improve disease course in multiple sclerosis and other conditions in which the integrity of myelin is a key concern.

Benefits in cardiac function by CD38 suppression: Improvement in NAD+ levels, exercise capacity, heart rate variability and protection against catecholamine-induced ventricular arrhythmias.

CD38 enzymatic activity regulates NAD+ and cADPR levels in mammalian tissues, and therefore has a prominent role in cellular metabolism and calcium homeostasis. Consequently, it is reasonable to hypothesize about its involvement in cardiovascular physiology as well as in heart related pathological conditions. AIM: To investigate the role of CD38 in cardiovascular performance, and its involvement in cardiac electrophysiology and calcium-handling. METHODS AND RESULTS: When submitted to a treadmill exhaustion test, a way of evaluating cardiovascular performance, adult male CD38KO mice showed better exercise capacity. This benefit was also obtained in genetically modified mice with catalytically inactive (CI) CD38 and in WT mice treated with antibody 68 (Ab68) which blocks CD38 activity. Hearts from these 3 groups (CD38KO, CD38CI and Ab68) showed increased NAD+ levels. When CD38KO mice were treated with FK866 which inhibits NAD+ biosynthesis, exercise capacity as well as NAD+ in heart tissue decreased to WT levels. Electrocardiograms of conscious unrestrained CD38KO and CD38CI mice showed lower basal heart rates and higher heart rate variability than WT mice. Although inactivation of CD38 in mice resulted in increased SERCA2a expression in the heart, the frequency of spontaneous calcium release from the sarcoplasmic reticulum under stressful conditions (high extracellular calcium concentration) was lower in CD38KO ventricular myocytes. When mice were challenged with caffeine-epinephrine, CD38KO mice had a lower incidence of bidirectional ventricular tachycardia when compared to WT ones. CONCLUSION: CD38 inhibition improves exercise performance by regulating NAD+ homeostasis. CD38 is involved in cardiovascular function since its genetic ablation decreases basal heart rate, increases heart rate variability and alters calcium handling in a way that protects mice from developing catecholamine induced ventricular arrhythmias.

The CD38 glycohydrolase and the NAD sink: implications for pathological conditions.

Nicotinamide adenine dinucleotide (NAD) acts as a cofactor in several oxidation-reduction (redox) reactions and is a substrate for a number of nonredox enzymes. NAD is fundamental to a variety of cellular processes including energy metabolism, cell signaling, and epigenetics. NAD homeostasis appears to be of paramount importance to health span and longevity, and its dysregulation is associated with multiple diseases. NAD metabolism is dynamic and maintained by synthesis and degradation. The enzyme CD38, one of the main NAD-consuming enzymes, is a key component of NAD homeostasis. The majority of CD38 is localized in the plasma membrane with its catalytic domain facing the extracellular environment, likely for the purpose of controlling systemic levels of NAD. Several cell types express CD38, but its expression predominates on endothelial cells and immune cells capable of infiltrating organs and tissues. Here we review potential roles of CD38 in health and disease and postulate ways in which CD38 dysregulation causes changes in NAD homeostasis and contributes to the pathophysiology of multiple conditions. Indeed, in animal models the development of infectious diseases, autoimmune disorders, fibrosis, metabolic diseases, and age-associated diseases including cancer, heart disease, and neurodegeneration are associated with altered CD38 enzymatic activity. Many of these conditions are modified in CD38-deficient mice or by blocking CD38 NADase activity. In diseases in which CD38 appears to play a role, CD38-dependent NAD decline is often a common denominator of pathophysiology. Thus, understanding dysregulation of NAD homeostasis by CD38 may open new avenues for the treatment of human diseases.

The additional prognostic value of myocardial perfusion SPECT in patients with known coronary artery disease with high exercise capacity.

BACKGROUND: The prognostic value of myocardial perfusion imaging (MPI) in patients with known coronary artery disease (CAD) and high exercise capacity is still unknown. We sought to determine the MPI additional prognostic value over electrocardiography (ECG) stress testing alone in patients with known CAD who achieved ≥ 10 metabolic equivalents (METs). METHODS AND RESULTS: We evaluated 926 patients with known CAD referred for MPI with exercise stress. Patients were followed for a mean of 32.4 ± 9.7 months for the occurrence of all-cause death or nonfatal myocardial infarction (MI). Those achieving ≥ 10 METs were younger, predominantly male, and had lower prevalence of cardiovascular risk factors. Patients reaching ≥ 10 METs had a lower annualized rate of hard events compared to their counterparts achieving < 10 METs (1.13%/year vs 3.95%/year, P < .001). Patients who achieved ≥ 10 METs with abnormal scans had a higher rate of hard events compared to those with normal scans (3.37%/year vs 0.57%/year, P = .023). Cardiac workload < 10 METs and an abnormal MPI scan were independent predictors of hard events. CONCLUSIONS: MPI is able to stratify patients with known CAD achieving ≥ 10 METs for the occurrence of all-cause death and nonfatal MI, with incremental prognostic value over ECG stress test alone.

The NADase enzyme CD38: an emerging pharmacological target for systemic sclerosis, systemic lupus erythematosus and rheumatoid arthritis.

PURPOSE OF REVIEW: Here we review recent literature on the emerging role of nicotinamide adenine dinucleotide (NAD) metabolism and its dysfunction via the enzyme CD38 in the pathogenesis of rheumatologic diseases. We evaluate the potential of targeting CD38 to ameliorate NAD-related metabolic imbalance and tissue dysfunction in the treatment of systemic sclerosis (SSc), systemic lupus erythematous (SLE), and rheumatoid arthritis (RA). RECENT FINDINGS: In this review, we will discuss emerging basic, preclinical, and human data that point to the novel role of CD38 in dysregulated NAD-homeostasis in SSc, SLE, and RA. In particular, recent studies implicate increased activity of CD38, one of the main enzymes in NAD catabolism, in the pathogenesis of persistent systemic fibrosis in SSc, and increased susceptibility of SLE patients to infections. We will also discuss recent studies that demonstrate that a cytotoxic CD38 antibody can promote clearance of plasma cells involved in the generation of RA antibodies. SUMMARY: Recent studies identify potential therapeutic approaches for boosting NAD to treat rheumatologic diseases including SSc, RA, and SLE, with particular attention to inhibition of CD38 enzymatic activity as a target. Key future directions in the field include the determination of the cell-type specificity and role of CD38 enzymatic activity versus CD38 structural roles in human diseases, as well as the indicators and potential side effects of CD38-targeted treatments.

The NADase CD38 is induced by factors secreted from senescent cells providing a potential link between senescence and age-related cellular NAD+ decline.

Tissue nicotinamide adenine dinucleotide (NAD+) decline has been implicated in aging. We have recently identified CD38 as a central regulator involved in tissue NAD+ decline during the aging process. CD38 is an ecto-enzyme highly expressed in endothelial and inflammatory cells. To date, the mechanisms that regulate CD38 expression in aging tissues characterized by the presence of senescent cells is not completely understood. Cellular senescence has been described as a hallmark of the aging process and these cells are known to secrete several factors including cytokines and chemokines through their senescent associated secretory phenotype (SASP). Here we investigated if the cellular senescence phenotype is involved in the regulation of CD38 expression and its NADase activity. We observed that senescent cells do not have high expression of CD38. However, the SASP factors secreted by senescent cells induced CD38 mRNA and protein expression and increased CD38-NADase activity in non-senescent cells such as endothelial cells or bone marrow derived macrophages. Our data suggest a link between cellular senescence and NAD+ decline in which SASP-mediated upregulation of CD38 can disrupt cellular NAD+ homeostasis.

Comparison of the prognostic value of myocardial perfusion imaging using a CZT-SPECT camera with a conventional anger camera.

BACKGROUND: Recent studies have shown that myocardial perfusion imaging (MPI) in cadmium-zinc-telluride (CZT) cameras allow faster exams with less radiation dose but there are little data comparing its prognosis information with that of dedicated cardiac Na-I SPECT cameras OBJECTIVE: The objective of this study is to compare the prognostic value of MPI using an ultrafast protocol with low radiation dose in a CZT-SPECT and a traditional one. METHODS: Group 1 was submitted to a two-day MIBI protocol in a conventional camera, and group 2 was submitted to a 1-day MIBI protocol in CZT camera. MPI were classified as normal or abnormal, and perfusion scores were calculated. Propensity score matching methods were performed RESULTS: 3554 patients were followed during 33±8 months. Groups 1 and 2 had similar distribution of age, gender, body mass index, risk factors, previous revascularization, and use of pharmacological stress. Group 1 had more abnormal scans, higher scores than group 2. Annualized hard events rate was higher in group 1 with normal scans but frequency of revascularization was similar to normal group 2. Patients with abnormal scans had similar event rates in both groups CONCLUSION: New protocol of MPI in CZT-SPECT showed similar prognostic results to those obtained in dedicated cardiac Na-I SPECT camera, with lower prevalence of hard events in patients with normal scan.

Prognostic value of myocardium perfusion imaging with a new reconstruction algorithm.

BACKGROUND: It has been demonstrated that a new reconstruction algorithm for myocardium perfusion imaging (MPI) allows faster acquisition with similar accuracy. The prognostic value of MPI performed with this software and short acquisition time is unknown. METHODS: To determine the prognostic value we followed 3184 consecutive MPI patients between March 2008 and March 2010. A 2-day protocol with low dose 99mTc-MIBI (10-12 mCi) and a 6-minute acquisition was used. Exercise stress was used in 62.6% of the studies. Scans were reconstructed using the software "Evolution for cardiac". Perfusion defects were quantified by summed stress score (SSS) and categorized in four groups: SSS0 = 0; SSS1 = 1-3; SSS2 = 4-8; and SSS3 ≥ 9. Patients were phone contacted every 6 months for follow up and hard events were defined as death or myocardial infarction (MI) and total events as hard events plus late revascularization. RESULTS: The mean radiation dose was <7 mSv/patient. Mean F/U was 33 ± 20 months; 140 of the patients were lost to follow up and 86 were censored due early revascularization (<60 days after MPS). There were 140 hard events: 89 deaths and 51 MI. Mean age was 61.5 ± 12.3 years and 57.7% were male. Hard event rate was 0.8%/year in patients with normal MPS and 3.7%/year in those with abnormal MPS. Patients with larger defects had nine times more hard events than patients with SSS = 0 (14.2% vs 1.6%). Revascularization was more frequent in patients with abnormal MPS than normal MPS (21.7% vs 3.9%; P < 0.001). Cox proportional hazard analysis showed that SSS was an independent predictor of hard events and revascularization. CONCLUSIONS: The use of reduced-dose, fast myocardial perfusion SPECT and the new processing algorithm lowers acquisition time and radiation exposure compared to conventional SPECT without compromising the well-established prognostic value of MPI.

Ecto-CD38-NADase inhibition modulates cardiac metabolism and protects mice against doxorubicin-induced cardiotoxicity.

AIMS: Doxorubicin (DXR) is a chemotherapeutic agent that causes dose-dependent cardiotoxicity. Recently, it has been proposed that the NADase CD38 may play a role in doxorubicin-induced cardiotoxicity (DIC). CD38 is the main NAD+-catabolizing enzyme in mammalian tissues. Interestingly, in the heart, CD38 is mostly expressed as an ecto-enzyme that can be targeted by specific inhibitory antibodies. The goal of the present study is to characterize the role of CD38 ecto-enzymatic activity in cardiac metabolism and the development of DIC. METHODS AND RESULTS: Using both a transgenic animal model and a non-cytotoxic enzymatic anti-CD38 antibody, we investigated the role of CD38 and its ecto-NADase activity in DIC in pre-clinical models. First, we observed that DIC was prevented in the CD38 catalytically inactive (CD38-CI) transgenic mice. Both left ventricular systolic function and exercise capacity were decreased in wild-type but not in CD38-CI mice treated with DXR. Second, blocking CD38-NADase activity with the specific antibody 68 (Ab68) likewise protected mice against DIC and decreased DXR-related mortality by 50%. A reduction of DXR-induced mitochondrial dysfunction, energy deficiency, and inflammation gene expression were identified as the main mechanisms mediating the protective effects. CONCLUSION: NAD+-preserving strategies by inactivation of CD38 via a genetic or a pharmacological-based approach improve cardiac energetics and reduce cardiac inflammation and dysfunction otherwise seen in an acute DXR cardiotoxicity model.

Heavy-chain antibody targeting of CD38 NAD+ hydrolase ectoenzyme to prevent fibrosis in multiple organs.

The functionally pleiotropic ectoenzyme CD38 is a glycohydrolase widely expressed on immune and non-hematopoietic cells. By converting NAD+ to ADP-ribose and nicotinamide, CD38 governs organismal NAD+ homeostasis and the activity of NAD+-dependent cellular enzymes. CD38 has emerged as a major driver of age-related NAD+ decline underlying adverse metabolic states, frailty and reduced health span. CD38 is upregulated in systemic sclerosis (SSc), a chronic disease characterized by fibrosis in multiple organs. We sought to test the hypothesis that inhibition of the CD38 ecto-enzymatic activity using a heavy-chain monoclonal antibody Ab68 will, via augmenting organismal NAD+, prevent fibrosis in a mouse model of SSc characterized by NAD+ depletion. Here we show that treatment of mice with a non-cytotoxic heavy-chain antibody that selectively inhibits CD38 ectoenzyme resulted in NAD+ boosting that was associated with significant protection from fibrosis in multiple organs. These findings suggest that targeted inhibition of CD38 ecto-enzymatic activity could be a potential pharmacological approach for SSc fibrosis treatment.

A nitroalkene derivative of salicylate alleviates diet-induced obesity by activating creatine metabolism and non-shivering thermogenesis.

Obesity-related type II diabetes (diabesity) has increased global morbidity and mortality dramatically. Previously, the ancient drug salicylate demonstrated promise for the treatment of type II diabetes, but its clinical use was precluded due to high dose requirements. In this study, we present a nitroalkene derivative of salicylate, 5-(2-nitroethenyl)salicylic acid (SANA), a molecule with unprecedented beneficial effects in diet-induced obesity (DIO). SANA reduces DIO, liver steatosis and insulin resistance at doses up to 40 times lower than salicylate. Mechanistically, SANA stimulated mitochondrial respiration and increased creatine-dependent energy expenditure in adipose tissue. Indeed, depletion of creatine resulted in the loss of SANA action. Moreover, we found that SANA binds to creatine kinases CKMT1/2, and downregulation CKMT1 interferes with the effect of SANA in vivo. Together, these data demonstrate that SANA is a first-in-class activator of creatine-dependent energy expenditure and thermogenesis in adipose tissue and emerges as a candidate for the treatment of diabesity.

CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging.

Nicotinamide adenine dinucleotide (NAD) levels decline during aging, contributing to physical and metabolic dysfunction. The NADase CD38 plays a key role in age-related NAD decline. Whether the inhibition of CD38 increases lifespan is not known. Here, we show that the CD38 inhibitor 78c increases lifespan and healthspan of naturally aged mice. In addition to a 10% increase in median survival, 78c improved exercise performance, endurance, and metabolic function in mice. The effects of 78c were different between sexes. Our study is the first to investigate the effect of CD38 inhibition in naturally aged animals.

Dihydronicotinamide Riboside Is a Potent NAD+ Precursor Promoting a Pro-Inflammatory Phenotype in Macrophages.

Nicotinamide adenine dinucleotide (NAD) metabolism plays an important role in the regulation of immune function. However, a complete picture of how NAD, its metabolites, precursors, and metabolizing enzymes work together in regulating immune function and inflammatory diseases is still not fully understood. Surprisingly, few studies have compared the effect of different forms of vitamin B3 on cellular functions. Therefore, we investigated the role of NAD boosting in the regulation of macrophage activation and function using different NAD precursors supplementation. We compared nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), and nicotinamide (NAM) supplementation, with the recently described potent NAD precursor NRH. Our results show that only NRH supplementation strongly increased NAD+ levels in both bone marrow-derived and THP-1 macrophages. Importantly, NRH supplementation activated a pro-inflammatory phenotype in resting macrophages, inducing gene expression of several cytokines, chemokines, and enzymes. NRH also potentiated the effect of lipopolysaccharide (LPS) on macrophage activation and cytokine gene expression, suggesting that potent NAD+ precursors can promote inflammation in macrophages. The effect of NRH in NAD+ boosting and gene expression was blocked by inhibitors of adenosine kinase, equilibrative nucleoside transporters (ENT), and IκB kinase (IKK). Interestingly, the IKK inhibitor, BMS-345541, blocked the mRNA expression of several enzymes and transporters involved in the NAD boosting effect of NRH, indicating that IKK is also a regulator of NAD metabolism. In conclusion, NAD precursors such as NRH may be important tools to understand the role of NAD and NADH metabolism in the inflammatory process of other immune cells, and to reprogram immune cells to a pro-inflammatory phenotype, such as the M2 to M1 switch in macrophage reprogramming, in the cancer microenvironment.

Endogenous metabolism in endothelial and immune cells generates most of the tissue vitamin B3 (nicotinamide).

In mammals, nicotinamide (NAM) is the primary NAD precursor available in circulation, a signaling molecule, and a precursor for methyl-nicotinamide (M-NAM) synthesis. However, our knowledge about how the body regulates tissue NAM levels is still limited. Here we demonstrate that dietary vitamin B3 partially regulates plasma NAM and NAM-derived metabolites, but not their tissue levels. We found that NAD de novo synthesis from tryptophan contributes to plasma and tissue NAM, likely by providing substrates for NAD-degrading enzymes. We also demonstrate that tissue NAM is mainly generated by endogenous metabolism and that the NADase CD38 is the main enzyme that produces tissue NAM. Tissue-specific CD38-floxed mice revealed that CD38 activity on endothelial and immune cells is the major contributor to tissue steady-state levels of NAM in tissues like spleen and heart. Our findings uncover the presence of different pools of NAM in the body and a central role for CD38 in regulating tissue NAM levels.

FBF1 deficiency promotes beiging and healthy expansion of white adipose tissue.

Preadipocytes dynamically produce sensory cilia. However, the role of primary cilia in preadipocyte differentiation and adipose homeostasis remains poorly understood. We previously identified transition fiber component FBF1 as an essential player in controlling selective cilia import. Here, we establish Fbf1tm1a/tm1a mice and discover that Fbf1tm1a/tm1a mice develop severe obesity, but surprisingly, are not predisposed to adverse metabolic complications. Obese Fbf1tm1a/tm1a mice possess unexpectedly healthy white fat tissue characterized by spontaneous upregulated beiging, hyperplasia but not hypertrophy, and low inflammation along the lifetime. Mechanistically, FBF1 governs preadipocyte differentiation by constraining the beiging program through an AKAP9-dependent, cilia-regulated PKA signaling, while recruiting the BBS chaperonin to transition fibers to suppress the hedgehog signaling-dependent adipogenic program. Remarkably, obese Fbf1tm1a/tm1a mice further fed a high-fat diet are protected from diabetes and premature death. We reveal a central role for primary cilia in the fate determination of preadipocytes and the generation of metabolically healthy fat tissue.

CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels.

Decreased NAD+ levels have been shown to contribute to metabolic dysfunction during aging. NAD+ decline can be partially prevented by knockout of the enzyme CD38. However, it is not known how CD38 is regulated during aging, and how its ecto-enzymatic activity impacts NAD+ homeostasis. Here we show that an increase in CD38 in white adipose tissue (WAT) and the liver during aging is mediated by accumulation of CD38+ immune cells. Inflammation increases CD38 and decreases NAD+. In addition, senescent cells and their secreted signals promote accumulation of CD38+ cells in WAT, and ablation of senescent cells or their secretory phenotype decreases CD38, partially reversing NAD+ decline. Finally, blocking the ecto-enzymatic activity of CD38 can increase NAD+ through a nicotinamide mononucleotide (NMN)-dependent process. Our findings demonstrate that senescence-induced inflammation promotes accumulation of CD38 in immune cells that, through its ecto-enzymatic activity, decreases levels of NMN and NAD+.

The Prognostic Value and Clinical Use of Myocardial Perfusion Scintigraphy in Asymptomatic Patients after Percutaneous Coronary Intervention.

BACKGROUND: The role of myocardial perfusion scintigraphy (MPS) in the follow-up of asymptomatic patients after percutaneous coronary intervention (PCI) is not established. OBJECTIVES: To evaluate the prognostic value and clinical use of MPS in asymptomatic patients after PCI. METHODS: Patients who underwent MPS consecutively between 2008 and 2012 after PCI were selected. The MPS were classified as normal and abnormal, the perfusion scores, summed stress score (SSS), and summed difference score (SDS) were calculated and converted into percentage of total perfusion defect and ischemic defect. The follow-up was undertaken through telephone interviews and consultation with the Mortality Information System. Primary endpoints were death, cardiovascular death, and nonfatal acute myocardial infarction (AMI), and secondary endpoint was revascularization. Logistic regression and COX method were used to identify the predictors of events, and the value of p < 0.05 was considered statistically significant. RESULTS: A total of 647 patients were followed for 5.2 ± 1.6 years. 47% of MPS were normal, 30% were abnormal with ischemia, and 23% were abnormal without ischemia. There were 61 deaths, 27 being cardiovascular, 19 non-fatal AMI, and 139 revascularizations. The annual death rate was higher in those with abnormal perfusion without ischemia compared to the groups with ischemia and normal perfusion (3.3% × 2% × 1.2%, p = 0.021). The annual revascularization rate was 10.3% in the ischemia group, 3.7% in those with normal MPS, and 3% in those with abnormal MPS without ischemia. The independent predictors of mortality and revascularization were, respectively, total perfusion defect greater than 6%, and ischemic defect greater than 3%. Forty-two percent of the patients underwent MPS less than 2 years after PCI, and no significant differences were observed in relation to those who underwent it after that period. CONCLUSION: Although this information is not contemplated in guidelines, in this study MPS was able to predict events in asymptomatic after PCI patients, regardless of when they were performed.

Prognostic performance of coronary computed tomography angiography in asymptomatic individuals as compared to symptomatic patients with an appropriate indication.

INTRODUCTION: Current Appropriatene Usa Criteria exclude coronary computed tomography angiography (CTA) in asymptomatic individuals. We compared the prognostic value of coronary CTA in asymptomatic individuals to symptomatic patients with "definitely appropriate" indications for coronary CTA. METHODS: Consecutive patients without previously known CAD referred for a CTA exam were divided into 2 groups. One group consisted ofasymptomatic individuals, the other of symptomatic patients with a "definitely appropriate" indication for coronary CT (unable to exercise and/or with an uninterpretable electrocardiogram and at an intermediate pre-test probability of obstructive coronary artery disease). Patients that did not fit into either groups were excluded. The segment stenosis score (SSS) was calculated based on coronary CTA and patients were followed for a composite endpoint of all-cause death, acute myocardial infarction and late revascularization. RESULTS: A total of 1080 patients (60 ± 12 years, 65% male) were included in the study (674 "asymptomatic" and 406 "appropriate"). SSS >4 was more frequent in "asymptomatic" than in "appropriate" CT data sets (27% vs 20%, p = 0.02). After a mean follow-up of 4.4 ± 1.8 yrs, 49 patients reached the composite endpoint. On multivariable analysis adjusting for CAD risk factors and symptoms, only a high-risk CTA study and past smoking were independently predictive of events. CONCLUSIONS: Although currently not regarded as "definitely appropriate", the use of coronary CTA in a selected asymptomatic population had higher yield for identifying high-risk individuals than appropriately indicated studies in symptomatic patients and provided thequal prognostic information.

Prognostic value of a faster, low-radiation myocardial perfusion SPECT protocol in a CZT camera.

To determine the prognostic value of a new, ultrafast, low dose myocardial perfusion SPECT (MPS) protocol in a cadmium-zinc telluride (CZT) camera. CZT cameras have introduced significant progress in MPS imaging, offering high-quality images despite lower doses and scan time. Yet, it is unknown if, with such protocol changes, the prognostic value of MPS is preserved. Patients had a 1-day 99 m-Tc-sestamibi protocol, starting with the rest (185-222 MBq) followed by stress (666-740 MBq). Acquisition times were 6 and 3 min, respectively. MPS were classified as normal or abnormal perfusion scans and summed scores of stress, rest, and difference (SSS, SRS and SDS), calculated. Patients were followed with 6-month phone calls. Hard events were defined as death or nonfatal myocardial infarction. Late revascularization was that occurring after 60 days of MPS. 2930 patients (age 64.0 ± 12.1 years, 53.3% male) were followed for 30.7 ± 7.5 months. Mean dosimetry was 6 mSv and mean total study time, 48 ± 13 min. The annual hard event and late revascularization rate were higher in patients with greater extension of defect and ischemia. SSS was higher in patients with hard events compared to those without events (2.6 ± 4.9 vs. 5.0 ± 6.3, p < 0.001), as well as the SDS (0.7 ± 1.9 vs. 1.7 ± 3.4, p < 0.00). The same was true for patients with or without late revascularization (SSS: 2.5 ± 4.7 vs. 6.6 ± 7.1; SDS: 0.6 ± 1.7 vs. 2.9 ± 3.8, p < 0.01). A new, faster, low-radiation, MPS protocol in a CZT camera maintain the ability to stratify patients with increased risk of events, showing that, in the presence of greater extension of defect or ischemia, patients presented higher rates of hard events and late revascularization.