Differential Use of Glycoprotein IIb/IIIa Inhibitors with Bivalirudin in Patients with STEMI Undergoing PCI: A Systematic Review and Meta-Analysis.

AIM: The efficacy and safety of bivalirudin when used concurrently with glycoprotein IIb/IIIa inhibitors (GPI) is uncertain. In this systematic review and meta-analysis, we aimed to evaluate the efficacy and safety of bivalirudin versus heparin in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) and to explore the impact of differential use (greater and balanced) of GPI. METHODS: Online databases were queried from inception to March 2023 to identify eight randomized controlled trials (n = 22,483) for inclusion. The primary outcomes included all-cause mortality, major bleeding, major adverse cardiovascular events (MACE), and net adverse clinical events (NACE). Secondary efficacy endpoints included cardiac death, reinfarction, stent thrombosis (ST), and stroke. Data were pooled using a random-effects model to derive risk ratios (RRs) and 95% confidence intervals (CIs). RESULTS: When compared to heparin, bivalirudin was associated with a significant reduction in all-cause mortality (RR 0.83; 95% CI 0.72-0.97; P = 0.02), major bleeding (RR 0.73; 95% CI 0.57-0.93; P = 0.01), cardiac death (RR 0.79; 95% CI 0.66-0.94; P = 0.01), and NACE (RR 0.80; 95% CI 0.72-0.89; P < 0.0001). However, while the bivalirudin arm showed an increased likelihood of ST in the greater GPI subgroup (RR 1.70; 95% CI 1.13-2.56; P = 0.01), it was associated with a decreased likelihood of ST in the balanced GPI subgroup (RR 0.40; 95% CI 0.24-0.65; P = 0.0003). CONCLUSION: Overall, our findings suggest that bivalirudin may be a more efficacious intervention than heparin for reducing certain adverse events in patients with STEMI undergoing primary PCI.

Abnormal lipoprotein(a) levels predict coronary artery calcification in Southeast Asians but not in Caucasians: use of noninvasive imaging for evaluation of an emerging risk factor.

Subclinical atherosclerosis can be quantified by coronary artery calcium (CAC) scoring. Due to its high specificity for atherosclerosis, CAC is an excellent phenotypic tool for the evaluation of emerging risk markers. Lipoprotein(a) [Lp(a)] is atherogenic due to the presence of apoB and may be thrombogenic through its apo(a) component. Lp(a) has been linked to cardiovascular events in Caucasians; however, its link to atherosclerosis in various ethnicities remains unclear. We evaluated the ability of Lp(a) mass to predict subclinical atherosclerosis in Southeast Asians and Caucasians, as measured by CAC. Traditional lipid measurements, Lp(a) measurements, and CAC by 64-slice multidetector computed tomography was performed in 103 consecutive patients in the USA and in 104 consecutive patients in Jakarta, Indonesia. Proportion of positive CAC and median CAC in Southeast Asians and in Caucasians was 61.5% and 63.1%, and 23.5 (interquartile range, 0-270) and 13 (interquartile range, 0-388), respectively. Significantly higher proportion of Southeast Asians had elevated Lp(a) levels, compared to Caucasians (51.0% vs. 29.2%; p = 0.005). In Southeast Asians, Lp(a) remained an independent predictor of CAC with an odds ratio of 4.97 (95% confidence interval, 1.56-15.88; p < 0.0001), but not in Caucasians. Receiver operating characteristic analysis showed an improvement in area under the curve from 0.81 to 0.86 (p = 0.05) when including Lp(a) in the predictive model in Southeast Asians. This translated to 7% of Southeast Asians reclassified to correct CAC status. Lp(a) measurements may have a role in risk stratification of Southeast Asians. Ethnic variation should be taken into account when considering the use of Lp(a) measurements in risk assessment.

Lesion- and vessel-specific coronary artery calcium scores are superior to whole-heart Agatston and volume scores in the diagnosis of obstructive coronary artery disease.

BACKGROUND: The whole-heart coronary artery calcium (CAC) score has poor predictive value for obstructive coronary artery disease (CAD). We hypothesized that vessel- and lesion-specific CAC scores are more accurate. OBJECTIVES: To evaluate the usefulness of vessel- and lesion-specific CAC in predicting obstructive CAD and to assess the incremental value added by the vessel- and lesion-specific CAC to the conventional whole-heart CAC approach. METHODS: Ninety-one patients with CAC scores and invasive angiography (XRA) data were enrolled. Besides whole-heart CAC, Agatston score (AgSc) and volume score (VolSc) were measured individually for each lesion in the 4 major epicardial coronary arteries. Maximum and average lesion-specific scores in each vessel were also determined. For the primary analysis, obstructive CAD was defined as 50% diameter stenosis by XRA. RESULTS: Whole-heart AgSc and VolSc were not different between patients with and without obstructive CAD (P = .23 and P = .18), whereas vessel- and lesion-specific scores were (maximum lesion specific AgSc, P < .0001). Maximum lesion-specific AgSc had superior diagnostic performance compared with whole-heart AgSc (area under receiver operating characteristics, 0.71 vs 0.58). Overall sensitivity, specificity, and diagnostic accuracy were improved. When specificity was fixed at 80%, sensitivity of maximum lesion-specific AgSc was superior to whole-heart AgSc (56.6% vs 35.1%). Most importantly, with lesion-specific AgSc, fewer patients were classified as "indeterminate" compared with whole-heart AgSc (17.9% vs 50%). CONCLUSIONS: Vessel- and lesion-specific CAC scores are superior to the whole-heart AgSc and VolSc in predicting obstructive CAD. This simple refinement in CAC scoring may significantly improve the clinical predictive role of CAC imaging.

FDG-PET imaging of atherosclerosis: Do we know what we see?

Imaging atherosclerosis may help to identify subjects harboring rupture-prone atherosclerotic plaques who may benefit from preventive interventions. Potential of plaques to rupture depends on their structural changes and metabolic activation, which are difficult to assess using anatomic imaging modalities. Recent studies suggested that functional imaging with positron emission tomography (PET) utilizing fluorine-18-labeled 2-deoxy-d-glucose (FDG) has the potential to assess plaque metabolism and add to prediction of vascular risk. Aortic, iliac, and carotid plaques can be detected with FDG-PET, even though not all plaques exhibit high FDG uptake. Detection of coronary artery plaques is more cumbersome due to technical limitations of PET and fast movement of these vessels during cardiac and respiratory cycles. Studies on substrate accumulating FDG in plaques are contradictory and mostly do not extend beyond correlation analyses. Vascular FDG uptake has an excellent short-term stability, but larger fluctuations of uptake long-term, which may complicate interpretation of such changes in therapeutic trials. FDG uptake in major arteries correlates with some cardiovascular risk factors and atherosclerosis markers, but clinical utility of such correlations is unclear. What is more important is that recently reported studies in cancer patients showed correlation between higher baseline FDG uptake and subsequent cardiovascular mortality. Anti-atherogenic therapy and therapeutic lifestyle changes seem to decrease vascular FDG uptake but it is not clear whether the latter predicts subsequent lower morbidity and mortality. These initial findings suggest that vascular FDG-PET may in the future find some utility in management of patients with atherosclerosis, but a number of important issues need to be addressed first. We need to: (1) determine optimal standard ways of performing imaging and quantifying vascular FDG uptake; (2) understand molecular mechanisms governing FDG accumulation in plaques; (3) perform studies prospectively linking vascular FDG uptake to cardiovascular events in non-cancer patients. As of today, vascular FDG-PET is not ready for its prime time in clinical practice.

Angiotensin-converting enzyme and angiotensin II receptor subtype 2 genotypes in type 1 diabetes and severe hypoglycaemia requiring emergency treatment: a case cohort study.

AIMS: In type 1 diabetes, individual susceptibility to severe hypoglycaemia is likely to be influenced by genetic factors. We have previously reported an association of the deletion (D-) allele of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and the A-allele of the angiotensin II receptor subtype 2 (AT2R) 1675 G>A polymorphism with risk of severe hypoglycaemia in such patients. The aim of this study was to test the hypothesis that these alleles are more frequent in patients suffering from the most severe episodes of hypoglycaemia requiring medical emergency treatment. METHODS: The case cohort study consisted of 108 cases of type 1 diabetic patients with severe hypoglycaemia requiring medical emergency treatment during a 1-year period and 262 consecutive controls without such events. ACE I/D and AT2R 1675G>A genotype distributions were compared between cases and controls. RESULTS: The proportion of D-allele carriers was higher amongst cases than controls (83 vs. 73%; P=0.032). In contrast, AT2R genotype distribution was similar in cases and controls. In a multiple regression analysis, D-allele carriage remained a significant risk factor for being a case [odds ratio: 1.9 (1.0-3.6)] together with male sex, impaired symptomatic awareness of hypoglycaemia and presence of nephropathy. CONCLUSION: The D-allele of the ACE gene is associated with severe hypoglycaemia requiring emergency treatment in type 1 diabetic patients with preserved spontaneous ACE activity. This supports the association between high ACE activity and occurrence of severe hypoglycaemia.

Quantification of left ventricular parameters obtained by automated software for 64-slice multidetector computed tomography and comparison with magnetic resonance imaging.

The dataset obtained with 64-slice multidetector CT (MDCT) for coronary artery evaluation can be used to calculate important left ventricular (LV) volumetric parameters. We compared LV parameters derived by new, commercially available, fully automated software for MDCT (Syngo Circulation, Siemens, Germany) to cardiac magnetic resonance (CMR) as a reference standard. Twenty patients underwent CMR after completing a clinically indicated MDCT. Ejection fraction (EF), end-systolic volume (ESV), end-diastolic volume (EDV), stroke volume (SV), and myocardial mass (MM) for MDCT were obtained using automated software and were compared to CMR measurements, with papillary muscles (PMs) included in, or excluded from, the blood pool. The Pearson correlation coefficient (r) and Bland-Altman method were used to determine agreement between methods. When PMs were included in the blood pool, the correlation was excellent for EF (r=0.92, p\0.001), ESV (r=0.86, p\0.001), and EDV (r=0.80, p\0.001). When PMs were excluded from CMR, correlation was still very good for EF (r=0.89, p\0.001), ESV (r=0.82, p\0.001), and EDV (r=0.82, p\0.001). MDCT values for SV and MM showed a good correlation compared to both CMR methods. When PMs were included, the correlation was good for SV (r=0.70, p\0.001), and MM (r=0.70, p\0.001); when they were excluded, the correlation was less robust but still significant for SV (r=0.71, p\0.001) and MM (r=0.73, p\0.001). In conclusion, EF, ESV, and EDV obtained by MDCT using simple, automated software correlated very well with CMR; SV and MM showed good correlation. Automated analysis of volumetric parameters by MDCT can be reliably utilized for clinical purposes.

Role of single photon emission computed tomography/computed tomography in localization of ectopic parathyroid adenoma: a pictorial case series and review of the current literature.

The parathyroid glands are located posterior to the upper and lower poles of the thyroid and are derived from the third and fourth pharyngeal pouches. Usually there are only 2 superior glands, whereas only 40% of patients have their inferior glands located near the inferior thyroid poles. Ectopic locations include the carotid sheath, anterior mediastinum, retropharynx, or intrathyroidal locations. Single photon emission computed tomography/computed tomography (SPECT/CT) offers the advantage of combining function and anatomy for exact localization of ectopic parathyroid adenomas. In this pictorial review, we present 4 cases of hyperparathyroidism caused by ectopic parathyroid adenomas and review the literature on the additional value of their localization with SPECT/CT. Combined SPECT/CT scanners permit more reliable localization of ectopic adenomas. The additional information can aid in exact preoperative localization. In one study of 16 patients, SPECT/CT identified 39% more lesions compared with SPECT imaging alone. In other comparisons of planar, SPECT and SPECT/CT imaging modalities, SPECT/CT permitted the highest reader confidence in localization, especially for mediastinal adenomas. Larger studies are needed to establish the role and cost-effectiveness of SPECT/CT.

Influence of symptomatic status on the prevalence of obstructive coronary artery disease in patients with zero calcium score.

BACKGROUND: CAC has been used to predict obstructive CAD on invasive coronary angiography. However, it is unknown how the prevalence of obstructive CAD in patients with zero CAC is influenced by the presence or absence of chest pain. METHODS: 210 consecutive patients referred for CAC and CorCTA were included in this analysis. Chest pain was defined based on the Diamond-Forrester classification. RESULTS: 134 patients (64%) were symptomatic and 76 (36%) were asymptomatic. Seventy patients had negative (33%); 140 had positive CAC (67%). In the symptomatic group with zero CAC, 8.2% (4/49) had an obstructive, non-calcified plaque; of these, 3 were <45 years. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of CAC in the symptomatic population for detection of obstructive CAD were 0.86 (0.66-0.95), 0.42 (0.33-0.52), 0.28 (0.19-0.39) and 0.92 (0.8-0.97), respectively (p=0.007). No asymptomatic subject with zero CAC had obstructive CAD. Sensitivity, specificity, PPV and NPV of CAC in the asymptomatic population for detection of obstructive CAD were 1.00 (0.66-1.00), 0.32 (0.21-0.45), 0.18 (0.10-0.31) and 1.00 (0.80-1.00), respectively (p=0.05). Optimal cut-points to predict obstructive CAD and AUC were significantly different in symptomatic versus asymptomatic subjects (91 and 0.78 vs. 296 and 0.89, respectively) (p=0.005). CAC performed much better in symptomatic patients >45 years compared to younger patients to exclude obstructive CAD (AUC: 0.83 vs. 0.5, p<0.001; NPV=0.98). CONCLUSIONS: CAC is better in asymptomatic compared to symptomatic subjects, especially in patients

Role of Menkes ATPase in angiotensin II-induced hypertension: a key modulator for extracellular superoxide dismutase function.

The extracellular superoxide dismutase (SOD3), a secretory copper-containing enzyme, regulates angiotensin II (Ang II)-induced hypertension by modulating levels of extracellular superoxide anion. The present study was designed to determine the role of the copper transporter Menkes ATPase (MNK) in Ang II-induced SOD3 activity and hypertension in vivo. Here we show that chronic Ang II infusion enhanced systolic blood pressure and vascular superoxide anion production in MNK mutant (MNK(mut)) mice as compared with those in wild-type mice, which are associated with impaired acetylcholine-induced endothelium-dependent vasorelaxation in MNK(mut) mice. These effects in MNK(mut) mice are rescued by infusion of the SOD mimetic Tempol. By contrast, norepinephrine-induced hypertension, which is not associated with an increase in vascular superoxide anion production, is not affected in MNK(mut) mice. Mechanistically, basal and Ang II infusion-induced increase in vascular SOD3-specific activity is significantly inhibited in MNK(mut) mice. Coimmunoprecipitation analysis reveals that Ang II stimulation promotes association of MNK with SOD3 in cultured vascular smooth muscle cell and in mouse aortas, which may contribute to SOD3-specific activity by increasing copper delivery to SOD3 through MNK. In summary, MNK plays an important role in modulating Ang II-induced hypertension and endothelial function by regulating SOD3 activity and vascular superoxide anion production and becomes a potential therapeutic target for oxidant stress-dependent cardiovascular diseases.

Absolute coronary artery calcium scores are superior to MESA percentile rank in predicting obstructive coronary artery disease.

BACKGROUND: Coronary artery calcium scoring (CAC) is an excellent non-invasive method to evaluate coronary atherosclerotic burden. To better predict the risk of future events in an individual, their absolute CAC score is compared to an age- and gender-matched cohort in order to assign a percentile rank. However, it is unknown whether absolute CAC or percentile rank is better in predicting obstructive coronary artery disease (CAD). We hypothesized that absolute CAC is superior to percentile rank in predicting obstructive CAD. METHODS: 210 consecutive patients referred to our institution for CAC and coronary artery computed tomography angiography (CTA) were included. CAC scores were expressed as Agatston score; percentile rank as published by the Multi-Ethnic Study of Atherosclerosis. Coronary artery stenoses were graded semi-quantitatively. Receiver operating characteristics curves (ROC) were used to assess the performance of CAC to predict obstructive CAD. RESULTS: In the overall group, the area under the curve (AUC) was significantly greater for absolute CAC compared to MESA percentile rank in predicting obstructive CAD (0.80 vs. 0.72, P = 0.006). Subgroup analysis revealed similar findings: AUC for absolute CAC was greater than for MESA percentile rank in males (0.82 vs. 0.71, P = 0.008), females (0.78 vs. 0.72, P = 0.085), symptomatic patients (0.78 vs. 0.72, P = 0.067) and in asymptomatic subjects (0.89 vs. 0.74, P = 0.05). CONCLUSION: Absolute CAC is superior to MESA percentile rank in predicting obstructive CAD. This finding was seen in both symptomatic and asymptomatic patients as well as in males and females.

Novel role of antioxidant-1 (Atox1) as a copper-dependent transcription factor involved in cell proliferation.

Copper plays a fundamental role in regulating cell growth. Many types of human cancer tissues have higher copper levels than normal tissues. Copper can also induce gene expression. However, transcription factors that mediate copper-induced cell proliferation have not been identified in mammals. Here we show that antioxidant-1 (Atox1), previously appreciated as a copper chaperone, represents a novel copper-dependent transcription factor that mediates copper-induced cell proliferation. Stimulation of mouse embryonic fibroblasts (MEFs) with copper markedly increased cell proliferation, cyclin D1 expression, and entry into S phase, which were completely abolished in Atox1(-/-) MEFs. Promoter analysis and EMSA revealed that copper stimulates the Atox1 binding to a previously undescribed cis element in the cyclin D1 promoter. The ChIP assay confirms that copper stimulates Atox1 binding to the DNA in vivo. Transfection of Atox1 fused to the DNA-binding domain of Gal4 demonstrated a copper-dependent transactivation in various cell types, including endothelial and cancer cells. Furthermore, Atox1 translocated to the nucleus in response to copper through its highly conserved C-terminal KKTGK motif and N-terminal copper-binding sites. Finally, the functional role of nuclear Atox1 is demonstrated by the observation that re-expression of nuclear-targeted Atox1 in Atox1(-/-) MEFs rescued the defective copper-induced cell proliferation. Thus, Atox1 functions as a novel transcription factor that, when activated by copper, undergoes nuclear translocation, DNA binding, and transactivation, thereby contributing to cell proliferation.

A lesson for everyone in drug-drug interactions.

An 84-year-old man was admitted to the hospital for severe rhabdomyolysis induced by drug-drug interactions between simvastatin and ketoconazole and he recovered completely. Guidelines are suggesting lower goals for low density cholesterol leading to increased statin use. As the population is aging and treated with multiple medications for other co-morbidities, it is imperative for physician to be aware of potential fatal drug-drug interactions, in our case statins, and look for alternatives.

A left ventricular lipoma presenting as heart failure in a septuagenarian: a first case report.

A 78-year-old Caucasian female presented as an outpatient with a 6-month history of severe progressive exertional dyspnea interfering with ambulating at home. Physical Exam revealed signs of heart failure with laboratory studies being normal. A subsequent echocardiogram revealed a mass in the left ventricle and the patient underwent successful resection of the mass with complete resolution of her symptoms. Histologic examination was consistent with a benign lipoma. After a comprehensive PubMed literature, we believe to report the first case of a left ventricular lipoma diagnosed and treated in the eighth decade of life.

Congestive heart failure-related anemia and a role for erythropoietin.

Congestive heart failure (CHF) is a common clinical problem, especially affecting the elderly. Current strategies of neurohormonal blockade with medications like angiotensin converting enzyme inhibitors have improved morbidity and mortality, but further improvement in outcomes requires new strategies. Both anemia and chronic renal disease commonly accompany congestive heart failure; their close relationship, in which one disease exacerbates the other, has been termed the cardio-renal-anemia syndrome. Correction of anemia in CHF patients using recombinant erythropoietin is feasible; small studies suggest that anemic congestive heart failure patients may have improved morbidity with this therapy. Recent animal and human studies of erythropoietin have shown that its benefit may be derived from both hematological and newly discovered non-hematological properties. Anemia might soon be considered a modifiable risk factor for optimal CHF management.

Frequency and risk factors of severe hypoglycemia in insulin-treated type 2 diabetes: a literature survey.

Intensive treatment regimens including early initiation of insulin treatment are important to prevent late complications in type 2 diabetes. The assumed risk of severe hypoglycemia (SH) is a major barrier to initiation of insulin treatment. To assess the relevance of this risk we evaluated the frequency of SH as reported in the literature. Using Medline and Embase search we identified 11 studies (5 retrospective and 6 prospective) including at least 50 patients with insulin-treated type 2 diabetes followed for at least 6 months in which frequency of SH was reported. The incidence of SH in the retrospective studies varied from 15 to 73 episodes per 100 patient-year with a proportion of the patients having one or more episodes between 1.4 to 15%. In the prospective studies, both incidence rate and proportion of the patients having one or more episodes of SH were lower than in the retrospective studies. Only few studies looked into the impact of risk factors on the rate of SH. Impaired hypoglycemia awareness, high age, long duration of diabetes and insulin therapy increased the risk, while no association was found with HbA1c and insulin dose. The present knowledge of SH in insulin-treated type 2 diabetes is characterized by the paucity of data and the heterogeneity of the few studies available. Large and long-lasting studies with SH as primary endpoint are warranted in order to further clarify the occurrence of SH and influence of the risk factors in unselected patients with insulin-treated type 2 diabetes.

A unique case of pulmonary artery leiomyosarcoma.

Primary pulmonary artery leiomyosarcomas are rare, and the diagnosis is usually confused with other, more common, diseases, especially pulmonary embolism. A 52-year-old male, previously healthy, sustained a cardiac arrest. Chest CT-angiography diagnosed a "saddle embolus". Local thrombolysis was tried without any obvious success. At this point, the possibility of neoplasm was entertained. A cardiac MRI showed a nonhomogeneous mass in the proximal pulmonary artery. Successful surgery was performed, and histological examination of the resected mass was consistent with leiomyosarcoma. A follow-up cardiac MRI showed no residual mass. The dilemma associated with diagnosing pulmonary artery leiomyosarcomas will be discussed.

Autoregulation of glomerular filtration rate in patients with type 2 diabetes during isradipine therapy.

OBJECTIVE: Calcium-channel blockade impairs renal autoregulation in animals. Impaired renal autoregulation leads to transmission of the systemic blood pressure (BP) into the glomerulus, resulting in capillary hypertension. Information on the impact of calcium antagonist treatment on renal autoregulation in humans is lacking. This study examines the effect of isradipine treatment on the autoregulation of the glomerular filtration rate (GFR). RESEARCH DESIGN AND METHODS: We performed a randomized double-blind crossover study with 5 mg o.d. isradipine retard and matching placebo in 16 hypertensive patients with type 2 diabetes. Each treatment arm lasted 4 weeks. On the last day of each treatment period, GFR (single-shot 51Cr-EDTA plasma clearance technique for 4 h) was measured twice between 8:00 A.M. and 5:00 P.M., first without clonidine and then after intravenous injection of 75 micro g clonidine. BP was measured every 10 min (Takeda TM2420; A&D, Tokyo). RESULTS: Clonidine reduced mean arterial BP (MABP) by 15 +/- 1 vs. 11 +/- 1 mmHg (means +/- SE) during placebo and isradipine treatment, respectively (P < 0.05). GFR was reduced from 102 +/- 4 to 99 +/- 4 ml. min(-1). 1.73 m(-2) with placebo (P < 0.01) and from 106 +/- 5 to 98 +/- 5 ml. min(-1). 1.73 m(-2) during treatment with isradipine (P < 0.01). Mean difference (95% CI) between changes in GFR with placebo and isradipine was -4.6 ml. min(-1). 1.73 m(-2) (-10.0 to 0.6) (P = 0.08). Six patients had a reduction in GFR >13% (exceeding the normal limit of autoregulation) combined with a complete pressure-passive vasculature (defined as DeltaMABP% < or = DeltaGFR%) during isradipine treatment versus none during the placebo treatment (P < 0.05). CONCLUSIONS: Isradipine impairs GFR autoregulation in a sizeable proportion of hypertensive type 2 diabetic patients.