Impact on percutaneous coronary intervention for acute coronary syndromes during the COVID-19 outbreak in a non-overwhelmed European healthcare system: COVID-19 ACS-PCI experience in Ireland.

AIMS: To evaluate temporal trends of acute coronary syndromes (ACS) treated via percutaneous coronary intervention (PCI) throughout the COVID-19 outbreak in a European healthcare system affected but not overwhelmed by COVID-19-related pathology. METHODS AND RESULTS: We performed a retrospective multicentre analysis of the rates of PCI for the treatment of ACS within the period 2 months pre and post the first confirmed COVID-19 case in Ireland, as well as comparing PCI for ST-elevation myocardial infarction (STEMI) with the corresponding period in 2019. During the 2020 COVID-19 period (29 February-30 April 2020), there was a 24% decline in PCI for overall ACS (incidence rate ratio (IRR) 0.76; 95% CI 0.65 to 0.88; p<0.001), including a 29% reduction in PCI for non-ST-elevation ACS (IRR 0.71; 95% CI 0.57 to 0.88; p=0.002) and an 18% reduction in PCI for STEMI (IRR 0.82; 95% CI 0.67 to 1.01; p=0.061), as compared with the 2020 pre-COVID-19 period (1 January-28 February 2020). A 22% (IRR 0.78; 95% CI 0.65 to 0.93; p=0.005) reduction of PCI for STEMI was seen as compared with the 2019 reference period. CONCLUSION: This study demonstrates a significant reduction in PCI procedures for the treatment of ACS since the COVID-19 outbreak in Ireland. The reasons for this decline are still unclear but patients need to be encouraged to seek medical attention when cardiac symptoms appear, in order to avoid incremental cardiac morbidity and mortality due to a reduction in coronary revascularisation for the treatment of ACS.

MiR-93-5p is a novel predictor of coronary in-stent restenosis.

AIMS: MicroRNAs (miRNAs), small non-coding RNAs, have been implicated as regulators of multiple phases of atherothrombosis, and some reports have suggested altered levels in coronary artery in-stent restenosis (ISR). We recently demonstrated that miR-93-5 p was able to discriminate between patients with stable coronary artery disease (CAD) and those with no CAD, after adjusting for traditional risk factors (RFs). Thus, we wanted to determine if circulating miRNAs could predict coronary ISR. OBJECTIVE: To determine if circulating miRNAs have diagnostic capability for determining ISR in a cohort of matched patients with and without ISR. APPROACH AND RESULTS: To determine if miRNA plasma levels are elevated in coronary ISR, we conducted a study comprising 78 patients (39 with no ISR and 39 with ISR) and measured plasma miRNAs in each. We then determined the predictive ability of differential miRNAs, adjusting for Framingham Heart Study (FHS) RFs, and stent length and diameter, to discriminate between ISR and no ISR. After correction for multiple testing, two miRNAs-miR425-5p and miR-93-5 p-were differential between patients with ISR and patients without ISR. Only miR-93-5 p remained a strong independent predictor of ISR after correction for FHS RFs (OR 6.30, p=0.008) and FHS RFs plus stent length and diameter (OR 4.80, p=0.02) and improved discriminatory power for ISR over FHS RFs alone in receiver operator characteristic curve analysis. CONCLUSION: This novel finding that miR-93-5 p independently predicts ISR extends our recent observation that miR-93-5 p predicted CAD after adjustment for traditional CAD RFs. These data suggest further potential diagnostic utility.

miRNA-93-5p and other miRNAs as predictors of coronary artery disease and STEMI.

BACKGROUND: MicroRNAs (miRNAs), small non-coding RNAs, have been implicated as regulators of all mediators of atherosclerosis, and some reports have suggested increased levels in coronary artery disease (CAD) and acute myocardial infarction (AMI). However, the potential of miRNAs as biomarkers or predictors of disease remains to be established. METHODS: We designed a study comprising 150 patients (50 Control, 50 Stable CAD, and 50 ST Elevation Myocardial Infarction (STEMI)), and measured plasma miRNAs in each. We then determined the ability of differential miRNAs, adjusting for Framingham Heart Study (FHS) risk factors, to discriminate between CAD vs Control, and STEMI vs Control. RESULTS: Three miRNAs (miR15a-5p, miR16-5p, and miR93-5p) were significantly increased in Stable CAD vs Control groups and one (miR146a-5p) was significantly decreased in Stable CAD vs Control. One miRNA - miR499a-5p - was significantly increased in the STEMI group compared to Controls. After adjustment for FHS risk factors, miR93-5p levels remained an independent predictor of the presence of CAD (Odds Ratio [OR]=8.76, P=0.002). All 4 miRNAs improved discriminatory power for CAD over FHS alone in ROC analysis. Similarly, after adjustment for risk factors miR499-5p remained an independent predictor of STEMI (OR=3.03, P=0.001) and improved discriminatory power for STEMI in ROC analyses. CONCLUSION: We identified 4 miRNAs that were differentially expressed among stable CAD and control patients, and 1 miRNA that was elevated in STEMI patients vs controls. MiR93-5p was the strongest predictor of CAD after adjustment for traditional risk factors, suggesting potential diagnostic utility.

MicroRNA Expression in Coronary Artery Disease.

The pathogenesis of atherosclerosis involves the interplay of inflammation, altered cellular activity, angiogenesis, and neointima formation. The main cellular participants in atherosclerosis include vascular endothelial cells, smooth muscle cells, and monocytes. The recent discovery of small, non-coding RNAs, microRNAs (miRNAs), and their influence on these processes has provided a greater molecular insight into atherosclerosis. This in turn has led to increase focus on the potential utility of miRNA subtypes as biomarkers for coronary artery disease. Furthermore miRNAs could potentially provide therapeutic targets for the treatment of atherosclerosis and its complications. In this review, we discuss the experimental and clinical evidence for the role of miRNAs in the pathogenesis of coronary artery disease, the limitations of the data and challenges facing the field.

A global perspective on psychosocial risk factors for cardiovascular disease.

Worldwide, there is variation in the incidence CVD with the greater burden being borne by low and middle-income countries. Traditional risk factors do not fully explain the CVD risk in populations, and there is increasing awareness of the impact the social environment and psychological factors have on CVD incidence and outcomes. The measurement of psychosocial variables is uniquely complex as variables are difficult to define objectively and local understanding of psychosocial risk factors may be subject to cultural influences. Notwithstanding this, there is a growing evidence base for the independent role they play in the pathogenesis of CVD. Consistent associations have been seen for general psychological stress, work-related stress, locus of control and depression with CVD risk. Despite the strength of this association the results from behavioural and pharmacological interventions have not clearly resulted in improved outcomes.

Influence of race on death and ischemic complications in patients with non-ST-elevation acute coronary syndromes despite modern, protocol-guided treatment.

BACKGROUND: In the setting of acute coronary syndromes (ACS), nonwhite patients are less likely to undergo invasive cardiac procedures and may have worse clinical outcomes than white patients. Whether the disparate outcomes exist independently of potential biases in treatment patterns remains unclear. METHODS AND RESULTS: We examined the association between race and outcome in the Treat Angina with Aggrastat and Determine Cost of Therapy With an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction 18 study (TACTICS-TIMI 18), a randomized trial of invasive versus conservative treatment strategy in patients with non-ST-elevation ACS. There were 1722 white and 461 nonwhite patients. After adjustment for differences in medical characteristics, nonwhite patients were at significantly increased risk for death, MI, or rehospitalization for ACS (hazard ratio [HR], 1.54; P=0.003). Rates of protocol-guided angiography and revascularization were similar in both groups. For non-protocol-guided care, however, we found significant disparities, with nonwhite patients less likely to be taking their cardiac medications at follow-up (odds ratio [OR], 0.59; P=0.0002), to undergo non-protocol-mandated angiography (OR, 0.40; P=0.03), to receive a stent if undergoing percutaneous coronary intervention (OR, 0.55; P=0.045), and to have less procedural success after percutaneous coronary intervention (acute gain, 1.40+/-0.83 versus 1.81+/-0.92 mm; P=0.004). Nonetheless, an invasive strategy was similarly efficacious in white (HR, 0.66; 95% CI, 0.50 to 0.88) and nonwhite (HR, 0.85; 95% CI, 0.52 to 1.39) patients (P(interaction)=0.52), especially in those with troponin elevation or ST deviation. CONCLUSIONS: After adjustment for baseline characteristics, nonwhite patients had a significantly worse prognosis than white patients, regardless of treatment approach. In the absence of protocol guidance, important disparities emerged between the care given the 2 groups. An early invasive strategy is beneficial in and should be considered for all patients, regardless of race.

Postinfarction ventricular septal defect with pseudoaneurysm repair after failed percutaneous closure.

Ventricular septal defect with intramyocardial dissection of the ventricular free wall is a rare complication of myocardial infarction associated with poor prognosis. We describe a patient who developed a ventricular septal defect with intramyocardial dissection of the right ventricular free wall. Initially the patient was successfully stabilized by the placement of a percutaneous closure device. The placement of the device allowed initial hemodynamic recovery of the patient and subsequent definitive surgical repair. This case illustrates the importance of collaboration between interventional cardiologists and cardiac surgeons in the treatment of complex postinfarction ventricular septal defects.

Hemoglobin A1c level and future cardiovascular events among women.

BACKGROUND: Available data suggest that hemoglobin A(1c) (A(1c)), also known as glycosylated hemoglobin, levels may be related to cardiovascular risk in the general population without diabetes mellitus. We sought to test this hypothesis prospectively in a cohort of women without overt cardiovascular disease. METHODS: We conducted a nested case-control study of the Women's Health Study cohort. We identified 464 case patients with incident myocardial infarction, stroke, or coronary revascularization and 928 unmatched control subjects who remained free of cardiovascular events at case diagnosis. The mean follow-up was 7 years. RESULTS: Of the overall study population, 136 had a history of diabetes mellitus or an overtly elevated baseline A(1c) level (>6.4%) and were excluded from the primary analyses. Among women without diabetes mellitus or an elevated baseline A(1c) level, mean +/- SD baseline levels of A(1c) were significantly higher among future cases than controls (5.47% +/- 0.27% vs 5.37% +/- 0.22%; P<.001). The crude relative risks (RRs) of incident cardiovascular events for increasing quartiles of A(1c) were 1.00, 0.98, 1.33, and 2.25 (95% confidence interval [CI] for the highest vs the lowest quartile, 1.59-3.18). The A(1c) levels correlated with several other traditional cardiovascular risk factors, and in fully adjusted models, the predictive effect of A(1c) was attenuated and not significant (RR for the highest vs the lowest quartile, 1.00; 95% CI, 0.65-1.54). In contrast, in the population including women with diabetes mellitus at enrollment, diabetes mellitus (RR, 4.97; 95% CI, 2.81-8.77) remained a strong independent determinant of cardiovascular risk in fully adjusted analyses, while A(1c) levels did not (RR for the highest vs the lowest quartile, 1.11; 95% CI, 0.73-1.71). CONCLUSIONS: The A(1c) level is associated with future cardiovascular risk among women without diabetes mellitus, but this relationship is largely attributable to a strong correlation with other cardiovascular risk factors. In contrast, diabetes mellitus is a strong independent determinant of cardiovascular risk, even after adjustment for A(1c) levels.

C-reactive protein and the risk of developing hypertension.

CONTEXT: Although it has been hypothesized that hypertension is in part an inflammatory disorder, clinical data linking inflammation with incident hypertension are scarce. OBJECTIVE: To examine whether C-reactive protein levels, a marker of systemic inflammation, are associated with incident hypertension. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study that began in 1992 of 20 525 female US health professionals aged 45 years or older who provided baseline blood samples with initially normal levels of blood pressure (BP) (systolic BP <140 mm Hg and diastolic BP <90 mm Hg, and no history of hypertension or antihypertensive medications) and then followed up for a median of 7.8 years for the development of incident hypertension. Plasma C-reactive protein levels were measured and baseline coronary risk factors were collected. MAIN OUTCOME MEASURE: Incident hypertension, defined as either a new physician diagnosis, the initiation of antihypertensive treatment, or self-reported systolic BP of at least 140 mm Hg or a diastolic BP of at least 90 mm Hg. RESULTS: During follow-up, 5365 women developed incident hypertension. In crude models, the relative risks (RRs) and 95% confidence intervals (CIs) of developing hypertension from the lowest (referent) to the highest levels of baseline C-reactive protein were 1.00, 1.25 (95% CI, 1.14-1.40), 1.51 (95% CI, 1.35-1.68), 1.90 (95% CI, 1.72-2.11), and 2.50 (95% CI, 2.27-2.75) (linear trend P<.001). In fully adjusted models for coronary risk factors, the RRs and 95% CIs were 1.00, 1.07 (95% CI, 0.95-1.20), 1.17 (95% CI, 1.04-1.31), 1.30 (95% CI, 1.17-1.45), and 1.52 (95% CI, 1.36-1.69) (linear trend P<.001). C-reactive protein was significantly associated with an increased risk of developing hypertension in all prespecified subgroups evaluated, including those with very low levels of baseline BP, as well as those with no traditional coronary risk factors. Similar results were found when treating C-reactive protein as a continuous variable and controlling for baseline BP. CONCLUSION: C-reactive protein levels are associated with future development of hypertension, which suggests that hypertension is in part an inflammatory disorder.

Blood pressure, C-reactive protein, and risk of future cardiovascular events.

BACKGROUND: Accumulating data suggest a link between blood pressure and vascular inflammation. METHODS AND RESULTS: We examined the relationship between blood pressure, C-reactive protein (CRP), and incident first cardiovascular events among 15 215 women followed prospectively over a median of 8.1 years. In cross-sectional analyses at baseline, median levels of CRP for women with blood pressure <120/75, 120 to 129/75 to 84, 130 to 139/85 to 89, 140 to 159/90 to 94, and > or =160/95 mm Hg were 0.96, 1.42, 2.20, 2.82, and 3.34 mg/L, respectively (P for trend <0.0001). Increasing categories of blood pressure were significant predictors of CRP levels at baseline. In prospective analyses, both elevated CRP levels (> or =3 mg/L) and increasing categories of blood pressure were independent determinants of future cardiovascular events, and CRP had incremental prognostic value at all levels of blood pressure. The adjusted hazard ratio for women with blood pressure > or =160/95 mm Hg and CRP levels > or =3 mg/L was 8.31 (95% CI, 4.44 to 15.55, P<0.0001) compared with those with blood pressure <120/75 and CRP levels <3 mg/L. After participants had been divided into 4 groups on the basis of CRP levels (<3 or > or =3 mg/L) and blood pressure levels (<130/85 or > or =130/85), the risk factor-adjusted hazard ratios were as follows: low CRP/low blood pressure, 1.0; high CRP/low blood pressure, 1.87 (P=0.002); low CRP/high blood pressure, 2.54 (P<0.0001); and high CRP/high blood pressure, 3.27 (P<0.0001). CONCLUSIONS: CRP and blood pressure are independent determinants of cardiovascular risk, and their predictive value is additive.

Effect of pravastatin on LDL particle concentration as determined by NMR spectroscopy: a substudy of a randomized placebo controlled trial.

AIM: Recent data suggests that LDL particle concentration, as determined by Nuclear Magnetic Resonance (NMR) spectroscopy, may be associated with cardiovascular risk. We sought to determine the effect of randomization to pravastatin therapy on LDL particle concentration-NMR, among a primary prevention population. METHODS AND RESULTS: LDL particle concentration-NMR, LDL size-NMR, and standard chemical lipid parameters were measured at baseline and after 12 weeks among 500 individuals without overt coronary disease randomly allocated to pravastatin 40mg (n=256) or placebo (n=244). Randomization to pravastatin therapy caused a 19% reduction in median LDL particle concentration-NMR at 12 weeks, as compared to a 4.2% increase among those randomized to placebo (P<0.001 for pravastatin group compared to placebo). Pravastatin therapy caused a median 24.9% reduction in LDL cholesterol measured chemically compared to a 0.9% increase in the placebo group (P<0.001). Pravastatin therapy did not cause a significant change in median LDL size-NMR (0.5% increase in pravastatin group vs 0.0% in placebo group; P=0.25). The change in LDL particle concentration with pravastatin correlated inversely with baseline LDL size (r=-0.24; P<0.001) such that the largest reduction in LDL particle concentration-NMR was among those with the smallest LDL size-NMR at baseline (median% change =21.4% for tertile 1 of LDL size, 19.9% for tertile 2, and 16.5% for tertile 3; P=0.03). In contrast, pravastatin-induced changes in LDL cholesterol did not correlate with baseline LDL size-NMR (r=-0.05; P=0.47). CONCLUSION: Among individuals without overt hyperlipidemia or known coronary artery disease, randomized allocation to pravastatin (40mg) therapy for 12 weeks caused a reduction in LDL particle concentration-NMR, the magnitude of which was dependent on baseline LDL size-NMR.

Inflammatory biomarkers of the patient with myocardial insufficiency.

PURPOSE OF REVIEW: Inflammation plays a central role in the genesis of atherosclerosis and its complications. In this regard, plasma levels of several markers of inflammation have been shown to predict risk of future cardiovascular events, including cardiovascular death, myocardial infarction, and ischemic stroke. Furthermore, the predictive value of inflammatory markers is independent of traditional risk markers such as lipid levels, or cardiac troponin levels among those with acute coronary syndromes. RECENT FINDINGS: Indeed, recent data suggest that among more than 27,000 apparently healthy women, the predictive value of C-reactive protein, the most extensively studied marker of vascular inflammation, was at least as good as that of low-density lipoprotein cholesterol. In addition, hypothesis-generating data suggest that the benefits of proven interventions such as statin therapy and glycoprotein IIb/IIIa receptor blockade may be most effective among those with elevated markers of inflammation. SUMMARY: Combining our evolving understanding of the vascular biology of atherosclerosis with clinical studies of inflammatory markers and mediators may help refine our diagnostic and therapeutic armamentarium for cardiovascular disease.

Potential cost-effectiveness of C-reactive protein screening followed by targeted statin therapy for the primary prevention of cardiovascular disease among patients without overt hyperlipidemia.

BACKGROUND: Evidence suggests that statin therapy reduces the rate of cardiovascular events among patients with low lipid levels but elevated C-reactive protein levels. However, no cost-effectiveness analyses have been performed to assist in determining whether large-scale randomized trials are merited to test this hypothesis. METHODS: We used a Markov model to estimate the benefits, costs, and incremental cost-effectiveness of C-reactive protein screening followed by targeted statin therapy for elevated C-reactive protein levels, compared with dietary counseling alone, for the primary prevention of cardiovascular events among patients with low-density lipoprotein cholesterol levels <149 mg/dL. All costs were in 2000 U.S. dollars. RESULTS: The potential incremental cost-effectiveness ratio for screening followed by statin therapy compared with no screening and no statin therapy was $48,100 per quality-adjusted life-year (QALY) for 58-year-old men and $94,400 per QALY for 58-year-old women. Screening was most cost-effective for 65-year-old men ($42,600 per QALY) and least cost-effective for 35-year-old women ($207,300 per QALY). Our results were most sensitive to the baseline risk of coronary heart disease, the cost of statin therapy, and the efficacy of statin therapy for preventing myocardial infarction in patients with high C-reactive protein levels. If a 58-year-old man who smokes and is hypertensive was considered, screening for C-reactive protein followed by statin therapy would be cost saving if the cost of statin therapy was reduced to $500 per year. If the cost of statin therapy was reduced to $1 per day, the cost-effectiveness of screening would be $4900 per QALY for 58-year-old men and $19,600 per QALY for women of the same age. If the costs associated with elective revascularization (percutaneous coronary intervention or coronary artery bypass surgery) were included in the base case analyses, the incremental cost-effectiveness ratios for screening would be $40,100 per QALY for 58-year-old men and $87,300 per QALY for women. CONCLUSION: A strategy involving C-reactive protein screening to target statin therapy for the primary prevention of cardiovascular disease among middle-aged patients without overt hyperlipidemia could be relatively cost-effective and, in some cases, cost saving.

C-reactive protein and other inflammatory risk markers in acute coronary syndromes.

Markers of myocyte necrosis such as cardiac troponin or creatine kinase-myocardial band are invaluable tools for risk stratification among patients presenting with acute coronary syndromes (ACS). Nonetheless, many patients without any evidence of myocyte necrosis may be at high risk for recurrent ischemic events. In consideration of the important role that inflammatory processes play in determining plaque stability, recent work has focused on whether plasma markers of inflammation may help improve risk stratification. Of these markers, C-reactive protein (CRP) has been the most widely studied, and there is now robust evidence that CRP is a strong predictor of cardiovascular risk among apparently healthy individuals, patients undergoing elective revascularization procedures, and patients presenting with ACS. Moreover, even among patients with troponin-negative ACS, elevated levels of CRP are predictive of future risk. Other, more upstream markers of the inflammatory cascade, such as interleukin (IL)-6, have also been found to be predictive of recurrent vascular instability. A recent report from the second FRagmin during InStability in Coronary artery disease trial investigators suggests that elevated levels of an inflammatory marker such as IL-6 may indicate which patients may benefit most from an early invasive strategy. Other inflammatory markers currently under investigation include lipoprotein-associated phospholipase A(2), myeloperoxidase, and pregnancy-associated plasma protein A. Of all these novel markers, CRP appears to meet most of the criteria required for potential clinical application. Furthermore, the benefits of lifestyle modification and drug therapy with aspirin or statins may be most marked among those with elevated CRP levels.

Soluble CD40 ligand levels indicate lipid accumulation in carotid atheroma: an in vivo study with high-resolution MRI.

OBJECTIVE: The CD40/CD40 ligand pathway mediates inflammatory processes important in atherogenesis and the formation of the intraplaque lipid pool. We tested the hypothesis that plasma levels of soluble CD40 ligand are elevated in patients with evidence of a lipid pool on high-resolution magnetic resonance imaging (MRI) of carotid stenoses. METHODS AND RESULTS: We recruited 49 patients with evidence of carotid atherosclerosis on ultrasonography; 3 patients could not undergo carotid MRI because of claustrophobia. The remaining 46 patients underwent high-resolution MRI of the carotid arteries. Two radiologists blinded to all other data determined the presence or absence of an intraplaque lipid pool based on the loss of signal between the 20-ms echo time (TE20) and the fat-suppressed TE55 fast spin-echo images. Plasma levels of soluble CD40 ligand were determined by ELISA. Baseline levels of soluble CD40 ligand were higher among patients with evidence of intraplaque lipid (n=14) than among those without it (n=32; median, 2.54 ng/mL; interquartile range [IQR], 1.85 to 3.52 vs median, 1.58 ng/mL; IQR, 1.21 to 2.39; P=0.02). In contrast, soluble CD40 ligand levels were not correlated with percent diameter stenosis (r=-0.19; P=0.21). The relative risk for intraplaque lipid associated with soluble CD40 ligand levels above the median was 6.0 (95% confidence interval, 1.15 to 31.23; P=0.03). The magnitude of this predictive effect did not substantially change after adjustment for traditional cardiovascular risk factors (relative risk, 5.12; 95% confidence interval, 0.78 to 33.73; P=0.09). CONCLUSIONS: Plasma levels of soluble CD40 ligand may predict patients with features of high-risk atherosclerotic lesions. These data provide novel insight into the mechanism through which elevated levels of soluble CD40 ligand may reflect cardiovascular risk in humans and illustrate the potential value of interfacing high-resolution MRI with studies of vascular inflammation.