Reference invasive tests of microvascular injury in myocardial infarction

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Novel insights into the assessment and therapeutics of microcirculatory injury in acute myocardial infarction

Introduction: Microvascular injury in acute ST-segment elevation myocardial infarction (STEMI) is an important predictor of adverse prognosis. However, persistent microvascular injury typically passes undetected after primary percutaneous coronary intervention (PCI), and is a problem of unmet therapeutic need. The aim of this work was to gain greater insight into the invasive assessment of acute microvascular injury following primary PCI, for risk-stratification, and to provide mechanistic insights into the effects of intracoronary alteplase on the microcirculation. Methods: The first part of the thesis sought to establish the influence of coronary flow on the effects of adjunctive intracoronary alteplase, and to investigate the effects of intracoronary alteplase on invasive physiology measures of microvascular function. Through a multi-centre, prospective, randomised controlled trial (T-TIME, NCT02257294), alteplase 10mg, and alteplase 20mg were compared to placebo, in patients undergoing primary PCI. Eligible participants presented within 6 hours from STEMI onset, and the study drug was administered before stent implantation. In 421 patients, TIMI (thrombolysis in myocardial infarction) flow grade was determined in the infarct-related artery immediately before study drug administration. In a subset of 144 patients, invasive physiology parameters were measured in the infarct-related artery at the end of the primary PCI procedure (the prespecified T-TIME physiology sub-study). These invasive physiology parameters included index of microcirculatory resistance (IMR), coronary flow reserve (CFR) and resistive reserve ratio (RRR). Microvascular obstruction (MVO) and myocardial haemorrhage were assessed on cardiovascular magnetic resonance (CMR) imaging at 2 to 7 days post-STEMI, and CMR imaging was repeated at 3 months. The second part of the thesis sought to prospectively compare IMR, CFR, RRR, myocardial perfusion grade (MPG) and TIMI frame count (TFC), for predicting MVO and myocardial haemorrhage, and clinical outcomes at 1 year, in the T-TIME physiology sub-study. The following adjudicated clinical outcomes were assessed: major adverse cardiac events, heart failure hospitalisations, and all-cause death/ heart failure hospitalisations. Furthermore, a retrospective analysis was performed in 271 acute STEMI patients from a single-centre observational study (MR-MI, NCT02072850), for the derivation of a newly conceived invasive physiology parameter termed temperature recovery time (TRT). The associations between TRT and MVO (on 2 to 7 day CMR imaging) and clinical outcomes, were assessed in the MR-MI cohort, and were prospectively validated in the T-TIME physiology sub-study population. Results: The main findings are summarised as follows: - Low-dose intracoronary alteplase given early during primary PCI, was associated with increased occurrence of MVO and myocardial haemorrhage in participants who had TIMI flow ≤2 immediately preceding drug administration. - In participants with TIMI 3 flow immediately preceding drug administration, there was no difference in MVO or myocardial haemorrhage with intracoronary alteplase compared to placebo. - There was overall no difference in microvascular function, measured by IMR, CFR and RRR, between intracoronary alteplase and placebo groups. - In patients with ischaemic time <2 hours, CFR and RRR were higher with alteplase 20mg vs. placebo, whereas in patients with ischaemic times ≥4 hours, MVO extent was higher with alteplase 20mg vs. placebo. - In acute STEMI patients, lower RRR, IMR >40, and MPG ≤1 were associated with more MVO, myocardial haemorrhage presence and adverse clinical outcomes, whereas CFR ≤2 was not. - In acute STEMI patients, TFC >27 was associated with adverse clinical outcomes, but was not associated with MVO or myocardial haemorrhage. - Higher TRT independently predicted more MVO and adverse clinical outcomes, in two independent acute STEMI cohorts. Conclusions: The findings from this PhD are novel and clinically relevant. Invasive measures of microvascular injury during primary PCI allows potential for early administration of targeted adjunctive therapies to the highest risk patients. The data support IMR in conjunction with RRR instead of CFR, to select patients for adjunctive therapies. Moreover, TRT was found to detect failed microvascular perfusion and may have potential to refine risk stratification in acute STEMI. The findings raise a question as to the safety of intracoronary administration of alteplase in the context of STEMI when there is <TIMI 3 flow. Finally, the data suggest that future studies evaluating the effects of intracoronary fibrinolysis should limit recruitment to patients with short ischaemic time

Sex-based associations with microvascular injury and outcomes after ST-segment elevation myocardial infarction

Objectives: We aimed to assess for sex differences in invasive parameters of acute microvascular reperfusion injury and infarct characteristics on cardiac MRI after ST-segment elevation myocardial infarction (STEMI). Methods: Patients with STEMI undergoing emergency percutaneous coronary intervention (PCI) were prospectively enrolled. Index of microcirculatory resistance (IMR) and coronary flow reserve (CFR) were measured in the culprit artery post-PCI. Contrast-enhanced MRI was used to assess infarct characteristics, microvascular obstruction and myocardial haemorrhage, 2 days and 6 months post-STEMI. Prespecified outcomes were as follows: (i) all-cause death/first heart failure hospitalisation and (ii) cardiac death/non-fatal myocardial infarction/urgent coronary revascularisation (major adverse cardiovascular event, MACE) during 5- year median follow-up. Results: In 324 patients with STEMI (87 women, mean age: 61 ± 12.19 years; 237 men, mean age: 59 ± 11.17 years), women had anterior STEMI less often, fewer prescriptions of beta-blockers at discharge and higher baseline N-terminal pro-B-type natriuretic peptide levels (all p &lt; 0.05). Following emergency PCI, fewer women than men had Thrombolysis in Myocardial Infarction (TIMI) myocardial perfusion grades ≤ 1 (20% vs 32%, p = 0.027) and women had lower corrected TIMI frame counts (12.94 vs 17.65, p = 0.003). However, IMR, CFR, microvascular obstruction, myocardial haemorrhage, infarct size, myocardial salvage index, left ventricular remodelling and ejection fraction did not differ significantly between sexes. Female sex was not associated with MACE or all-cause death/first heart failure hospitalisation. Conclusion: There were no sex differences in microvascular pathology in patients with acute STEMI. Women had less anterior infarcts than men, and beta-blocker therapy at discharge was prescribed less often in women

Calculated plasma volume status predicts outcomes after transcatheter aortic valve implantation

Objectives: Congestion can worsen outcomes after transcatheter aortic valve implantation (TAVI), but can be difficult to quantify non-invasively. We hypothesised that preprocedural plasma volume status (PVS), estimated using a validated formula that enumerates percentage change from ideal PV, would provide prognostic utility post-TAVI. Methods: This retrospective cohort study identified patients who underwent TAVI (2007–2017) from a prospectively collected database. Actual ([1-haematocrit] × [a + (b × weight (Kg))] and ideal (c × weight (Kg)) PV were quantified from equations where a, b and c are sex-dependent constants. Calculated PVS was then derived (100% x [(actual – ideal PV)/ideal PV]). Results: In 564 patients (mean age 82±7 years, 49% male), mean PVS was −2.7±10.2%, with PV expansion (PVS &gt;0%) evident in 39%. Only logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) independently predicted a PVS &gt;0% (OR 1.85, p=0.002). On Cox analyses, a PVS &gt;0% was associated with greater mortality at 3 (HR 2.29, 95% CI 1.11 to 4.74, p=0.03) and 12 months (HR 2.00, 95% CI 1.23 to 3.26, p=0.006) after TAVI, independently of, and incremental to, the EuroSCORE and New York Heart Association class. A PVS &gt;0% was also independently associated with more days in intensive care (coefficient: 0.41, 95% CI 0.04 to 0.78, p=0.03) and in hospital (coefficient: 1.95, 95% CI 0.48 to 3.41, p=0.009). Conclusion: Higher PVS values, calculated simply from weight and haematocrit, are associated with greater mortality and longer hospitalisation post-TAVI. PVS could help refine risk stratification and further investigations into the utility of PVS-guided management in TAVI patients is warranted

Low-dose alteplase during primary percutaneous coronary intervention according to ischemic time

Background: Microvascular obstruction affects one-half of patients with ST-segment elevation myocardial infarction and confers an adverse prognosis. Objectives: This study aimed to determine whether the efficacy and safety of a therapeutic strategy involving low-dose intracoronary alteplase infused early after coronary reperfusion associates with ischemic time. Methods: This study was conducted in a prospective, multicenter, parallel group, 1:1:1 randomized, dose-ranging trial in patients undergoing primary percutaneous coronary intervention. Ischemic time, defined as the time from symptom onset to coronary reperfusion, was a pre-specified subgroup of interest. Between March 17, 2016, and December 21, 2017, 440 patients, presenting with ST-segment elevation myocardial infarction within 6 h of symptom onset (&lt;2 h, n = 107; ≥2 h but &lt;4 h, n = 235; ≥4 h to 6 h, n = 98), were enrolled at 11 U.K. hospitals. Participants were randomly assigned to treatment with placebo (n = 151), alteplase 10 mg (n = 144), or alteplase 20 mg (n = 145). The primary outcome was the amount of microvascular obstruction (MVO) (percentage of left ventricular mass) quantified by cardiac magnetic resonance imaging at 2 to 7 days (available for 396 of 440). Results: Overall, there was no association between alteplase dose and the extent of MVO (p for trend = 0.128). However, in patients with an ischemic time ≥4 to 6 h, alteplase increased the mean extent of MVO compared with placebo: 1.14% (placebo) versus 3.11% (10 mg) versus 5.20% (20 mg); p = 0.009 for the trend. The interaction between ischemic time and alteplase dose was statistically significant (p = 0.018). Conclusion: In patients presenting with ST-segment elevation myocardial infarction and an ischemic time ≥4 to 6 h, adjunctive treatment with low-dose intracoronary alteplase during primary percutaneous coronary intervention was associated with increased MVO. Intracoronary alteplase may be harmful for this subgroup. (A Trial of Low-Dose Adjunctive Alteplase During Primary PCI [T-TIME]; NCT02257294

Effect of coronary flow on intracoronary alteplase: a prespecified analysis from a randomised trial

Objectives: Persistently impaired culprit artery flow (&lt;TIMI 3) during primary percutaneous coronary intervention is a surrogate for failed myocardial perfusion. We evaluated the effects of intracoronary alteplase according to TIMI flow grade immediately preceding drug administration. Methods: In T-TIME (trial of low-dose adjunctive alTeplase during primary PCI), patients ≤6 hours from onset of ST-elevation myocardial infarction (STEMI) were randomised to placebo, alteplase 10 mg or alteplase 20 mg, administered by infusion into the culprit artery, pre-stenting. In this prespecified, secondary analysis, coronary flow was assessed angiographically at the point immediately before drug administration. Microvascular obstruction, myocardial haemorrhage and infarct size were assessed by cardiovascular magnetic resonance (CMR) at 2–7 days and 3 months. Results: TIMI flow was assessed after first treatment (balloon angioplasty/aspiration thrombectomy), immediately pre-drug administration, in 421 participants (mean age 61±10 years, 85% male) and was 3, 2 or 1 in 267, 134 and 19 participants respectively. In patients with TIMI flow ≤2 pre-drug, there was higher incidence of microvascular obstruction with alteplase (alteplase 20 mg (53.1%) and 10 mg (59.5%) combined versus placebo (34.1%); OR=2.47 (95% CI 1.16 to 5.22, p=0.018) interaction p=0.005) and higher incidence of myocardial haemorrhage (alteplase 20 mg (53.1%) and 10 mg (57.9%) combined vs placebo (27.5%); OR=3.26 (95% CI 1.44 to 7.36, p=0.004) interaction p=0.001). These effects were not observed in participants with TIMI 3 flow pre-drug. There were no interactions between TIMI flow pre-drug, alteplase and 3-month CMR findings. Conclusion: In patients with impaired culprit artery flow (&lt;TIMI 3) after initial balloon angioplasty/thrombus aspiration, intracoronary alteplase was associated with increased presence of microvascular obstruction and myocardial haemorrhage

Wrist mass in a 93-year-old woman

Clinical introduction A 93-year-old woman presented electively for transaortic valve implantation (TAVI), for severe aortic stenosis. She had a history of hypertension and hypothyroidism, and she was taking clopidogrel, antihypertensives and levothyroxine. In preparation for her TAVI procedure she underwent coronary angiography 4 months previously. Her coronary angiogram revealed severe three vessel disease, however, the consensus from the multidisciplinary team meeting, at that time, was to manage the coronary disease medically. Physical examination revealed a large, non-tender swelling on the volar aspect of her wrist (figure 1). The swelling had progressively enlarged in size over the preceding 4 months. Duplex ultrasonography was performed, but was technically difficult. Turbulent bidirectional flow was seen within the wrist swelling, however the connecting tract from which the flow originated was not adequately visualised

Arachidonate 5-lipoxygenase (5-LO) promoter genotype and risk of myocardial infarction: A case–control study

Background: Leukotrienes are inflammatory mediators derived from arachidonic acid via the 5-lipoxygenase pathway. Both experimental and clinical studies implicate the 5-lipoxygenase pathway in the pathophysiology of atherosclerosis. In a previous study, a microsatellite polymorphism in the 5-lipoxygenase gene promoter involving the binding site for the transcription factor Sp1, was associated with carotid intima media thickness (CIMT). Compared to subjects carrying the common allele, subjects carrying two variant alleles had significantly greater CIMT. Elevated CIMT is a risk factor for coronary events. In this study we investigated whether carriage of two variants alleles for the 5-lipoxygenase promoter polymorphism is associated with increased risk of myocardial infarction (MI). Methods: 1464 subjects, comprising 746 MI cases (under 65 years of age) and 718 controls, were genotyped for the 5-lipoxygenase microsatellite polymorphism by PCR amplification of the promoter region and allele discrimination by capillary electrophoresis. Results: The distribution of subjects grouped into those homozygote for the common allele, subjects carrying one variant allele, and subjects carrying two variant alleles was similar in cases and controls (cases: 66.9%/29.8%/3.3%, controls: 66.0%/29.4%/4.6%, p = 0.48). The odds ratio for MI for subjects carrying two variant alleles compared to subjects carrying at least one common allele was 0.72 (95% CI: 0.42–1.22, p = 0.22). The odds ratio was not affected by adjustment for other demographic risk factors. Conclusions: Despite their association with a marker of atherosclerosis, variant 5-lipoxygenase promoter genotypes are not a major risk factor for MI, at least in Caucasian subjects of Northern European origin

Obesity and cardiovascular outcomes: a review

The prevalence of obesity is increasing at an epidemic rate globally with more than 1 billion adults overweight and at least 300 million of them clinically obese. This is expected to rise further in the next 20 to 30 years. Obesity is known to be an independent risk factor for serious health conditions, including hypertension, type 2 diabetes, and cardiovascular diseases. Given the association of obesity with cardiovascular disease, it could be speculated that obese individuals would have adverse outcomes after a cardiovascular event compared to those with normal body mass index (BMI). However, various studies have reported a paradoxical U-shaped relationship between obesity and mortality from various diseases, including myocardial infarction and heart failure, suggesting that patients with higher BMI have similar or lower short- and long-term mortality rates. This phenomenon has been termed the ‘obesity paradox’ or ‘reverse epidemiology’. The goal of this review is to evaluate the potential mechanisms behind the obesity paradox and its implications