Comorbidities associated with reduced myocardial flow reserve in non-obstructive disease

Introduction Microvascular Dysfunction defined as a Myocardial Flow Reserve (MFR) <2 or <2.5 depending on the center, may present in the absence of significant obstruction (1,2); it is included as a diagnosis criteria of Microvascular Angina (MVA) (3,4) and is an independent risk factor associated with poor prognosis (5–7). Traditional Coronary Artery Disease (CAD)risk factors have also been associated with MVA (8–10), however, there is reduced data in latin populations with high prevalence of comorbidities. The aim of this study was to identify the comorbidities that alter MFR with 13N-ammonia Positron Emission Tomography/Cardiac Tomography (PET/CT) and Cardiac Computed Tomography Angiography (CCTA) in a cardiovascular imaging referral center. Methods Retrospective cross-sectional study of patients with suspected CAD in which both PET/CT and CCTA were performed. Inclusion:CCTA with obstruction <50%. Exclusion: incomplete study, previous infarction or intervention. Clinical data was assessed. Mean (±DE) or median (interquartile range) to present continuous variables according to their distribution; T student or U Man Whitney to compare them. For each variable two groups were conformed depending on its presence or absence in order to compare MFR between them. Statistical analysis was performed with Statistical Package for Social Science (SPSs Inc, Chicago, IL; version 23.0) and GraphPad Prism version 9.0. p<0.05 was considered as significant. Results 335 patients included. MFR difference for each variable: female sex, hypertension (HT), Type 2 diabetes (T2D) and smoking – Appendix 1. Significant MFR difference for HT (p=0.024) and T2D (p=0.046). Severe ischemia had significant MFR reduction (p=0.006); patients with both HT and mild ischemia (p=0.018) – Appendix 2. Discussion Individuals with HT and T2D had a significantly lower MFR, consistent with previous studies (8,9). Absence of correlation with other risk factors, such as smoking (10) and female sex (11); latter may be caused by a significant lower number of women (108 vs 227). Further analysis in this subgroup ought to be done. When comparing MFR between level-of-ischemia groups, microvascular function was not reduced until severe ischemia. Remarkably, if we analyze the coexistence of HT with ischemia, MFR is reduced even in patients with mild ischemia. This finding highlights the importance of HT which alters function in early stages even in the absence of significant obstruction. This is one of the first studies correlating MFR with comorbidities in our population. Limitations the retrospective nature of the study. Conclusions MFR non-invasive assessment by PET/CT allows identifying very early stages of MVD, even in asymptomatic patients and when there's no evidence of ischemia or CAD. Therefore, timely recognition of this problem is mandatory to implement action strategies to stop the triggered events' cascade. FUNDunding Acknowledgement Type of funding sources: None.

Outcomes in the ISCHEMIA Trial Based on Coronary Artery Disease and Ischemia Severity

Background: The ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) postulated that patients with stable coronary artery disease (CAD) and moderate or severe ischemia would benefit from revascularization. We investigated the relationship between severity of CAD and ischemia and trial outcomes, overall and by management strategy. Methods: In total, 5179 patients with moderate or severe ischemia were randomized to an initial invasive or conservative management strategy. Blinded, core laboratory–interpreted coronary computed tomographic angiography was used to assess anatomic eligibility for randomization. Extent and severity of CAD were classified with the modified Duke Prognostic Index (n=2475, 48%). Ischemia severity was interpreted by independent core laboratories (nuclear, echocardiography, magnetic resonance imaging, exercise tolerance testing, n=5105, 99%). We compared 4-year event rates across subgroups defined by severity of ischemia and CAD. The primary end point for this analysis was all-cause mortality. Secondary end points were myocardial infarction (MI), cardiovascular death or MI, and the trial primary end point (cardiovascular death, MI, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest). Results: Relative to mild/no ischemia, neither moderate ischemia nor severe ischemia was associated with increased mortality (moderate ischemia hazard ratio [HR], 0.89 [95% CI, 0.61–1.30]; severe ischemia HR, 0.83 [95% CI, 0.57–1.21]; P =0.33). Nonfatal MI rates increased with worsening ischemia severity (HR for moderate ischemia, 1.20 [95% CI, 0.86–1.69] versus mild/no ischemia; HR for severe ischemia, 1.37 [95% CI, 0.98–1.91]; P =0.04 for trend, P =NS after adjustment for CAD). Increasing CAD severity was associated with death (HR, 2.72 [95% CI, 1.06–6.98]) and MI (HR, 3.78 [95% CI, 1.63–8.78]) for the most versus least severe CAD subgroup. Ischemia severity did not identify a subgroup with treatment benefit on mortality, MI, the trial primary end point, or cardiovascular death or MI. In the most severe CAD subgroup (n=659), the 4-year rate of cardiovascular death or MI was lower in the invasive strategy group (difference, 6.3% [95% CI, 0.2%–12.4%]), but 4-year all-cause mortality was similar. Conclusions: Ischemia severity was not associated with increased risk after adjustment for CAD severity. More severe CAD was associated with increased risk. Invasive management did not lower all-cause mortality at 4 years in any ischemia or CAD subgroup. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01471522.

Nails Involvement in Winiwarter-Buerger Disease

<b><i>Introduction:</i></b> Buerger disease, or thromboangiitis obliterans, is an inflammatory and occlusive process involving small and medium size arteries and veins, which generally affects the lower limbs of young adult male with the habit of smoking. <b><i>Case Presentation:</i></b> This paper reports 2 patients who developed nail lesions as the first sign of Buerger disease. <b><i>Conclusion:</i></b> Signs and symptoms of Buerger’s disease are secondary to the inflammatory process and arterial occlusion which results in severe ischemia. Involvement of nails is not common, but we found 2 different clinical features which have not been previously reported in the literature: chronic paronychia, and proximal leukonychia or onycholysis and nail bed erosion.

Effects of remote ischemic preconditioning on the deformability and aggregation of red blood cells in a rat endotoxemia model

BACKGROUND: The prevention of rheologic alterations in erythrocytes may be important for reducing sepsis-associated morbidity and mortality. Remote ischemic preconditioning (RIPC) has been shown to prevent tissue damage caused by severe ischemia and mortality resulting from sepsis. However, the effect of RIPC on erythrocytes in sepsis is yet to be determined. OBJECTIVE: To investigate the effect of RIPC on rheologic alterations in erythrocytes in sepsis. METHODS: Thirty male Sprague-Dawley rats were used in this study. An endotoxin-induced sepsis model was established by intraperitoneally injecting 20 mg/kg LPS (LPS group). RIPC was induced in the right hind limb using a tourniquet, with three 10-minute of ischemia and 10 min of reperfusion cycles immediately before the injection of LPS (RIPC/LPS group) or phosphate-buffered saline (RIPC group). The aggregation index (AI), time to half-maximal aggregation (T1/2), and maximal elongation index (EImax) of the erythrocytes were measured 8 h after injection. RESULTS: The AI, T1/2, and EImax values in the LPS and RIPC/LPS groups differed significantly from those in the RIPC group, but there were no differences between the values in the LPS and RIPC/LPS groups. CONCLUSIONS: RIPC did not prevent rheologic alterations in erythrocytes in the rat model of LPS-induced endotoxemia.

Clinical and imaging variables associated to Microvascular Angina, a 13N-AMMONIA MPI Approach

Funding Acknowledgements Type of funding sources: None. On Behalf of MiniFellows Research Group CLINICAL AND IMAGING VARIABLES IN MICROVASCULAR ANGINA. A 13N-AMMONIA MPI APPROACH Background Patients with typical angina may have no obstructive artery disease1 and 2/3 may present microvascular dysfunction(MVD)2 which is associated with poor prognosis3,4,5. In 2017 the Coronary Vasomotion Disorders International Study Group (COVADIS) included it as a criteria of MVA6; later, included in MINOCA ESC 2020 guidelines.7 For diagnosis6,7: symptoms of ischemia; absence of relevant epicardial CAD (&lt;50% diameter reduction or FFR &gt;0.80); myocardial ischemia; impaired coronary microvascular function (CFR &lt; 2 or &lt;2.5 depending on methodology). Our aim was to identify clinical and imaging variables in patients with MVA due to 13N-ammonia Positron Emission Tomography/Cardiac Tomography(PET/CT) and Cardiac Computed Tomography Angiography(CCTA) in a cardiovascular imaging referral center. Methods.Retrospective, cross-sectional study of patients with suspected CAD. For inclusion: ischemia quantitation (summed stress score,SDS &lt; 3) and obstruction &lt;50% in all vessels. Exclusion criteria: previous infarction, intervention, or incomplete study. Clinical data was assessed. Both studies performed on the same day. Frequencies and percentages to report categorical variables; x2 and Fisher´s exact tests to compare them. Mean (+/-DE) or median (interquartile range) to report continuous variables according to their distribution, and T student or Wilcoxon test to compare them. Results 274 patients included: Group A (CFR &lt;2) and group B (CFR 2)(108vs166). Difference for systemic hypertension(p &lt;0.001), type 2 diabetes mellitus(p &lt;0.001), dyslipidemia(p = 0.019), smoking(p &lt;0.001). Group B presented higher incidence for mild ischemia(p = 0.004) while MVA for severe ischemia(p = 0.002). Difference between groups for EDV and ESV at rest (p = 0.002), EDV at stress(p = 0.03) and at rest(p &lt; 0.001), LVEF at rest and stress(p &lt; 0.001) and for a negative change of LVEF(p &lt; 0.001). Also, reduced Calcium Score(SC)(p &lt; 0.001) Discussion With a higher prevalence reported in women8,9, no difference for women in both groups. Presentation been reported as atypical 3,6,10, as in our study. Traditional risk factors may affect the microvascular circulation earlier in the disease. Regarding mild and severe ischemia, CFR´s may be lower in defect perfusion zones and presence of both ischemia and MVD has worse prognosis11 suggesting ischemia could had already developed in this group. LVEF drop supports the relation between CFR and ventricular function12. Finally, MVA group had a reduced CS, associated with CAD and worse prognosis, suggesting it also affects the microvasculature function. Conclusions 13N-ammonia PET/CT MPI with CCTA is a great combination to diagnose MVA, whose main component is microvascular dysfunction. Recognizing the risk factors associated with this pathology allows making opportune detections, implementing early treatment strategies, controlling symptoms and avoiding the disease"s evolution

High Frequency QRS analysis to supplement ST-Analysis for Myocardial Ischemia: multi-center prospective cohort

Funding Acknowledgements Type of funding sources: None. Background Exercise testing is a well-known non-invasive assessment method for myocardial ischemia in patients with suspected coronary artery disease (CAD). Stress electrocardiography (ECG) alone is underutilized in this population despite guideline recommendations in part due to poor diagnostic accuracy. High frequency QRS analysis (HF-QRS) is a novel tool to supplement standard ST-analysis during stress ECG and has been shown in single-center retrospective analyses to identify any and substantial ischemia with high diagnostic accuracy. We sought to compare the diagnostic accuracy of HF-QRS + standard ST-analysis compared to standard ST-analysis alone for the identification of moderate to severe myocardial ischemia by exercise SPECT MPI. Methods The study population included 388 consecutive patients who underwent exercise SPECT MPI. An ischemic HF-QRS pattern was defined as an absolute reduction of ≥1 μV and a relative reduction of ≥50% between maximal and minimal values of the mean root square of the 150-250 Hz band signal in ≥3 leads. The diagnostic accuracy of HF-QRS + ST-analysis was compared with ST-analysis alone for moderate to severe myocardial ischemia using chi-square analysis and semi-quantitative gated SPECT MPI as the gold standard. The incremental diagnostic value of HF-QRS was assessed by logistic regression analysis. The likelihood of any ischemia by number of leads positive for HF-QRS was also determined. Results The study cohort was 71% male and 84% Caucasian with a mean age of 58.3 ± 11.8 years. ST- and HF-QRS analyses were positive in 96 (24.7%) and 121 (31.2%) of patients, respectively. HF-QRS had a substantially higher sensitivity than ST-analysis for moderate-severe ischemia (66.7% vs. 40.0%, p &lt;0.003). There was no statistically significant difference in specificities for HF-QRS vs ST-analysis for moderate-severe ischemia. (70.5% vs 75.7%, p = 0.08). There was a stepwise increase in ischemia as number of positive HF-QRS leads increased (p = 0.0004). HF-QRS demonstrated incremental diagnostic value to clinical risk factors without ST-analysis (p = 0.006) compared to Clinical + ST depressions (p &lt; 0.001) versus clinical factors. Conclusions This multicenter, prospective study expands the literature showing the benefit of HF-QRS analysis. HF-QRS analysis substantially improves detection of moderate-severe ischemia over ST-analysis and clinical risk factors in patients undergoing exercise stress ECG. This noninvasive adjunct may improve CAD risk stratification and encourage use of stress ECG without imaging, reducing costs and radiation exposure.

Prognostic value of heart rate reserve in patients with suspected coronary artery disease undergoing stress myocardial perfusion imaging

Funding Acknowledgements Type of funding sources: None. Background. The prognostic value of stress myocardial perfusion single-photon emission computed tomography (MPS) has been widely demonstrated. Also, chronotropic incompetence, evaluated by heart rate reserve (HRR) is associated with increased risk of adverse events. Yet, the incremental prognostic value of HRR over stress MPS data has not been fully investigated. Purpose. To assess the incremental prognostic value of HRR over stress MPS finding in patients with suspected coronary artery disease (CAD) undergoing exercise stress MPS. Methods. The study population consisted of 866 consecutive patients with suspected CAD undergoing exercise stress-MPS at University of Naples Federico II, between May 2002 and January 2014 as part of their diagnostic program. The primary study endpoint was all-cause mortality. All patients were followed for at least 60 months. HRR was calculated as the difference between peak exercise and resting HR, divided by the difference of age-predicted maximal and resting HR and expressed as percent. The summed difference score (SDS) was considered an index of ischemic burden. Patients were considered to have mild ischemia with a SDS of 2 to 6, and moderate-severe ischemia with a SDS ≥6. During follow-up, the occurrence of all-cause of deaths was noted and considered as event. Follow-up was censored at 84 months. Results. During follow-up, 61 deaths occurred, with a 7% cumulative event rate. Patients experiencing death were older (56.2 ± 10.7 years vs. 66.4 ± 8.6 years), with a higher prevalence of male gender (56% vs. 87 %, P &lt; 0.05) and diabetes mellitus (23% vs. 36%, P &lt; 0.05). At stress-MPS, patients with event had lower mean values of HRR (53.2 ± 21.3% vs. 61.5 ± 16.4%, P &lt; 0.0001) and higher prevalence of moderate-severe ischemia (24% vs. 8%, P &lt; 0.0001). The best trade-off between sensitivity and specificity for identifying chronotropic incompetence was a HRR &lt;67% with an area under the receiver operating characteristic curve of 0.62. The event free survival was lower in patients with HRR &lt;67% compared to those with HRR ≥67% (log-rank 9.75, P &lt; 0.005). Accordingly, the annualized event rate was 0.006 in patients with HRR &lt;67% and 0.014 in those with HRR ≥67% (P &lt; 0.001). At Cox regression analysis, univariable predictors of all-cause mortality were age, male gender, diabetes mellitus, HRR and moderate-severe ischemia (all P &lt; 0.05). At multivariable analysis age, male gender, HRR and moderate-severe ischemia were independent predictors of all-cause mortality (all P &lt; 0.05). HRR improved the prognostic power of a model including clinical data and MPS findings for the prediction of all-cause mortality, increasing the global chi-square from 76.16 to 82.68 (P &lt; 0.005). Conclusion. Chronotropic incompetence assessed by HRR evaluation, has independent and incremental prognostic value in predicting all cause of death in patients with suspected CAD undergoing exercise stress-MPS.

Current aspects of stable ischemic heart disease. ISСHEMIA study: breakthrough or constant optimism in approaches to treatment. Myocardial ischemia in non-obstructive coronary arteries (INOCA)

Approaches to stable coronary artery disease (CАD) treatment have been subject to debate for a long time. One of the first and fundamental studies in stable coronary artery disease patients treatment is the COURAGE study, which showed the advantage of rational drug therapy in comparison with percutaneous intervention in such patients. However, CAD high prevalence with medical and social significance cause the need for future development of relationship between conservative and invasive approaches in the problem of this disease treatment. It was particularly the focus of recently completed multicentre ISCHEMIA trail. The aim of review is to analyze the available data on the management of stable coronary artery disease patients based on the ISCHEMIA study data. Results. In the largest multicenter randomized clinical trial ISCHEMIA, the primary outcome (cardiovascular death, myocardial infarction, cardiac arrest with effective resuscitation, hospitalization due to heart failure) rate was 13.3% in the routine invasive strategy group and 15.5% in the conservative strategy group (p = 0.34). The main secondary outcome rate also does not differ between groups significantly. Quality of life in the non-invasive group was higher only in those patients who had angina at baseline. Study subanalysis demonstrated that left coronary artery borderline stenosis accompanied by a poor prognosis, and an invasive strategy improves angina symptoms. Also, low density lipoprotein cholesterol target values achievement predictors were determined. In addition, women, participated in ISCHEMIA study had more frequent angina episodes, regardless less extensive coronary artery damage, and less severe ischemia manifestations than men. Among stable CAD accompanied moderate to severe ischemia and severe chronic kidney disease patients, no evidence initial invasive strategy, compared initial conservative strategy, in relation of death or non-fatal myocardial infarction risk reduction was found. Conclusion: ISCHEMIA trial data demonstrated necessity more carefully stable coronary artery disease patients selection for invasive treatment, taking into account angina pectoris severity and modern antianginal therapy possibilities.