Five-Year Outcomes with PCI Guided by Fractional Flow Reserve.

BACKGROUND: We hypothesized that fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) would be superior to medical therapy as initial treatment in patients with stable coronary artery disease. METHODS: Among 1220 patients with angiographically significant stenoses, those in whom at least one stenosis was hemodynamically significant (FFR, ≤0.80) were randomly assigned to FFR-guided PCI plus medical therapy or to medical therapy alone. Patients in whom all stenoses had an FFR of more than 0.80 received medical therapy and were entered into a registry. The primary end point was a composite of death, myocardial infarction, or urgent revascularization. RESULTS: A total of 888 patients underwent randomization (447 patients in the PCI group and 441 in the medical-therapy group). At 5 years, the rate of the primary end point was lower in the PCI group than in the medical-therapy group (13.9% vs. 27.0%; hazard ratio, 0.46; 95% confidence interval [CI], 0.34 to 0.63; P<0.001). The difference was driven by urgent revascularizations, which occurred in 6.3% of the patients in the PCI group as compared with 21.1% of those in the medical-therapy group (hazard ratio, 0.27; 95% CI, 0.18 to 0.41). There were no significant differences between the PCI group and the medical-therapy group in the rates of death (5.1% and 5.2%, respectively; hazard ratio, 0.98; 95% CI, 0.55 to 1.75) or myocardial infarction (8.1% and 12.0%; hazard ratio, 0.66; 95% CI, 0.43 to 1.00). There was no significant difference in the rate of the primary end point between the PCI group and the registry cohort (13.9% and 15.7%, respectively; hazard ratio, 0.88; 95% CI, 0.55 to 1.39). Relief from angina was more pronounced after PCI than after medical therapy. CONCLUSIONS: In patients with stable coronary artery disease, an initial FFR-guided PCI strategy was associated with a significantly lower rate of the primary composite end point of death, myocardial infarction, or urgent revascularization at 5 years than medical therapy alone. Patients without hemodynamically significant stenoses had a favorable long-term outcome with medical therapy alone. (Funded by St. Jude Medical and others; FAME 2 ClinicalTrials.gov number, NCT01132495 .).

Fractional flow reserve in patients with reduced ejection fraction.

AIMS: Fractional flow reserve (FFR) has never been investigated in patients with reduced ejection fraction and associated coronary artery disease (CAD). We evaluated the impact of FFR on the management strategies of these patients and related outcomes. METHODS AND RESULTS: From 2002 to 2010, all consecutive patients with left ventricular ejection fraction (LVEF) ≤50% undergoing coronary angiography with ≥1 intermediate coronary stenosis [diameter stenosis (DS)% 50-70%] treated based on angiography (Angiography-guided group) or according to FFR (FFR-guided group) were screened for inclusion. In the FFR-guided group, 433 patients were matched with 866 contemporary patients of the Angiography-guided group. For outcome comparison, 617 control patients with LVEF >50% were included. After FFR, stenotic vessels per patient were significantly downgraded compared with the Angiography-guided group (1.43 ± 0.98 vs. 1.97 ± 0.84; P < 0.001). This was associated with lower revascularization rate (52% vs. 62%; P < 0.001) in the FFR-guided vs. the Angiography-guided group. All-cause death at 5 years of follow-up was significantly lower in the FFR-guided as compared with Angiography-guided group [22% vs. 31%. HR (95% CI) 0.64 (0.51-0.81); P < 0.001]. Similarly, rate of major adverse cardiovascular and cerebrovascular events (MACCE: composite of all-cause death, myocardial infarction, revascularization, and stroke) was significantly lower in the FFR-guided group [40% vs. 46% in the Angiography-guided group. HR (95% CI) 0.81 (0.67-0.97); P = 0.019]. Higher rates of death and MACCE were observed in patients with reduced LVEF compared with the control cohort. CONCLUSIONS: In patients with reduced LVEF and CAD, FFR-guided revascularization was associated with lower rates of death and MACCE at 5 years as compared with the Angiography-guided strategy. This beneficial impact was observed in parallel with less coronary artery bypass grafting and more patients deferred to percutaneous coronary intervention or medical therapy.

Fractional flow reserve-guided percutaneous coronary intervention vs. medical therapy for patients with stable coronary lesions: meta-analysis of individual patient data.

Aims: To assess the effect of fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) with contemporary drug-eluting stents on the composite of cardiac death or myocardial infarction (MI) vs. medical therapy in patients with stable coronary lesions. Methods and results: We performed a systematic review and meta-analysis of individual patient data (IPD) of the three available randomized trials of contemporary FFR-guided PCI vs. medical therapy for patients with stable coronary lesions: FAME 2 (NCT01132495), DANAMI-3-PRIMULTI (NCT01960933), and Compare-Acute (NCT01399736). FAME 2 enrolled patients with stable coronary artery disease (CAD), while the other two focused on non-culprit lesions in stabilized patients after acute coronary syndrome. A total of 2400 subjects were recruited from 54 sites world-wide with 1056 randomly assigned to FFR-guided PCI and 1344 to medical therapy. The pre-specified primary outcome was a composite of cardiac death or MI. We included data from extended follow-ups for FAME 2 (up to 5.5 years follow-up) and DANAMI-3-PRIMULTI (up to 4.7 years follow-up). After a median follow-up of 35 months (interquartile range 12-60 months), a reduction in the composite of cardiac death or MI was observed with FFR-guided PCI as compared with medical therapy (hazard ratio 0.72, 95% confidence interval 0.54-0.96; P = 0.02). The difference between groups was driven by MI. Conclusion: In this IPD meta-analysis of the three available randomized controlled trials to date, FFR-guided PCI resulted in a reduction of the composite of cardiac death or MI compared with medical therapy, which was driven by a decreased risk of MI.

Angiography Versus Hemodynamics to Predict the Natural History of Coronary Stenoses: Fractional Flow Reserve Versus Angiography in Multivessel Evaluation 2 Substudy.

BACKGROUND: Among patients with documented stable coronary artery disease and in whom no revascularization was performed, we compared the respective values of angiographic diameter stenosis (DS) and fractional flow reserve (FFR) in predicting natural history. METHODS: The present analysis included the 607 patients from the FAME 2 trial (Fractional Flow Reserve Versus Angiography in Multivessel Evaluation 2) in whom no revascularization was performed. FFR varied from 0.20 to 1.00 (average 0.74±0.16), and DS (by quantitative coronary analysis) varied from 8% to 98% (average 53±15). The primary end point, defined as vessel-oriented clinical end point (VOCE) at 2 years, was a composite of prospectively adjudicated cardiac death, vessel-related myocardial infarction, vessel-related urgent, and not urgent revascularization. The stenoses were divided into 4 groups according to FFR and %DS values: positive concordance (FFR≤0.80; DS≥50%), negative concordance (FFR>0.80; DS<50%), positive mismatch (FFR≤0.80; DS<50%), and negative mismatch (FFR>0.80; DS≥50%). RESULTS: The rate of VOCE was highest in the positive concordance group (log rank: X2=80.96; P=0.001) and lowest in the negative concordance group. The rate of VOCE was higher in the positive mismatch group than in the negative mismatch group (hazard ratio, 0.38; 95% confidence interval, 0.21-0.67; P=0.001). There was no significant difference in VOCE between the positive concordance and positive mismatch groups (FFR≤0.80; hazard ratio, 0.77; 95% confidence interval, 0.57-1.09; P=0.149) and no significant difference in rate of VOCE between the negative mismatch and negative concordance groups (FFR>0.80; hazard ratio, 1.89; 95% confidence interval, 0.96-3.74; P=0.067). CONCLUSIONS: In patients with stable coronary disease, physiology (FFR) is a more important determinant of the natural history of coronary stenoses than anatomy (DS). CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT01132495.

Catheter-based functional metrics of the coronary circulation.

In patients with stable chest pain, decision making about treatment strategy should be based on anatomical and functional information on the coronary circulation. Traditionally, the functional data are obtained by non-invasive testing which aims at detecting and localizing 'myocardial ischemia.' Yet, the diagnostic accuracy of diagnostic testing is over-rated in the literature, so that in clinical practice, a sizable proportion of patients undergo a coronary angiogram without prior useful functional information. Therefore, several methods have been developed to obtain similar information in the catheterization laboratory. Here we review briefly some of these methods. Some of them are used routinely in clinical practice, and others are under development.

Beneficial effects of low-dose aspirin on aortic stiffness in hypertensive patients.

While treatment with low-dose aspirin has been established as a therapeutic tool for secondary prevention, the role of aspirin on primary prevention remains controversial. Aortic stiffness and wave reflections are independent predictors of cardiovascular events. The aim of the present study was to investigate the effect of low-dose aspirin on aortic stiffness and wave reflections in hypertensive patients. We studied 30 patients with grade I hypertension. Fifteen patients were treated with 160 mg of aspirin and 15 patients with placebo. Aortic stiffness and wave reflections were assessed by measuring carotid-femoral pulse wave velocity (PWV) and heart rate-adjusted augmentation index (AIx75), respectively. All measurements were conducted at baseline and 2 weeks after treatment. In the aspirin group, there was a significant reduction in PWV compared to the placebo group (from 8.9±1.5 to 8.5±1.6 m/s for the aspirin group vs from 8.6±1.4 to 8.7±1.6 m/s for the placebo group, net change: -0.5 m/s; p=0.02). AIx75 showed a marginal decrease (from 28.0±5.4 to 26.2±5.0% for the aspirin group vs from 31.2±9.7 to 30.6±9.2% for the placebo group, net change: -1.2%; p=0.06). In conclusion, a 2-week course of aspirin administration has a favorable effect on aortic stiffness and, to a lesser extent, on wave reflections in hypertensive patients. Whether the reduction in arterial stiffness is translated to fewer cardiovascular events needs to be confirmed by future prospective studies.

Subacute saphenous vein graft stent thrombosis due to unusual drug interaction: a case report.

Background: Stent thrombosis is a potentially lethal complication of coronary angioplasty and responsible for 20% of all post-angioplasty myocardial infarctions. Unusual causes may be overlooked and difficult to identify. Case summary: A 70-year-old male with history of triple aortocoronary bypass presented with acute inferolateral ST-segment elevation myocardial infarction (STEMI). Critical stenosis of the vein graft to the right coronary artery was revealed, and with the use of distal embolic protection device, successful angioplasty with stent was performed under double antiplatelet treatment with aspirin and ticagrelor. Two weeks later, he presented again at the emergency department with an acute inferolateral STEMI. Subacute stent thrombosis with complete occlusion of the stented vein graft was evident. Repeated balloon dilatations restored the flow stabilizing the patient; optical coherence tomography showed good stent expansion and apposition. Scrutinizing the patient's history, we discovered comedication with carbamazepine that is a CYP3A4 inducer and reduces ticagrelor's effect. Switching to prasugrel ensured potent antiplatelet treatment, and the patient was discharged 5 days later. The 6-month follow-up was uneventful and free of symptoms. Discussion: Stent thrombosis has dire consequences, and the precipitating factors should always be investigated. Inadequate platelet inhibition secondary to non-compliance to therapy or resistance and suboptimal stent expansion/apposition are its main causes. Drug interactions are an underrecognized factor that may significantly alter the potency of antiplatelet drugs and also lead to stent thrombosis; thus, treatment is essential to be tailored to each patient comedication.

SAGE Score in Normotensive and Pre-Hypertensive Patients: A Proof of Concept. / Escore SAGE em Normotensos e Pré-Hipertensos: Uma Prova de Conceito.

BACKGROUND: The SAGE score was developed to detect individuals at risk for increased pulse wave velocity (PWV). So far, studies have been focused on hypertensive patients. OBJECTIVE: To assess the ability of the score to detect non-hypertensive and pre-hypertensive patients at risk for increased PWV. METHODS: Retrospective cross-sectional study of analysis of central blood pressure data and calculation of the SAGE score of non-hypertensive and pre-hypertensive patients. Each score point was analyzed for sensitivity, specificity, positive and negative predictive values, using the cut-off point for positive diagnosis a PVW ≥ 10m/s, ≥9.08 m/s (75thpercentile) and ≥7.30 m/s (50thpercentile). A p<0.05 was considered statistically significant. RESULTS: The sample was composed of 100 normotensive and pre-hypertensive individuals, with mean age of 52.64 ± 14.94 years and median PWV of 7.30 m/s (6.03 - 9.08). The SAGE score was correlated with age (r=0.938, p<0.001), glycemia (r=0.366, p<0.001) and glomerular filtration rate (r=-0.658, p<0.001). The area under the ROC curve was 0.968 (p<0.001) for PWV ≥ 10 m/s, 0.977 (p<0.001) for PWV ≥ 9.08 m/s and 0.967 (p<0.001) for PWV ≥ 7.30 m/s. The score 7 showed a specificity of 95.40% and sensitivity of 100% for PWV≥10 m/s. The cut-off point would be of five for a PWV≥9.08 m/s (sensitivity =96.00%, specificity = 94.70%), and two for a PWV ≥ 7.30 m/s. CONCLUSION: The SAGE score could identify individuals at higher risk of arterial stiffness, using different PWV cutoff points. However, the development of a specific score for normotensive and pre-hypertensive subjects is needed.

FUNDAMENTO: O SAGE foi desenvolvido para identificar hipertensos com chance de velocidade de onda de pulso (VOP) aumentada. Até o momento, as publicações do escore foram em hipertensos. OBJETIVO: Verificar a capacidade do SAGE de identificar os normotensos ou pré-hipertensos com chance de aumento da VOP. MÉTODOS: Transversal retrospectivo, incluiu exames de normotensos e pré-hipertensos que realizaram a medida central da pressão arterial e apresentavam os parâmetros para o cálculo do escore. Para cada pontuação do escore, foi analisada a sensibilidade, especificidade, valor preditivo positivo e negativo utilizando como ponto de corte para o diagnóstico positivo VOP ≥ 10m/s, ≥9,08 m/s (percentil 75) e ≥7,30 m/s (percentil 50). Um valor de p<0,05 foi adotado como estatisticamente significante. RESULTADOS: A amostra foi de 100 participantes normotensos ou pré-hipertensos, com média (DP) de 52,64 (14,94) anos e VOP mediana de 7,30 m/s (6,03 ­ 9,08). O SAGE apresentou correlação com idade (r=0,938, p<0,001), glicemia (r=0,366, p<0,001) e taxa de filtração de glomerular (r=-0,658, p<0,001). A área sob a curva ROC foi de 0,968 (p<0,001) para VOP≥10 m/s, 0,977 (p<0,001) para VOP≥9,08 m/s e 0,967 (p<0,001) para VOP≥7,30 m/s. O escore 7 apresentou especificidade de 95,40% e sensibilidade de 100% para VOP≥10 m/s. O ponto de corte seria cinco para VOP≥9,08 m/s (s=96,00%, e= 94,70%), e dois para VOP≥7,30 m/s. CONCLUSÃO: O SAGE foi capaz de identificar indivíduos com maior chance de apresentar rigidez arterial, utilizando diferentes pontos de corte de VOP. Entretanto, o desenvolvimento de um escore específico para normontensos e pré-hipertensos faz-se necessário.

Magmaris Resorbable Magnesium Scaffold Versus Conventional Drug-Eluting Stent in ST-Segment Elevation Myocardial Infarction: 1-Year Results of a Propensity-Score-Matching Comparison.

Magmaris® (Biotronik AG, Switzerland) is the first RMS and early experience has shown promising results in stable coronary artery disease. Acute coronary syndromes have been hypothesized as a potential target group for bioresorbable scaffolds, but the efficacy and safety of RMS has not been extensively studied in ST-segment elevation myocardial infarction (STEMI). BEST-MAG is a prospective multicenter trial designed to evaluate optical coherence tomography (OCT-)guided implantation of resorbable magnesium scaffold (RMS) in STEMI. Consecutive STEMI patients fulfilling inclusion/exclusion criteria were treated with RMS following a standardized OCT-based implantation technique including systematic pre- and post-dilatation, and baseline plus final OCT imaging. The primary endpoint was a device oriented composite endpoint (DOCE) including cardiac death, target vessel myocardial infarction (TV-MI) and target lesion revascularization (TLR) within 12 months. Clinical outcomes were compared after propensity score matching (PSM) to the results of the randomized controlled BIOSTEMI trial comparing biodegradable polymer sirolimus eluting (BP-SES) and durable polymer everolimus eluting stents (DP-EES) in STEMI. Between 15th February 2019 and 25th May 2020, 30 patients were included in 5 centers. Procedural success was achieved in all cases based on OCT control with final scaffold expansion of 82 ± 11%. At twelve-months, DOCE rate was 13.3% (n = 4), including 4 cases of TLR (13.3%) and one case of TV-MI (3.3%). No cardiac death occurred, and no scaffold thrombosis (ScT) was observed. Using PSM, DOCE rates in BP-SES and DP-EES groups were 10% and 6% respectively and TLR rates were 3.3% and 0.0%. In this study, OCT-guided RMS implantation in selected STEMI patients appeared feasible but was associated with numerically higher rates of TLR as compared with conventional drug-eluting stents, although the limited number of patients included in this analysis does not allow drawing statistically significant conclusions.

A SAGE score cutoff that predicts high-pulse wave velocity as measured by oscillometric devices in Brazilian hypertensive patients.

We aimed to identify the optimal cutoff SAGE score for Brazilian hypertensive patients who had their pulse wave velocity (PWV) measured with oscillometric devices. A retrospective analysis of patients who underwent central blood pressure measurement using a validated oscillometric device, the Mobil-O-Graph® (IEM, Stolberg, Germany), between 2012 and 2019 was performed. Patients with arterial hypertension and available data on all SAGE parameters were selected. An ROC curve was constructed using the Youden index to define the best score to identify patients at high risk for high PWV. A total of 837 patients met the criteria for SAGE and diagnosis of hypertension. The median age was 59.0 years (interquartile range [IQR]: 47.0-68.0), and 50.7% of the patients were women. The following comorbidities and conditions were present: dyslipidemia (37.4%), diabetes (20.7%), a body mass index score ≥30 kg/m2 (36.6%), use of antihypertensive drugs (69.5%), and smoking (18.3%). The median peripheral blood pressure was 128 mmHg (IQR: 117-138 mmHg) for systolic and 81 mmHg (IQR: 73-90 mmHg) for diastolic blood pressure. The median PWV was 8.3 m/s (7.1-9.8 m/s), and the prevalence of high PWV (≥10 m/s) was 22.9% (192 patients). A cutoff SAGE score ≥8 was effective at identifying a high risk of PWV ≥ 10 m/s, achieving 67.19% sensitivity (95% CI: 60.1-73.8) and 93.95% specificity (95% CI: 91.8-95.7). With this cutoff point, 1 out of every 5 treated hypertensive patients would be referred for a PWV measurement. A SAGE score of ≥8 identified Brazilian hypertensive patients with a high risk of future cardiovascular events (PWV ≥ 10 m/s).

Guiding Myocardial Revascularization by Algorithmic Interpretation of FFR Pullback Curves: A Proof of Concept Study.

Background: Coronary artery disease distribution along the vessel is a main determinant of FFR improvement after PCI. Identifying focal from diffuse disease from visual inspections of coronary angiogram (CA) and FFR pullback (FFR-PB) are operator-dependent. Computer science may standardize interpretations of such curves. Methods: A virtual stenting algorithm (VSA) was developed to perform an automated FFR-PB curve analysis. A survey analysis of the evaluations of 39 vessels with intermediate disease on CA and a distal FFR <0.8, rated by 5 interventional cardiologists, was performed. Vessel disease distribution and PCI strategy were successively rated based on CA and distal FFR (CA); CA and FFR-PB curve (CA/FFR-PB); and CA and VSA (CA/VSA). Inter-rater reliability was assessed using Fleiss kappa and an agreement analysis of CA/VSA rating with both algorithmic and human evaluation (operator) was performed. We hypothesize that VSA would increase rater agreement in interpretation of epicardial disease distribution and subsequent evaluation of PCI eligibility. Results: Inter-rater reliability in vessel disease assessment by CA, CA/FFR-PB, and CA/VSA were respectively, 0.32 (95% CI: 0.17-0.47), 0.38 (95% CI: 0.23-0.53), and 0.4 (95% CI: 0.25-0.55). The raters' overall agreement in vessel disease distribution and PCI eligibility was higher with the VSA than with the operator (respectively, 67 vs. 42%, and 80 vs. 70%, both p < 0.05). Compared to CA/FFR-PB, CA/VSA induced more reclassification toward a focal disease (92 vs. 56.2%, p < 0.01) with a trend toward more reclassification as eligible for PCI (70.6 vs. 33%, p = 0.06). Change in PCI strategy did not differ between CA/FFR-PB and CA/VSA (23.6 vs. 28.5%, p = 0.38). Conclusions: VSA is a new program to facilitate and standardize the FFR pullback curves analysis. When expert reviewers integrate VSA data, their assessments are less variable which might help to standardize PCI eligibility and strategy evaluations. Clinical Trial Registration: https://www.clinicaltrials.gov/ct2/show/NCT03824600.

DISENGAGE Registry.

BACKGROUND: During fractional flow reserve (FFR) measurement, the simple presence of the guiding catheter (GC) within the coronary ostium might create artificial ostial stenosis, affecting the hyperemic flow. We aimed to investigate whether selective GC engagement of the coronary ostium might impede hyperemic flow, and therefore impact FFR measurements and related clinical decision-making. METHODS: In the DISENGAGE (Determination of Fractional Flow Reserve in Intermediate Coronary Stenosis With Guiding Catheter Disengagement) registry, FFR was prospectively measured twice (with GC engaged [FFReng] and disengaged [FFRdis]) in 202 intermediate stenoses of 173 patients. We assessed (1) whether ΔFFReng-FFRdis was significantly different from the intrinsic variability of repeated FFR measurements (test-retest repeatability); (2) whether the extent of ΔFFReng-FFRdis could be clinically significant and therefore able to impact clinical decision-making; and (3) whether ΔFFReng-FFRdis related to the stenosis location, that is, proximal and middle versus distal coronary segments. RESULTS: Overall, FFR significantly changed after GC disengagement: FFReng 0.84±0.08 versus FFRdis 0.80±0.09, P<0.001. Particularly, in 38 stenoses (19%) with FFR values in the 0.81 to 0.85 range, GC disengagement was associated with a shift from above to below the 0.80 clinical cutoff, resulting into a change of the treatment strategy from medical therapy to percutaneous coronary intervention. The impact of GC disengagement was significantly more pronounced with stenoses located in proximal and middle as compared with distal coronary segments (ΔFFReng-FFRdis, proximal and middle 0.04±0.03 versus distal segments 0.03±0.03; P=0.042). CONCLUSIONS: GC disengagement results in a shift of FFR values from above to below the clinical cutoff FFR value of 0.80 in 1 out of 5 measurements. This occurs mostly when the stenosis is located in proximal and middle coronary segments and the FFR value is close to the cutoff value.

Procedural microvascular activation in long lesions treated with bioresorbable vascular scaffolds or everolimus-eluting stents: the PROACTIVE trial.

AIMS: Significant platelet activation after long stented coronary segments has been associated with periprocedural microvascular impairment and myonecrosis. In long lesions treated either with an everolimus-eluting bioresorbable vascular scaffold (BVS) or an everolimus-eluting stent (EES), we aimed to investigate (a) procedure-related microvascular impairment, and (b) the relationship of platelet activation with microvascular function and related myonecrosis. METHODS AND RESULTS: Patients (n=66) undergoing elective percutaneous coronary intervention (PCI) in long lesions were randomised 1:1 to either BVS or EES. The primary endpoint was the difference between groups in changes of pressure-derived corrected index of microvascular resistance (cIMR) after PCI. Periprocedural myonecrosis was assessed by high-sensitivity cardiac troponin T (hs-cTnT), platelet reactivity by high-sensitivity adenosine diphosphate (hs-ADP)-induced platelet reactivity with the Multiplate Analyzer. Post-dilatation was more frequent in the BVS group, with consequent longer procedure time. A significant difference was observed between the two groups in the primary endpoint of ΔcIMR (p=0.04). hs-ADP was not different between the groups at different time points. hs-cTnT significantly increased after PCI, without difference between the groups. CONCLUSIONS: In long lesions, BVS implantation is associated with significant acute reduction in IMR as compared with EES, with no significant interaction with platelet reactivity or periprocedural myonecrosis.

Global Fractional Flow Reserve Value Predicts 5-Year Outcomes in Patients With Coronary Atherosclerosis But Without Ischemia.

Background Global fractional flow reserve (FFR) (ie, the sum of the FFR values in the 3 major coronary arteries) is a physiologic correlate of global atherosclerotic burden. The objective of the present study was to investigate the value of global FFR in predicting long-term clinical outcome of patients with stable coronary artery disease but no ischemia-inducing stenosis. Methods and Results We studied major adverse cardiovascular events (MACEs: all-cause death, myocardial infarction, and any revascularization) after 5 years in 1122 patients without significant stenosis (all FFR >0.80; n=275) or with at least 1 significant stenosis successfully treated by percutaneous coronary intervention (ie, post-percutaneous coronary intervention FFR >0.80; n=847). The patients were stratified into low, mid, or high tertiles of global FFR (≤2.80, 2.80-2.88, and ≥2.88). Patients in the lowest tertile of global FFR showed the highest 5-year MACE rate compared with those in the mid or high tertile of global FFR (27.5% versus 22.0% and 20.9%, respectively; log-rank P=0.040). The higher 5-year MACE rate was mainly driven by a higher rate of revascularization in the low global FFR group (16.4% versus 11.3% and 11.8%, respectively; log-rank P=0.038). In a multivariable model, an increase in global FFR of 0.1 unit was associated with a significant reduction in the rates of MACE (hazard ratio [HR], 0.988; 95% CI, 0.977-0.998; P=0.023), myocardial infarction (HR, 0.982; 95% CI, 0.966-0.998; P=0.032), and revascularization (HR, 0.985; 95% CI, 0.972-0.999; P=0.040). Conclusions Even in the absence of ischemia-producing stenoses, patients with a low global FFR, physiologic correlate of global atherosclerotic burden, present a higher risk of MACE at 5-year follow-up.

Usefulness of the SAGE score to predict elevated values of brachial-ankle pulse wave velocity in Japanese subjects with hypertension.

The score based on the office systolic blood pressure, age, fasting blood glucose level, and estimated glomerular filtration rate (SAGE score) has been proposed as a useful marker to identify elevated values of carotid-femoral pulse wave velocity (PWV). The present cross-sectional study was conducted to examine whether the SAGE score is also a useful marker to identify subjects with elevated brachial-ankle PWV values in Japanese subjects with hypertension. We measured the brachial-ankle PWV and calculated the SAGE score in a total of 1019 employees of a Japanese company with hypertension and 817 subjects with hypertension derived from a multicenter study cohort. The analyses in this study were based on data from these two study groups as well as on a composite population of the two (n = 1836). The receiver operating characteristic curve analysis showed that the area under the curve to identify subjects with brachial-ankle PWV values of ≥1800 cm/s was over 0.70 in each of the three study groups. Even after adjustments, a SAGE score ≥7 had a significant odds ratio for identifying subjects with brachial-ankle PWV values ≥1800 cm/s in the 1836 study subjects from the composite occupational and multicenter study cohort (odds ratio = 2.1, 95% confidence interval = 1.4-3.0, P < 0.01). Thus, in Japanese subjects with hypertension, the SAGE score may be a useful marker for identifying subjects with elevated brachial-ankle PWV values.

Divergent effects of laughter and mental stress on arterial stiffness and central hemodynamics.

OBJECTIVE: To investigate the effect of laughter and mental stress on arterial stiffness and central hemodynamics. Arterial stiffness and wave reflections are independent predictors of cardiovascular risk. Chronic psychological stress is an independent risk factor for cardiovascular events, whereas acute stress deteriorates vascular function. METHODS: Eighteen healthy individuals were studied on three occasions, according to a randomized, single-blind, crossover, sham procedure-controlled design. The effects of viewing a 30-minute segment of two films inducing laughter or stress were assessed. Carotid-femoral pulse wave velocity was used as an index of arterial stiffness; augmentation index was used as a measure of wave reflections. RESULTS: Laughter decreased pulse wave velocity (by 0.30 m/sec, p = .01), and augmentation index (by 2.72%, p = .05). Conversely, stress increased pulse wave velocity (by 0.29 m/sec, p = .05) and augmentation index (by 5.1%, p = .005). Laughter decreased cortisol levels by 1.67 microg/dl (p = .02), soluble P-selectin by 26 ng/ml (p = .02) and marginally von Willebrand factor (by 2.4%, p = .07) and increased total oxidative status (by 61 micromol/L, p < .001). Stress decreased interleukin-6 (by 0.11 pg/ml, p = .04) and increased total oxidative status (by 44 micromol/L, p = .007). Soluble CD40 ligand and fibrinogen remained unchanged. CONCLUSIONS: Positive (laughter) and negative (stress) behavioral interventions have divergent acute effects on arterial stiffness and wave reflections. These findings have important clinical implications extending the spectrum of lifestyle modifications that can ameliorate arterial function.

Effects of Intensive Blood Pressure Control in Patients with Evident Cardiovascular Disease: An Investigation Using the SPRINT Study Data.

BACKGROUND: Recent data advocate adoption of a more intensive treatment strategy for management of blood pressure (BP). OBJECTIVE: We investigated whether the overall effects of the Systolic Blood Pressure Intervention Trial (SPRINT) are applicable to cardiovascular disease (CVD) patients. METHODS: In a post hoc analysis we analyzed data from SPRINT that randomly assigned 9361 individuals to a systolic BP (SBP) target of <120 mmHg (intensive treatment) or <140 mmHg (standard treatment). 1562 patients had clinically evident CVD (age=70.3±9.3 years, 24% females) at study entry and were followed for 3.1 years. Further, we assessed the effect of low (<150 mmHg) baseline SBP on outcome. RESULTS: In CVD patients, there was no benefit from the intensive treatment regarding all endpoints, except for a marginally significant benefit on all-cause mortality (hazard ratio [HR]: 0.67; 95% confidence interval [CI], 0.45 to 1.00; p=0.0509). Further, while there was no increase in serious adverse events (SAE) in the intensive group, there was increased risk for study-related SAE, acute renal failure and electrolyte abnormalities. In patients with low baseline SBP there was a beneficial effect on allcause mortality (HR: 0.56; 95% CI: 0.33 to 0.96; p=0.033), but with greater stroke incidence (HR: 2.94; 95% CI: 1.04 to 8.29; p=0.042). CONCLUSION: We confirm the beneficial effect of the intensive strategy in SPRINT study on all-cause mortality and the harmful effect on specific adverse outcomes in patients with CVD. However, in patients with low baseline SBP stroke may increase.

Association of Estimated Pulse Wave Velocity With Survival: A Secondary Analysis of SPRINT.

Importance: Aortic stiffness, as assessed by carotid-femoral pulse wave velocity, is an independent predictor of future events in individuals with hypertension. Recent data suggest a predictive role of estimated pulse wave velocity (ePWV) calculated by previously published equations using age and blood pressure in future events in individuals with hypertension. Objective: To investigate whether ePWV and its response to treatment predict survival in the Systolic Blood Pressure Intervention Trial (SPRINT). Design, Setting, and Participants: This exploratory, hypothesis-generating, post hoc secondary analysis conducted from October 1, 2018, to August 31, 2019, examined data from 9361 participants in SPRINT and calculated ePWV at baseline and at 12 months. Adjusted hazard ratios (HRs) with 95% CIs of ePWV per 1 SD were estimated using Cox proportional hazards regression models. A total of 8450 patients were assigned to 4 groups according to their treatment allocation and their response in ePWV after 12 months. Interventions: Participants were assigned a systolic blood pressure target of less than 120 mm Hg (intensive treatment) or less than 140 mm Hg (standard treatment). Main Outcomes and Measures: The primary composite cardiovascular outcome was myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes. Results: In the SPRINT population (3332 women and 6029 men; mean [SD] age, 67.9 [9.4] years), ePWV predicted the primary outcome (HR, 1.30 [95% CI, 1.17-1.43]; P < .001) and all-cause death (HR, 1.65 [95% CI, 1.46-1.86]; P < .001) independent of the Framingham Risk Score. Estimated pulse wave velocity improved the C statistic model for the primary outcome from 0.676 (95% CI, 0.65-0.70) to 0.683 (95% CI, 0.66-0.71; P = .049) and improved the C statistic model for all-cause death from 0.67 (95% CI, 0.64-0.69) to 0.69 (95% CI, 0.66-0.72; P = .03). Net reclassification index indicated improvement in risk discrimination for survival compared with the Framingham Risk Score (categorical net reclassification index = 0.111; P < .001). Regarding response to treatment, intensive treatment was superior to standard treatment only when it was accompanied with a response in ePWV at the first year, while, within the standard treatment group, individuals whose ePWV responded to antihypertensive treatment had improved all-cause mortality, with a 42% lower risk of death compared with nonresponders (HR, 0.58 [95% CI, 0.36-0.94]; P = .03); effects were independent of changes in systolic blood pressure. Conclusions and Relevance: These results suggest that, in the SPRINT trial, ePWV predicted outcomes independent of the Framingham Risk Score, indicating an incremental role of markers of aortic stiffness on cardiovascular risk. Better survival of individuals whose ePWV responded to antihypertensive treatment independently of systolic blood pressure reduction suggests a role of markers of aortic stiffness as effective treatment targets in individuals with hypertension.