Changes In Coronary Flow Reserve Research Articles

Ticagrelor induces ischaemic preconditioning in coronary artery disease

Abstract Ticagrelor is a reversibly P2Y12 antagonist used in patient undergoing coronary interventions, able to block adenosine re-uptake through inhibition of ENT-1 cotransporter. The increased levels of adenosine are responsible for some of its side effects (dyspnea, bradycardia), but adenosine bioavailability increase could also provide beneficial effects. We sought to investigate whether ticagrelor, as compared to clopidogrel, could enhance ischemic preconditioning in patients with stable CAD undergoing PCI. Methods and results The "Ticagrelor and preconditioning in patients with stable coronary artery disease (TAPER-S)" trial was a prospective, randomized 1:1, blinded end-point trial enrolling stable patients with CAD requiring fractional flow reserve (FFR)-guided PCI. Ischemic preconditioning was assessed by measuring the ST-segment elevation at intracoronary ECG during a two-step sequential coronary balloon inflation (2 minutes each, with a 5-minute interval) in the reference vessel. The primary endpoint of the study was the comparison of the delta (difference in millimeters) of ST-segment elevation extent at first and second coronary balloon inflations between ticagrelor and clopidogrel arms. Secondary endpoints were: 1) changes in coronary flow reserve (CFR), index of mcrovascular resistance (IMR), and FFR measured in the index vessel before and at the end of PCI; 2) difference in anginal pain (measured with VAS) during inflations. Also, lab tests with assessment of adenosine serum concentration and ENT-1 expression were conducted at baseline and after index procedure. The study was stopped by the DSMB after two thirds (n=53) of the patients qualifying for the primary endpoint were enrolled. Indeed, an independent statistical report evaluating the blinded results at a pre-specified interim analysis found a statistically significant difference in primary endpoint between the groups. The primary endpoint was significantly higher with ticagrelor as compared to clopidogrel (p < 0.0001). Ticagrelor group was also associated with lower extent of chest pain during coronary balloon inflations (p=0.04), wheras no difference was observed in the delta between pre and post PCI values of FFR (p=0.70), CFR (p=0.72) or IMR (p=0.72). Among lab tests, ticagrelor administration promoted a statistically significant increase in adenosine serum concentration when compared with clopidogrel group, while ENT-1 expression was not different. Conclusions Ticagrelor induces ischemic preconditioning among patients with stable CAD undergoing PCI and reduces intraprocedural anginal pain. Adenosine bioavailability was confirmed to be increased in ticagrelor-treated patients. However, since ENT-1 expression was proved not to be different between groups and all patients in this study underwent adenosine infusion during pre-PCI FFR, our results suggest ticagrelor can further induce ischemic preconditioning via non-adenosine mediated mechanisms.

Coronary Flow Reserve Changes after Angiotensin Receptor-Neprilysin Inhibitor Treatment in Heart Failure with Reduced Ejection Fraction.

Sacubitril/valsartan has been shown to reduce hospital admissions and even mortality for heart failure. In heart failure and acute coronary syndrome, the effects of sacubitril/valsartan have been studied, but the effect on coronary artery flow is not known. We aimed to understand the effect of sacubitril/valsartan on coronary artery flow by using echocardiographic coronary flow reserve (CFR). Thirty-six patients (17 ischemic and 19 non-ischemic) with heart failure with reduced ejection fraction (EF of < 40%) eligible for sacubitril/valsartan treatment and 21 normal controls were recruited. The study group and controls were similar with regard to gender, smoking status, and age distribution (p = 0.874, p = 0.709, and p = 0.765, respectively). Blood pressure, heart rate, 6-minute walk test (6MWT), N terminal pro B type natriuretic peptide (NT-pro-BNP) level, standard echocardiography, from where left anterior descending mid-distal flow was seen, baseline peak diastolic flow rate and 2 minutes after dipyridamole infusion, and hyperemic peak diastolic flow rate were measured, and CFR with echocardiography was assessed prior to and at 6 months after sacubitril/valsartan initiation. Baseline peak diastolic flow rate did not exhibit a significant difference at 6 months (p = 0.143), but hyperemic peak diastolic flow rate, CFR, EF (%), and 6MWD values were significantly increased (all p < 0.001), and New York Heart Association Functional Class, NT-pro-BNP (pg/mL), left ventricule end diastolic diameter (mm), and left ventricule end systolic diameter (mm) values were significantly decreased (all p < 0.001) after sacubitril/valsartan treatment. Sacubitril/valsartan significantly alters coronary blood flow, especially its dynamic features, in patients with heart failure with reduced ejection fraction.

Dynamic Assessments of Coronary Flow Reserve after Myocardial Ischemia Reperfusion in Mice.

After cardiac ischemia, there is often insufficient myocardial perfusion, even if flow has been successfully and completely restored in an upstream artery. This phenomenon, known as the "no-reflow phenomenon," is attributed to coronary microvascular dysfunction and has been associated with poor clinical outcomes. In clinical practice, a reduction in coronary flow reserve (CFR) is frequently used as an indicator of coronary artery disease. CFR is defined as the ratio of the peak flow velocity induced by pharmacologic or metabolic factors to the resting flow velocity. This protocol focused on assessing the dynamic changes in CFR before and after ischemia-reperfusion (IR) using pulse wave Doppler measurements. In this study, normal mice exhibited the ability to increase the peak velocity of coronary blood flow up to two times higher than the resting values under isoflurane stimulation. However, after ischemia-reperfusion, the CFR at 1 h significantly decreased compared to the pre-operation baseline. Over time, the CFR showed gradual recovery, but it remained below the normal level. Despite the preservation of systolic function, early detection of microvascular dysfunction is crucial, and establishing a practical guide could aid doctors in this task, while also facilitating the study of cardiovascular disease progression over time.

Inflammation and coronary flow reserve in chronic stable coronary artery disease: Evidence for a long standing interplay

Abstract Funding Acknowledgements Type of funding sources: None. Background Low grade inflammation is involved in pathogenesis of ischemia and outcome in coronary artery disease (CAD). Dobutamine stress echo (DSE) and coronary flow reserve (CFR) are both related with incident CAD and respective outcome as well. Purpose To evaluate the potential relationship between inflammation, evaluated by high-sensitivity C-reactive protein as surrogate, and DSE outcome/left anterior descending artery (LAD) CFR in stable chronic CAD. Methods We studied 132 consecutive pts (age 58±12years, 18 females, 33 diabetics) with stable CAD, by DSE with concomitant evaluation of LAD CFR. A cut off 3 mg/dL was used to define high and low CRP groups (CRPH/30pts, CRPL/92pts). CRP distribution was positive skewed (median 1.7mg/l) and CRP was then normalized by log transformation (CRP 0.72±0.9, logCRP 3.2±3.3). Sixty-three out of 132 pts had a follow up DSE with a concomitant reevaluation of CFR at 98±74 months. Absolute and % changes of CFR were estimated. Results CRPH and CRPL groups had similar baseline: CFR (CRPH: 2.3±0.6, CRPL: 2.4±0.6mg/dl), creatinine (1.0±0.2 vs 1.1±0.4mg/dl), HbA1c (5.4±1.0 vs 5.6±1.3%) and LDL (109±46 vs 102±35mg/dl). CRPH and CRPL groups had also similar hemodynamic burden at DSE and incidence of positive DSE. dCFR and %dCFR were lower in CRPL (0.20±0.70 vs 0.69±0.92, p = 0.02 and 0.13±0.33 vs 0.46±0.67 p = 0.01). Further clustering based on optimal CAD treatment achieved at baseline (guidelines defined optimal resting heart rate and LDL) did not change the findings. CFR was inversely related with logCRP (figure 1: r=-0.21, p = 0.04) and creatinine (r=-0.18 p = 0.05). Moreover, during follow up the improvement in CFR (%dCFR) was related with baseline logCRP (figure 2: r=0.30 p = 0.03). In stepwise logistic regression analysis for prediction of a CFR&amp;gt;2, including categorical classification of CRP (&amp;gt;3), diabetes, LDL (&amp;gt;80), Lpa(&amp;gt;50) and resting heart rate, then only CRP&amp;gt;3 classification was finally selected (exp(B)=0.38, p = 0.01). Conclusion Inflammation activity evaluated by CRP in stable CAD is related with the estimated LAD CFR irrespectively from the DSE outcome, both at baseline evaluation as well as dynamically during a long term follow up. The relationship is independent from LDL, Lpa levels and diabetic substrate, thus implying a strong pathophysiological interplay.

Long-term changes in coronary physiology after aortic valve replacement.

The detrimental effects of long-standing severe aortic stenosis (AS) often include left ventricular hypertrophy (LVH) and exhaustion of coronary flow reserve (CFR), the reversibility of which is unclear after valve replacement. Our aims were to 1) investigate whether CFR in the left anterior descending artery (LAD) would improve following valve replacement, and if the change was related to changes in hyperaemic coronary flow (QLAD) and minimal microvascular resistance (Rμ,LAD); and 2) investigate the relationship between changes in CFR and changes in left ventricular mass (LVM) and stroke work (LVSW). We measured intracoronary bolus thermodilution-derived CFR, and continuous thermodilution-derived QLAD and Rμ,LAD before and 6 months after aortic valve replacement. Cardiac magnetic resonance imaging was used to quantify left ventricular anatomy and function for the calculation of LVM and LVSW. Results: Thirty-four patients were included (17 patients had transcatheter aortic valve implantation; 14 had surgical valve replacement with a bioprosthesis and 3 with a mechanical prosthesis) who underwent invasive assessment in the LAD. CFR increased from 2.5 (interquartile range [IQR] 1.5-3.3) at baseline to 3.1 (IQR 2.2-5.1) at follow-up (p=0.005), despite no significant change in QLAD (230±106 mL/min to 250±101 mL/min; p=0.26) or Rμ,LAD (347 [IQR 247-463] to 287 [IQR 230-456]; p=0.20). When indexed for LVM, QLAD was 39% (IQR 8-98%) higher at follow-up compared with baseline (p<0.001). The improvement in CFR was correlated with ΔLVSW, r= -0.39; p=0.047. Conclusions: CFR in the LAD increased significantly at follow-up although global hyperaemic flow and minimal microvascular resistance remained unchanged. Thus, a decrease in resting flow was the cause of CFR improvement. CFR improvement was associated with reduction in LVSW.

Abstract 11968: Association Between Reduction in Inflammation and Change in Cardiovascular Risk: Results From the Liira Study

Background: Coronary microvascular disease (CMD) is associated with increased cardiovascular (CV) risk in rheumatoid arthritis (RA). Studies suggest that higher RA disease activity is associated with a higher degree of CMD, as measured by coronary flow reserve (CFR). However, it is not known whether reducing inflammation results in improvement in CMD or other CV correlates. The objective of this study was to determine the association between reducing inflammation with changes in CV risk. Methods: The Lipids, Inflammation and CV risk in RA (LiiRA) study recruited RA patients age ≥18 yrs with active RA about to initiate a TNFi as part of clinical care. All subjects underwent a stress myocardial perfusion PET scan to quantify CFR at baseline and after 24 weeks. A lower CFR in the absence of obstructive CAD is indicative of CMD, CFR&lt; 2.5 defined CMD. Inflammatory markers and hs-cTnT were performed at baseline and 24 weeks. Primary and secondary outcomes was change in CFR and hs-cTnT, respectively, and tested by Spearman correlations. Results: A total of 66 subjects completed the study, 80% female, mean RA duration 7.7 yrs. Baseline estimated ASCVD risk was 5.6%, yet 47% had evidence of CMD. We observed a significant reduction in all inflammatory markers between baseline and follow-up, along with improvements in RA disease activity; however, no change in the mean CFR or hs-cTnT was observed. A reduction in hsCRP and IL-1beta was associated with a reduction in hs-cTnT. A non-significant trend for correlation of reduced IL-1beta with higher CFR was observed among subjects with CMD at baseline (Figure). Conclusion: There was a high prevalence of CMD at baseline, but CFR did not significantly improve. Reducing inflammation was correlated with improvements in measures of CV risk, mainly in the subset of patients with detectable hs-cTnT, particularly via the IL-1beta pathway. These data suggest that hs-cTnT may be a useful marker when considering targeting inflammation to reduce CV risk in RA.

The Dynamic Relationship Between Invasive Microvascular Function and Microvascular Injury Indicators, and Their Association With Left Ventricular Function and Infarct Size at 1-Month After Reperfused ST-Segment-Elevation Myocardial Infarction.

The invasive microvascular function indices, coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR), exhibit a dynamic pattern after ST-segment-elevation myocardial infarction. The effects of microvascular injury on the evolution of the microvascular function and the prognostic significance of the evolution of microvascular function are unknown. We investigated the relationship between the temporal changes of CFR and IMR, and cardiovascular magnetic resonance-derived microvascular injury characteristics in reperfused ST-segment-elevation myocardial infarction patients, and their association with 1-month left ventricular ejection fraction and infarct size (IS). In 109 ST-segment-elevation myocardial infarction patients who underwent angiography for primary percutaneous coronary intervention (PPCI) and at 1-month follow-up, invasive assessment of CFR and IMR were performed in the culprit artery during both procedures. Cardiovascular magnetic resonance was performed 2 to 7 days after PPCI and at 1 month and provided assessment of left ventricular ejection fraction, IS, microvascular obstruction, and intramyocardial hemorrhage. CFR and IMR significantly changed over 1 month (both, P<0.001). The absolute IMR change over 1 month (ΔIMR) showed association with both microvascular obstruction and intramyocardial hemorrhage presence (both, P=0.01). ΔIMR differed between patients with/without microvascular obstruction (P=0.02) and with/without intramyocardial hemorrhage (P=0.04) but not ΔCFR for both. ΔIMR demonstrated association with both left ventricular ejection fraction and IS at 1 month (P<0.001, P=0.001, respectively), but not ΔCFR for both. Receiver-operating characteristics curve analysis of ΔIMR showed a larger area under the curve than post-PPCI CFR and IMR, and ΔCFR to be associated with both 1-month left ventricular ejection fraction >50% and extensive IS (the highest quartile). In reperfused ST-segment-elevation myocardial infarction patients, CFR and IMR significantly improved 1 month after PPCI; the temporal change in IMR is closely related to the presence/absence of microvascular damage and IS. ΔIMR exhibits a stronger association for 1-month functional outcome than post-PPCI CFR, IMR, or ΔCFR.

Serial changes of coronary flow reserve over one year after transcatheter aortic valve implantation in patients with severe aortic stenosis.

Impaired coronary flow reserve (CFR) portends a poor prognosis in patients with aortic stenosis. The present study aims to investigate how CFR changes over one year after transcatheter aortic valve implantation (TAVI) in patients with severe aortic stenosis, and to explore factors related to the changes. Consecutive patients undergoing TAVI were registered. CFR in the left anterior descending artery was measured by transthoracic echocardiography on three occasions pre-TAVI, one-day post-TAVI, and one-year post-TAVI. A total of 59 patients were enrolled, 46 of whom completed one-year follow-up. CFR was impaired in 35 (59.3%) patients pre-TAVI, but the impairment was only seen in 2 patients (4%) one-year post-TAVI. CFR value improved from 1.75 (1.50-2.10) cm/s pre-TAVI, to 2.00 (1.70-2.30) one-day post-TAVI, and further to 2.60 (2.30-3.10) one-year post-TAVI (P<0.001). The median difference in CFR between pre-TAVI and one-year post-TAVI was 0.90 (0.53-1.20). Patients with significant improvement of CFR (more than the median value of 0.9) had larger aortic valve area (1.55 [1.38-1.92] vs. 1.36cm2 [1.26-1.69], P=0.042) and greater improvement in left ventricular ejection fraction (3.10 [-1.67-4.24] vs. -1.46 [-3.42-1.48] percentage points, P=0.019) than those without. CFR is impaired in a considerable proportion of patients with severe aortic stenosis, but improvement is seen immediately after TAVI, and one year later. Patients with significant improvement of CFR had larger aortic valve area and greater increase in left ventricular ejection fraction after TAVI.

Bone Marrow Cells Improve Coronary Flow Reserve in Ischemic Nonrevascularized Myocardium: A MiHeart/IHD Quantitative Perfusion CMR Substudy

ObjectivesThis study investigated whether intramyocardial bone marrow–derived hematopoietic progenitor cells (BMCs) increase coronary flow reserve (CFR) in ischemic myocardial regions where direct revascularization was unsuitable. BackgroundPatients with diffuse coronary artery disease frequently undergo incomplete myocardial revascularization, which increases their risk for future adverse cardiovascular outcomes. The residual regional ischemia related to both untreated epicardial lesions and small vessel disease usually contributes to the disease burden. MethodsThe MiHeart/IHD study randomized patients with diffuse coronary artery disease undergoing incomplete coronary artery bypass grafting to receive BMCs or placebo in ischemic myocardial regions. After the procedure, 78 patients underwent cardiovascular magnetic resonance (CMR) at 1, 6, and 12 months and were included in this cardiac magnetic resonance substudy with perfusion quantification. Segments were classified as target (injected), adjacent (surrounding the injection site), and remote from injection site. ResultsOf 1,248 segments, 269 were target (22%), 397 (32%) adjacent, and 582 (46%) remote. The target had significantly lower CFR at baseline (1.40 ± 0.79 vs 1.64 ± 0.89 in adjacent and 1.79 ± 0.79 in remote; both P < 0.05). BMCs significantly increased CFR in target and adjacent segments at 6 and 12 months compared with placebo. In target regions, there was a progressive treatment effect (27.1% at 6 months, P = 0.037, 42.2% at 12 months, P = 0.001). In the adjacent segments, CFR increased by 21.8% (P = 0.023) at 6 months, which persisted until 12 months (22.6%; P = 0.022). Remote segments in both the BMC and placebo groups experienced similar improvements in CFR (not significant at 12 months compared with baseline). ConclusionsBMCs, injected in severely ischemic regions unsuitable for direct revascularization, led to the largest CFR improvements, which progressed up to 12 months, compared with smaller but persistent CFR changes in adjacent and no improvement in remote segments.

Serial Changes of Coronary Flow Reserve Over One Year After Transcatheter Aortic Valve Implantation in Patients with Severe Aortic Stenosis

Serial Changes of Coronary Flow Reserve Over One Year After Transcatheter Aortic Valve Implantation in Patients with Severe Aortic Stenosis

Abstract 10441: Sex-Specific Decline in Coronary Flow Reserve with Aging

Introduction: Coronary vasomotor response is different between males and females. Overall, females have lower coronary flow reserve (CFR) than males due to higher baseline coronary flow than males. Hypothesis: Sex has an essential role in the interaction between age and CFR. Methods: We included 668 patients with nonobstructive coronary artery disease who underwent invasive coronary vasoreactivity testing using intracoronary incremental doses of adenosine (18-72 μg). Changes in CFR (hyperemic flow velocity/baseline flow velocity) with aging were separately analyzed between males (N=207, mean age 53±13 years) and females (N=461, mean age 54±12 years). We further divided patients by age of 53 which is average age of menopause. Results: In males, CFR decreased with aging in younger patients &lt;53 years and tended to decrease in older male patients (all ages [N=207]: r=-0.33, P &lt;0.0001; &lt;53 years [N=99]: r=-0.27, P =0.01; ≥53 years [N=108]: r=-0.17, P =0.07) ( Figure A ). In contrast, CFR did not decrease with aging in younger females &lt;53 years, whereas there was a significant negative correlation between CFR and age in older females ≥53 years (all ages [N=461]: r=-0.15, P =0.001; &lt;53 years [N=211]: r=-0.006, P =0.39; ≥53 years [N=250]: r=-0.25, P &lt;0.0001) ( Figure B ). Baseline microvascular resistance (BMR) was similar between younger and older males ( P =0.30), whereas older females had higher baseline BMR than younger females ( P &lt;0.0001) ( Figure C ). Conclusions: CFR decreased with aging in males and older females, but not in younger females, potentially highlighting the role of protective hormonal differences in maintaining low baseline coronary tone in younger females.

Abstract 9775: The Effect of Microvascular Injury on Temporal Evolution of Invasive Microvascular Function Indices After Reperfused ST-Segment Elevation Myocardial Infarction

Background: Despite successful primary percutaneous coronary intervention (PCI), the restoration of the microvascular flow fails in up to 50% of the reperfused ST-segment elevation myocardial infarction (STEMI) patients, worsening the prognosis. This study aims to identify how post-STEMI microvascular function indices evolve over 1-month and how these changes are affected by the presence of microvascular injury. Methods: The study was performed in 110 STEMI patients who underwent angiography for primary PCI and at 1-month follow-up. Invasive assessment of the coronary microcirculation in the culprit artery was performed during both procedures and included coronary flow reserve (CFR), index of microcirculatory resistance (IMR), and baseline microcirculatory resistance (BMR). Cardiovascular magnetic resonance imaging was performed 2 to 7 days after PCI to evaluate microvascular injury by microvascular obstruction (MVO) and intra-myocardial hemorrhage (IMH). Results: Over 1-month, mean CFR, IMR, and BMR all changed significantly (fig. 1). CFR increased in all patients both with and without MVO and IMH (all, p&lt;0.001). IMR significantly decreased in patients with MVO (p&lt;0.001) and IMH (p&lt;0.01), but less apparently in patients without MVO (p=0.04) and IMH (p=0.05). There was no significant difference for the absolute CFR change over 1-month between patients with/without MVO (p=0.34) and with/without IMH (p=0.41). The absolute IMR change over 1-month differed significantly between patients with/without MVO (p&lt;0.01) and with/without IMH (p=0.001). Conclusion(s): In STEMI patients, coronary microvascular function indices significantly improved one month after PCI. The occurrence of microvascular damage presented a close interaction with the recovery of IMR but not with the course of CFR.

Effect of hypoglycaemia on measures of myocardial blood flow and myocardial injury in adults with and without type 1 diabetes: A prospective, randomised, open-label, blinded endpoint, cross-over study.

AimsThis study examined the effect of experimentally‐induced hypoglycaemia on measures of myocardial blood flow and myocardial injury in adults with, and without, type 1 diabetes.MethodsIn a prospective, randomised, open‐label, blinded, endpoint cross‐over study, 17 young adults with type 1 diabetes with no cardiovascular risk factors, and 10 healthy non‐diabetic volunteers, underwent hyperinsulinaemic‐euglycaemic (blood glucose 4.5–5.5 mmol/L) and hypoglycaemic (2.2–2.5 mmol/L) clamps. Myocardial blood flow was assessed using transthoracic echocardiography Doppler coronary flow reserve (CFR) and myocardial injury using plasma high‐sensitivity cardiac troponin I (hs‐cTnI) concentration.ResultsDuring hypoglycaemia, coronary flow reserve trended non‐significantly lower in those with type 1 diabetes than in the non‐diabetic participants (3.54 ± 0.47 vs. 3.89 ± 0.89). A generalised linear mixed‐model analysis examined diabetes status and euglycaemia or hypoglycaemia as factors affecting CFR. No statistically significant difference in CFR was observed for diabetes status (p = .23) or between euglycaemia and hypoglycaemia (p = .31). No changes in hs‐cTnI occurred during hypoglycaemia or in the recovery period (p = .86).ConclusionsA small change in CFR was not statistically significant in this study, implying hypoglycaemia may require more than coronary vasomotor dysfunction to cause harm. Further larger studies are required to investigate this putative problem.

Effect of Rosuvastatin on Coronary Flow Reserve in Hypertensive Patients at Cardiovascular Risk.

BACKGROUNDIt has been unclear whether statin therapy directly improves coronary flow reserve (CFR) in hypertensive patients at cardiovascular risk, independent of lifestyle modification and antihypertensive medications.METHODSIn this double-blind, randomized controlled trial, we randomly assigned 95 hypertensive patients at cardiovascular risk to receive either rosuvastatin 10 mg or placebo for 12 months, in addition to antihypertensive therapy and lifestyle modification for hypercholesterolemia. Using Doppler echocardiography, coronary flow velocity in the distal left anterior descending artery was measured and CFR was calculated as the ratio of hyperemic to basal averaged peak diastolic flow velocity. The primary end point was change in CFR from baseline to 12 months follow-up.RESULTSLow-density lipoprotein-cholesterol was changed from 157 ± 23 to 84 ± 16 mg/dL in the rosuvastatin group (p < 0.001) and from 152 ± 19 to 144 ± 22 mg/dL in the control group (p = 0.041, but there were no significant differences between the treatment groups in the changes in C-reactive protein, high-density lipoprotein cholesterol, and blood pressures. CFR was changed from 3.03 ± 0.44 to 3.25 ± 0.49 in the rosuvastatin group (p < 0.001) and from 3.15 ± 0.54 to 3.17 ± 0.56 in the control group (p = 0.65). The primary end point of change in CFR was significantly different between the rosuvastatin group and the control group (0.216 ± 0.279 vs. 0.015 ± 0.217; p < 0.001).CONCLUSIONSCompared with lifestyle modification alone, addition of rosuvastatin significantly improved CFR in hypertensive patients at cardiovascular risk.

Combination Hydralazine and Isosorbide Dinitrate in Dialysis-Dependent ESRD (HIDE): A Randomized, Placebo-Controlled, Pilot Trial.

Combination therapy with isosorbide dinitrate (ISD) and hydralazine (HY) reduces heart failure mortality. The safety and tolerability in individuals requiring maintenance hemodialysis (HD) is unknown. Single-center, randomized, placebo-controlled, double-blind pilot trial to explore safety and tolerability of ISD/HY in maintenance HD. Participants were randomized to placebo or combination ISD/HY. Dose was escalated over 3 weeks from ISD 10 mg/HY 10 mg to ISD 40 mg/HY 75 mg three times per day with the maximum tolerated dose maintained for the subsequent 21 weeks. Primary endpoints included adverse events, adverse events precluding further treatment with study medication, serious hypotension (i.e., requiring hospitalization or emergency room visit), and recurrent intra-dialytic hypotension. Efficacy signals included change in mitral annular E' velocity by tissue Doppler echocardiography and change in left ventricular coronary flow reserve on positron emission tomography. A total of 17 individuals were randomized to ISD/HY (N=7) or placebo (N=10). All participants assigned to ISD/HY completed dose escalation to 40/75 mg, but dose reductions were required in two participants. No participants discontinued therapy. There were no serious hypotension events. Recurrent intradialytic hypotension was less frequent with ISD/HY (0.47 events/patient-year) than placebo (1.83 events/patient-year, P=0.04). In contrast, nausea (ISD/HY, 1.90 events/patient-year; placebo, 0.50 events/patient-year, P=0.03) was significantly more frequent, and headache and diarrhea were numerically but not significantly more frequent with ISD/HY. Adverse events were more frequent with ISD/HY (11.4 events/patient-year) than placebo (6.31 events/patient-year). We did not detect between-group differences in the change in E' (P=0.34); ISD/HY showed a mean increase of 0.6 cm/s (SD 1.1), and placebo showed a mean decrease of 0.04 cm/s (SD 0.9). Changes in coronary flow reserve were minimal, -0.3 (0.2) with ISD/HY and -0.03 (0.5) in the placebo group, P=0.19. ISD/HY appears to be well tolerated in patients being treated with maintenance HD, but headache and gastrointestinal side effects occur more frequently with ISD/HY compared with placebo.

Time-dependent improvement in coronary flow reserve in collateral donor artery following successful recanalization of the Coronary Chronic Total Occlusion

Abstract Background Coronary chronic total occlusion (CTO) is characterized by the presence of collateral blood vessels which can provide additional blood supply to CTO-artery dependent myocardium. Successful CTO recanalization is followed by significant decrease in collateral donor artery blood flow and collateral derecruitment. Purpose Study aim was to assess time-dependent changes in coronary flow reserve (CFR) in collateral donor artery after CTO recanalization and identify factors that influence these changes. Methods Our study enrolled 31 patients with CTO scheduled for percutaneous coronary intervention (PCI). Non-invasive CFR was measured before PCI in collateral donor artery, and 24h and 6 months post-PCI in CTO and collateral donor artery. Gated SPECT MIBI was performed before PCI, while quality of life was assessed by Seattle angina questionnaire (SAQ) pre-PCI, and 6 months after PCI. Results Collateral donor artery showed significant increase in CFR 24h after CTO recanalization compared to pre-PCI values (2.30±0.49 vs. 2.71±0.45, p=0.005), which remained unchanged after 6 months (2.68±0.24). Maximum baseline blood flow velocity of the collateral donor artery showed significant decrease measured 24h post-PCI compared to pre-PCI values (0.28±0.06 vs. 0.24±0.04m/s), and remained similar after 6-months. There was no significant difference in maximum hyperemic blood flow velocity pre-PCI, 24h and 6 months post-PCI. CFR change of the collateral donor artery 24h post-PCI compared to pre-PCI values showed inverse correlation with left ventricle ejection fraction (LVEF) measured on SPECT. CFR changes showed no correlation with the changes in quality of life assessed by SAQ post-PCI compared to pre-PCI. Conclusions Significant increase in CFR of the collateral donor artery was observed within 24h after successful recanalization of CTO artery, which maintained constant after the 6 months follow-up. This increase was largely driven by the significant reduction in the maximum baseline blood flow velocity within 24h after CTO recanalization compared to pre-PCI values. Our results suggest that possible benefit of CTO recanalization could be the improvement in physiology of the collateral donor artery. Funding Acknowledgement Type of funding source: None

Effects of Oral Drugs on Coronary Microvascular Function in Patients Without Significant Stenosis of Epicardial Coronary Arteries: A Systematic Review and Meta-Analysis of Coronary Flow Reserve

Objective: This study aims to investigate the impact of cardiovascular medications on the coronary flow reserve (CFR) in patients without obstructive coronary artery disease (CAD).Methods: We searched PubMed, EMBASE, and Cochrane databases from inception to 15 November 2019. Studies were included if they reported CFR from baseline to follow-up after oral drug therapy of patients without obstructive CAD. Data was pooled using random-effects modeling. The primary outcome was change in CFR from baseline to follow-up after oral drug therapy.Results: A total of 46 studies including 845 subjects were included in this study. Relative to baseline, the CFR was improved by angiotensin-converting enzymes (ACEIs), aldosterone receptor antagonists (ARBs) [standard mean difference (SMD): 1.12; 95% CI: 0.77–1.47], and statins treatments (SMD: 0.61; 95%CI: 0.36–0.85). Six to 12 months of calcium channel blocker (CCB) treatments improved CFR (SMD: 1.04; 95% CI: 0.51–1.58). Beta-blocker (SMD: 0.24; 95% CI: −0.39–0.88) and ranolazine treatment (SMD: 0.31; 95% CI: −0.39–1.01) were not associated with improved CFR.Conclusions: Therapy with ACEIs, ARBs, and statins was associated with improved CFR in patients with confirmed or suspicious CMD. CCBs also improved CFR among patients followed for 6–12 months. Beta-blocker and ranolazine had no impact on CFR.

A randomized trial comparing the acute coronary, systemic, and environmental effects of electronic vaping cigarettes versus heat-not-burn cigarettes in smokers of combustible cigarettes undergoing invasive coronary assessment: rationale and design of the SUR-VAPES 3 trial.

Traditional combustible cigarette (TCC) smoking remains a major cause of preventable cardiovascular morbidity and mortality. Modified risk products (MRP) such as electronic vaping cigarettes (EVC) and heat-not-burn cigarettes (HNBC) may be safer than TCC but may still have detrimental oxidative, platelet and vascular effects of particular importance to people with symptomatic coronary artery disease (CAD). We aimed to compare the acute coronary, systemic and environmental effects of two leading MRP in 20 TCC smokers admitted for invasive coronary assessment of CAD and willing to quit or after prior failed quitting attempts. After confirmation at angiography of an intermediate coronary stenosis, coronary flow reserve (CFR) will be appraised. Patients will then be randomized 1:1 to use a single EVC or a single HNBC in the catheterization laboratory, followed by repeat CFR measurement. The primary endpoint will be the change in CFR before and after product use. Quantitative coronary angiography, fractional flow reserve (FFR), and instantaneous wave-free ratio (iFR) will also be measured. We expected to accrue results able to: 1) test whether MRP have in general a detrimental impact on coronary vascular function in TCC smokers; 2) test whether EVC have a different impact than HNBC on coronary function; 3) provide ancillary pathophysiologic and translational insights on the acute risk and safety profile of MRP in TCC smokers with established cardiovascular disease, including complex correlations between coronary, cardiac, systemic and environmental effects. In addition, by directly informing participants of their individual results, they will be further empowered to quit TCC. The Sapienza University of Rome-Vascular Assessment of Proatherosclerotic Effects of Smoking (SUR-VAPES) 3 trial will provide important insights into the pathophysiologic cardiovascular impact of EVC and HNBC, also suitable to inform patients and individualize their smoking cessation strategy.

Enhanced coronary vasodilation in isolated Langendorff‐perfused hearts of asthmatic mice

Clinical studies have shown that asthma is associated with high risk of cardiovascular diseases. We previously demonstrated that asthmatic mice have impaired vascular reactivity and endothelial function in aorta. However, little is known regarding coronary vascular reactivity in asthmatic mice. This study aims to examine the coronary flow response to vasodilators and to short period of ischemia in isolated hearts of asthmatic mice. Asthmatic mice were induced by I.P. injection of ovalbumin (OVA, 0.2 μg) on days 1 and 6, followed by 5% OVA aerosol challenges on days 11–13. Hearts were isolated and perfused on day 14 to examine the coronary flow (CF) response. CF was measured using Langendorff system. Baseline CF was comparable between normal and sensitized mice. However, peak CF and repayment/debt ratio following a 15‐s occlusion were significantly higher (~1.14 and 1. 55 folds increase, respectively, p&lt;0.05) in sensitized versus control mice. In lines with the enhanced reactive hyperemic response, acetylcholine (ACH, 10−9‐105.5M) induced an augmented flow increase (Emax=2.8 ± 0.16 and 2.4 ± 0.14 times the baseline in sensitized versus control mice, respectively, p&lt;0.05) which was not affected by L‐NAME (nitric oxide synthase inhibitor). Additionally, sodium nitroprusside (SNP, 10−5 M) induced a ~25% more coronary flow increase (p&lt;0.05) in sensitized mice. Our data suggest that during early stage of sensitized asthmatic mouse model, the coronary circulation demonstrates an enhanced flow reserve though the baseline flow is unchanged. The changes in coronary flow reserve in asthmatic mice indicate one of the potential protective mechanisms against hypoxia/ischemia–induced heart injury in asthmatic patients. Supported by HL 027339 (SJM) and WVCTSI Pilot Grant NIH/NIGMS U54GM104942 (DSP)

Ticagrelor and preconditioning in patients with stable coronary artery disease (TAPER-S): a randomized pilot clinical trial

BackgroundTicagrelor is a reversibly binding, direct-acting, oral, P2Y12 antagonist used for the prevention of atherothrombotic events in patients with coronary artery disease (CAD). Ticagrelor blocks adenosine reuptake through the inhibition of equilibrative nucleoside transporter 1 (ENT-1) on erythrocytes and platelets, thereby facilitating adenosine-induced physiological responses such as an increase in coronary blood flow velocity. Meanwhile, adenosine plays an important role in triggering ischemic preconditioning through the activation of the A1 receptor. Therefore, an increase in ticagrelor-enhanced adenosine bioavailability may confer beneficial effects through mechanisms related to preconditioning activation and improvement of coronary microvascular dysfunction.MethodsTo determine whether ticagrelor can trigger ischemic preconditioning and influence microvascular function, we designed this prospective, open-label, pilot study that enrolled patients with stable multivessel CAD requiring staged, fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI). Participants will be randomized in 1:1 ratios either to ticagrelor (loading dose (LD) 180 mg, maintenance dose (MD) 90 mg bid) or to clopidogrel (LD 600 mg, MD 75 mg) from 3 to 1 days before the scheduled PCI. The PCI operators will be blinded to the randomization arm. The primary endpoint is the delta (difference) between ST segment elevations (in millimeters, mm) as assessed by intracoronary electrocardiogram (ECG) during the two-step sequential coronary balloon inflation in the culprit vessel. Secondary endpoints are 1) changes in coronary flow reserve (CFR), index of microvascular resistance (IMR), and FFR measured in the culprit vessel and reference vessel at the end of PCI, and 2) angina score during inflations. This study started in 2018 with the aim of enrolling 100 patients. Based on the rate of negative FFR up to 30% and a drop-out rate up to 10%, we expect to detect an absolute difference of 4 mm among the study arms in the mean change of ST elevation following repeated balloon inflations. All study procedures were reviewed and approved by the Ethical Committee of the Catholic University of Sacred Heart.DiscussionTicagrelor might improve ischemia tolerance and microvascular function compared to clopidogrel, and these effects might translate to better long-term clinical outcomes.Trial registrationEudraCT No. 2016–004746-28. No. NCT02701140. Trial statusInformation provided in this manuscript refers to the definitive version (n. 3.0) of the study protocol, dated 31 October 2017, and includes all protocol amendments. Recruitment started on 18 September 2018 and is currently ongoing. The enrollment is expected to be completed by the end of 2019.Trial sponsorFondazione Policlinico Universitario A. Gemelli – Roma, Polo di Scienze Cardiovascolari e Toraciche, Largo Agostino Gemelli 8, 00168 Rome, Italy.