Improvement In Coronary Flow Reserve Research Articles

Efficacy of Angiotensin-Converting Enzyme Inhibitors in Coronary Microvascular Dysfunction: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

Coronary microvascular dysfunction (CMD) is becoming increasingly recognized as an important contributor to the development of ischemic heart diseases. Without obstructive coronary artery disease, the physiological function of the coronary microcirculation can be altered by structural, functional, and molecular factors, leading to myocardial ischemia. CMD can significantly impact the quality of life and prognosis and imposes a huge financial burden on healthcare systems and people. This meta-analysis aims to investigate the efficacy of angiotensin-converting enzyme inhibitors (ACEIs) for treating CMD. A systematic literature review identified randomized controlled trials (RCTs) comparing ACEIs with placebo in CMD patients. Review Manager, 5.3 for Windows, was utilized. Using the Mantel-Haenszel (M-H) method, improvement in coronary flow reserve (CFR) and systolic blood pressure events was pooled as mean difference (MD) in a meta-analysis model with a fixed effect model, whereas the number of chest pain episodes was pooled as MD with a random effect model. Five randomized controlled trials involving 209 patients were included in the analysis. The analysis demonstrated a statistically significant improvement in CFR in the ACEIs group compared to the placebo group (MD -0.3, 95% CI -0.61 to 0.01, P = 0.05). However, there was no significant difference in the number of chest pain episodes between the ACEIs and placebo groups (MD 1.79, 95% CI -3.99 to 7.58, P = 0.54). Similarly, no significant difference in blood pressure change was observed between the two groups (MD 4.02, 95% CI -3.25 to 11.28, P = 0.28). In conclusion, the appropriate treatment for CMD is a source of contention because adequate data is lacking. Our findings suggest that ACEIs may have a positive effect on improving CFR in patients with microvascular angina. However, ACEIs did not demonstrate a significant impact on the number of chest pain episodes or systolic blood pressure in this patient population. Further research, including RCTs with larger sample sizes and longer follow-up durations, is warranted to provide more conclusive evidence on the role of ACEIs in CMD management.

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>2, including categorical classification of CRP (>3), diabetes, LDL (>80), Lpa(>50) and resting heart rate, then only CRP>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 14158: Impact of Gender Differences on Changes in Myocardial Perfusion Following Percutaneous Coronary Intervention of Chronic Total Coronary Occlusions

Introduction. Data on gender differences in chronic total coronary occlusion (CTO) percutaneous coronary intervention (PCI) are scarce. Prior studies have demonstrated CTO PCI to reduce ischemia, however female patients are less likely to undergo revascularization. This study sought to investigate the impact of gender on myocardial perfusion changes following CTO PCI as measured by [ 15 O]H 2 O positon-emission tomography (PET) perfusion imaging. Methods. A total of 212 patients were prospectively enrolled in a single-center CTO registry and underwent single-vessel CTO PCI, combined with [ 15 O]H 2 O PET imaging at baseline and three months follow-up. Baseline and follow-up resting myocardial blood flow (MBF), hyperemic MBF and coronary flow reserve (CFR) allocated to the CTO territory were quantitatively assessed. The presence of residual ischemia was defined as hMBF ≤2.3 mL·min -1 ·g -1 in the CTO area at follow-up. Results. This study comprised 34 (16%) females and (84%) males. Mean age in females was higher compared to males (68 ± 9 vs. 61 ± 10 years, p&lt;0.01). In women, resting MBF at baseline was more elevated than in men (1.02 ± 0.24 vs. 0.84 ± 0.21 mL·min -1 ·g -1 , p&lt;0.01). Similarly, baseline hMBF was found to be higher in females (1.81 ± 0.53 vs. 1.64 ± 0.53 mL·min -1 ·g -1 , p=0.03), and showed a higher increase after CTO PCI (Δ1.06 ± 0.71 vs. Δ0.71 ± 0.66 mL·min -1 ·g -1 , p=0.01). Improvement in CFR after CTO PCI was more evident in female patients (Δ1.17 ± 1.04 vs. Δ0.82 ± 0.89, p=0.04). At three months follow-up, the proportion of patients with residual ischemia was lower in women versus men (9 (27%) vs. 91 (51%), p=0.01). Conclusions. We found a higher increase in hyperemic MBF and CFR following CTO PCI in women compared to men, as measured by serial [ 15 O]H 2 O PET imaging. In addition, lower rates of residual ischemia were observed in women. This study suggests the potential benefit of a lower threshold for CTO PCI in female patients.

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.

Angiogenic CD34 Stem Cell Therapy in Coronary Microvascular Repair-A Systematic Review.

Ischemia with non-obstructive coronary arteries (INOCA) is an increasingly recognized disease, with a prevalence of 3 to 4 million individuals, and is associated with a higher risk of morbidity, mortality, and a worse quality of life. Persistent angina in many patients with INOCA is due to coronary microvascular dysfunction (CMD), which can be difficult to diagnose and treat. A coronary flow reserve <2.5 is used to diagnose endothelial-independent CMD. Antianginal treatments are often ineffective in endothelial-independent CMD and thus novel treatment modalities are currently being studied for safety and efficacy. CD34+ cell therapy is a promising treatment option for these patients, as it has been shown to promote vascular repair and enhance angiogenesis in the microvasculature. The resulting restoration of the microcirculation improves myocardial tissue perfusion, resulting in the recovery of coronary microvascular function, as evidenced by an improvement in coronary flow reserve. A pilot study in INOCA patients with endothelial-independent CMD and persistent angina, treated with autologous intracoronary CD34+ stem cells, demonstrated a significant improvement in coronary flow reserve, angina frequency, Canadian Cardiovascular Society class, and quality of life (ESCaPE-CMD, NCT03508609). This work is being further evaluated in the ongoing FREEDOM (NCT04614467) placebo-controlled trial.

The non-invasive coronary flow reserve predicts exercise capacity in patients undergoing cardiac rehabilitation

The benefit of exercise on peripheral muscles is established but the exact role of the coronary microcirculation in exercise capacity after cardiac rehabilitation (CR) is unclear. Our aim was to test the relationship between non-invasive coronary flow reserve (CFR) and exercise capacity in patients undergoing CR after acute myocardial infarction (AMI). CFR was performed by transthoracic Doppler echocardiography in the left anterior descending artery 24 h after angioplasty (CFR1) and after 20 sessions of CR program (at 4 ± 1 months)(CFR2) in 60 consecutive patients (57 ± 11 years, 30% women) with an anterior AMI successfully treated by primary coronary angioplasty. CFR was performed in a modified parasternale view using intravenous adenosine infusion (0.14 mg/kg/min within 2 minutes). CR program consisted of a half hour of fractioned exercise added of a half hour session of general gymnastics and bodybuilding. To test the exercise capacity, symptom limited exercise echocardiography was performed just after the CFR2, in a semi-supine position, starting at 25 watts, with 20-25 watts increments of workload every two minutes. CFR was measured successfully in all patients, and CFR2 was significantly higher than CFR1 (2.9 ± 0.65 vs. 1.9 ± 0.4, P < 0.001). Though CFR1 was correlated to left ventricular systolic function and its improvement at follow-up (all, P < 0.01), CFR2 was independently related to exercise capacity (mean workload 100 ± 30 watts, percent maximal heart rate 83 ± 12%, no ischemia, no new wall motion abnormalities in all tests) after adjusting for age, sex, and body mass index ( r = 0.6, P < 0.01). CFR predicts exercise capacity in patients undergoing a CR program after AMI. The improvement of CFR contributes to cardiac performance.

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

Nanoparticles loaded with hepatic growth factor and insulin-like growth factor-1 improve left ventricular repair in a porcine model of myocardial Ischemia reperfusion injury

Abstract Introduction Nanomedicine offers great potential for treatment of cardiovascular disease. We tested whether intramyocardial (IM) injection of pro-angiogenic hepatocyte growth factor (HGF) and anti-apoptotic, pro-myogenic insulin-like growth factor 1 (IGF-1) encapsulated in Alginate-Sulfate nanoparticles (AlgS-NP) improves left ventricular (LV) functional recovery in a porcine ischemia-reperfusion (I/R) model. Methods Myocardial infarction (MI) was induced by 75min balloon occlusion of the mid-LAD followed by reperfusion. After 1w, pigs (n=12) with marked LV dysfunction (EF&amp;lt;45%) were randomized to fusion imaging-guided IM injections of 8 mg Cy5-labelled AlgS-NP loaded with 200μg HGF and IGF-1 (GF) or with phosphate-buffered saline (CON) using the MYOSTAR injection catheter. AlgS-NP retention in the heart was determined by measuring Cy5 levels in peripheral blood. At 8w, treatment effect was evaluated using cardiac magnetic resonance imaging and coronary flow reserve (CFR) measurements, and further assessed using sirius red staining to measure myocardial fibrosis. Results At 1w after MI, LV ejection frqction (LVEF) was 37±5% (range 27–45%) and infarct size (IS)/LV mass 24±6% (range 19–38%). Myocardial retention of AlgS-NP was comparable between 2 groups (maximal systemic leakage after IM injection: 9% CON vs 20% GF, P=0.25). After 8 w, IS/LV mass decreased by one third in GF-treated pigs compared with 14% in CON (P=0.03, Fig. A) and was associated with a trend towards improvement in CFR (P=0.05, Fig. B). LVEF significantly increased in GF-treated pigs (6±2% vs. −1±1%, P=0.02, Fig. C), which was attributable to a greater reduction in end-systolic volume. The improvement in LVEF was also consistent with significant reduction of fibrosis (P=0.01, Fig. D) in the peri-infarct zone (PI). Conclusions Intramyocardial injection of AlgS-nanoparticle-encapsulated HGF and IGF-1 to the ischemic myocardium significantly improves LV repair, and offers the prospect of innovative treatment for patients with refractory ischemic heart disease. Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): EuroNanoMed, Horizon 2020

Long-term antihypertensive treatment improves ventricular-arterial interaction in hypertensive patients: a 3-year follow-up study

Abstract Background We investigated the effects of antihypertensive treatment on vascular function, longitudinal deformation and ventricular-arterial interaction in hypertensives. Methods In 200 untreated patients with arterial hypertension (age 52.5±11.6 years, 56% females), we measured at baseline and after a 3-year of antihypertensive treatment (160 received ACEi± diuretics and 40 CCBs± diuretics): a) 24h ambulatory blood pressure b) Carotid-femoral pulse wave velocity (PWV) b) Coronary flow reserve (CFR), LV mass index (LVMI), the global longitudinal strain (GLS). We calculated the ratio of PWV/GLS (-m/sec%) reflecting the ventricular-arterial interaction. Results Compared to baseline, there was an improvement of GLS (−19.9±3.4 vs. −18.7±3.1%), post-treatment. In parallel, there were improvement in CFR (2.72±0.61 vs. 2.55±0.64), PWV (10.3±1.9 vs. 11.2±2.1 m/s), LVMI and PWV/GLS (−0.539±0.146 vs. −0.618±0.178 -m/sec%) (p&amp;lt;0.01 for all comparisons). By multivariate analysis, the reduction of 24h meanBP as well as PWV independently determined the respective improvement of GLS (b=0.478, b=0.248, respectively, p&amp;lt;0.001). By ANOVA, the interaction term between changes of all the above parameters and antihypertensive treatment (ACE inhibitors vs calcium channel blockers) was not significant (p&amp;gt;0.05). Conclusions Long-term optimal blood pressure control with ACE inhibitors and CCBs improves LV longitudinal deformation along with reduction of arterial stiffness, leading to improved ventricular-arterial interaction in hypertensives. Funding Acknowledgement Type of funding source: None

Histone Acetyltransferase p300 Inhibitor Improves Coronary Flow Reserve in SIRT3 (Sirtuin 3) Knockout Mice.

BackgroundCoronary microvascular dysfunction is common in patients of myocardial infarction with non‐obstructive coronary artery disease. Coronary flow reserve (CFR) reflects coronary microvascular function and is a powerful independent index of coronary microvascular dysfunction and heart failure. Our previous studies showed that knockout of SIRT3 (Sirtuin 3) decreased CFR and caused a diastolic dysfunction. Few studies focus on the treatment of impaired CFR and heart failure. In the present study, we explored the role of C646, a histone acetyltransferase p300 inhibitor, in regulating CFR and cardiac remodeling in SIRT3 knockout (SIRT3KO) mice.Methods and ResultsAfter treating with C646 for 14 days, CFR, pulse‐wave velocity, and cardiac function were measured in SIRT3KO mice. SIRT3KO mice treated with C646 showed a significant improvement of CFR, pulse‐wave velocity, ejection fraction, and fractional shortening. Treatment with C646 reversed pre‐existing cardiac fibrosis, hypertrophy, and capillary rarefaction in SIRT3KO mice. Mechanistically, knockout of Sirtuin 3 resulted in significant increases in p300 expression and H3K56 acetylation. Treatment with C646 significantly reduced levels of p300 and H3K56 acetylation in SIRT3KO mice. Furthermore, treatment with C646 increased endothelial nitric oxide synthase expression and reduced arginase II expression and activity. The expression of NF‐κB (nuclear factor kappa‐light‐chain‐enhancer of activated B cells) and VCAM‐1 (vascular cell adhesion molecule 1) was also significantly suppressed by C646 treatment in SIRT3KO mice.ConclusionsC646 treatment attenuated p300 and H3K56 acetylation and improved arterial stiffness and CFR via improvement of endothelial cell (EC) dysfunction and suppression of NF‐κB.

P6220The non-invasive coronary flow reserve predicts exercise capacity in patients undergoing cardiac rehabilitation

Abstract Background The benefit of exercise on peripheral muscles is established but the exact role of the coronary microcirculation in exercise capacity after cardiac rehabilitation (CR) is unclear. Objective: Our aim was to test the relationship between non-invasive coronary flow reserve (CFR) and exercise capacity in patients undergoing CR after acute myocardial infarction (AMI). Methods CFR was performed by transthoracic Doppler echocardiography in the left anterior descending artery 24 h after angioplasty (CFR1) and after 20 sessions of CR program (at 4±1 months) (CFR2) in 60 consecutive patients (57±11 years, 30% women) with an anterior AMI successfully treated by primary coronary angioplasty. CFR was performed in a modified parasternal view using intravenous adenosine infusion (0.14 mg/kg/min within 2 minutes). CR program consisted of a half hour of fractioned exercise added of a half hour session of general gymnastics and body building. To test the exercise capacity, symptom limited exercise echocardiography was performed just after the CFR2, in a semi-supine position, starting at 25 watts, with 20–25 watts increments of workload every two minutes. Results CFR was measured successfully in all patients, and CFR2 was significantly higher than CFR1 (2.9±0.65 vs 1.9±0.4, p&lt;0.001). Though CFR1 was correlated to left ventricular systolic function and its improvement at follow-up (all, p&lt;0.01), CFR2 was independently related to exercise capacity (mean workload 100±30 watts, percent maximal heart rate 83±12%, no ischemia, no new wall motion abnormalities in all tests) after adjusting for age, sex, and body mass index (r=0.6, p&lt;0.01). Conclusion CFR predicts exercise capacity in patients undergoing a CR program after AMI. The improvement of CFR contributes to cardiac performance.

Effects of Interleukin 17A Inhibition on Myocardial Deformation and Vascular Function in Psoriasis

BackgroundInterleukin (IL)-17A activity is implicated in psoriasis. We investigated the effects of IL-17A inhibition on vascular and left ventricular (LV) function in patients with psoriasis. MethodsA total of 150 patients with psoriasis received either an anti-IL-17A agent (secukinumab, n = 50), cyclosporine (n = 50), or methotrexate treatment (n = 50). At baseline and after 4 and 12 months of treatment, we measured (1) LV global longitudinal strain (GLS), GLS rate (GLSR), GLSR at early diastole, LV twisting, and untwisting; (2) coronary flow reserve (CFR); (3) pulse wave velocity (PWV); and (4) malondialdehyde and protein carbonyl as markers of oxidative stress. ResultsCompared with cyclosporine and methotrexate, anti-IL-17A treatment resulted in a greater increase in GLS at 4 and 12 months after treatment (10% and 14% with anti-IL-17A vs 2% and 2% with cyclosporine vs 4% and 4% with methotrexate, respectively), GLSR, GLSR at early diastole (45% and 41% vs 5% and 4% vs 7% and 9%, respectively), and LV twisting (32% and 28% vs 6% and 8% vs 7% and 6%, respectively) (P < 0.05). Anti-IL-17A treatment resulted in greater improvement of CFR and PWV than cyclosporine or methotrexate (P < 0.05). PWV increased after cyclosporine treatment (+11% at 4 and +14% and 12 months) (P < 0.05). Markers of oxidative stress were reduced only after anti-IL-17A treatment (P < 0.05). Changes of myocardial deformation markers and CFR after anti-IL-17A treatment correlated with a concomitant reduction of oxidative stress. ConclusionsIn psoriasis, inhibition of IL-17A results in a greater improvement of vascular and myocardial function compared with cyclosporine or methotrexate treatment, indicating a beneficial effect on overall cardiovascular function.

Inhibition of prolyl hydroxylases alters cell metabolism and reverses pre-existing diastolic dysfunction in mice

BackgroundDiastolic dysfunction is emerging as a leading cause of heart failure in aging population. Induction of hypoxia tolerance and reprogrammed cell metabolism have emerged as novel therapeutic strategies for the treatment of cardiovascular diseases. Methods and resultsIn the present study, we showed that deletion of sirtuin 3 (SIRT3) resulted in a diastolic dysfunction together with a significant increase in the expression of prolyl hydroxylases (PHD) 1 and 2. We further investigated the involvement of PHD in the development of diastolic dysfunction by treating the 12–14 months old mice with a PHD inhibitor, dimethyloxalylglycine (DMOG) for 2 weeks. DMOG treatment increased the expression of hypoxia-inducible factor (HIF)-1α in the endothelium of coronary arteries. This was accompanied by a significant improvement of coronary flow reserve and diastolic function. Inhibition of PHD altered endothelial metabolism by increasing glycolysis and reducing oxygen consumption. Most importantly, treatment with DMOG completely reversed the pre-existing diastolic dysfunction in the endothelial-specific SIRT3 deficient mice. ConclusionsOur findings demonstrate that inhibition of PHD and reprogrammed cell metabolism can reverse the pre-existed diastolic dysfunction in SIRT3 deficient mice. Our study provides a potential therapeutic strategy of induction of hypoxia tolerance for patients with diastolic dysfunction associated with coronary microvascular dysfunction, especially in the aging population with reduced SIRT3.

Microvascular dysfunction following ST-elevation myocardial infarction and its recovery over time.

It is unclear whether microvascular dysfunction following ST-elevation myocardial infarction (STEMI) is prognostic for long-term left ventricular function (LVF), and whether recovery of the microvasculature status is associated with LVF improvement. The aim of this study was to assess whether microvascular dysfunction in the infarct-related artery (IRA), as assessed by coronary flow reserve (CFR) within one week after PPCI, was associated with LVF at both four months and two years. In 62 patients, CFR and hyperaemic microvascular resistance index (HMRI) in the IRA were assessed by intracoronary Doppler flow measurements within one week and at four months. CMR was performed at the same time points and also at two years. CFR at baseline was associated with left ventricular ejection fraction (LVEF) at four months (β=4.66, SE=2.10; p=0.03) and at two-year follow-up (β=5.84, SE=2.45; p=0.02). HMRI was not associated with LVF. In large infarcts, absolute improvement of CFR in the first four months was associated with LVEF improvement (β=5.09, SE=1.86, p=0.01). Microvascular dysfunction, assessed by CFR, in the subacute phase of STEMI is prognostic for LVEF at four months and two years. This underlines the pivotal role of microvascular dysfunction following STEMI.

Inhibition of DPP-4 by alogliptin improves coronary flow reserve and left ventricular systolic function evaluated by phase contrast cine magnetic resonance imaging in patients with type 2 diabetes and coronary artery disease

BackgroundThe present study determined whether dipeptidyl peptidase-4 (DPP-4) inhibition by alogliptin improves coronary flow reserve (CFR) and left ventricular election fraction (LVEF) in patients with type 2 DM and CAD. Materials and methodsTwenty patients with type 2 DM and known or suspected CAD were randomly allocated to receive diet therapy plus alogliptin (n=10; mean age, 73.3±6.6y) or a control group given diet therapy and glimepiride (n=10; mean age, 76.7±7.3y). Breath-hold PC cine MR images of the coronary sinus (CS) were acquired using a 1.5T MR scanner and 32 channel cardiac coils to assess blood flow of the CS at rest and during adenosine triphosphate (ATP) infusion. The CFR was calculated as CS blood flow during ATP infusion divided by that at rest. The CFR and LVEF were evaluated by MRI at baseline and at three months after starting therapy. ResultsHemoglobin A1c (HbA1c) was significantly reduced in both groups (alogliptin, 7.2±0.6% to 6.6±0.5%, p=0.034; control, 6.9±0.4% to 6.4±0.3%, p=0.008). However, CFR and LVEF significantly improved only in the alogliptin group (alogliptin: CFR, 2.15±0.61 to 2.85±0.80, p=0.042; LVEF, 59.4±6.3% to 68.0±8.6%, p=0.03; control: CFR, 2.17±0.37 to 2.38±0.32, p=0.19; LVEF, 58.2±9.1 to 60.3±8.8%, p=0.61). The % increases in CFR and in LVEF positively correlated (R=0.47 by Spearman's correlation coefficient; p=0.036). ConclusionThe inhibition of DPP-4 by alogliptin improved CFR and LVEF evaluated by MRI in patients with type 2 DM and CAD and the improvement in CFR was associated with increased LV systolic function.

The role of ivabradine in improving myocardial perfusion, adding to the antianginal benefits

The most common cause of oxygen demand/supply mismatch is atherosclerotic narrowing of the coronary artery, resulting in decreased coronary blood flow. However, endothelial dysfunction and/or microvascular dysfunction may be responsible for myocardial ischaemia and importantly may often coexist in patients with angina. Coronary flow reserve reflects the functional capacity of coronary circulation to adapt to the blood demand during increased cardiac work. In addition, coronary flow reserve predicts long-term adverse cardiovascular outcome. Therefore, a clear understanding of myocardial perfusion pathophysiology and a knowledge of the antianginal–anti-ischaemic drugs effect on coronary circulation are crucial for the judicious use of medications for the treatment of angina patients with coronary artery disease. This article discusses the role of ivabradine in improvement of myocardial perfusion based on data drawn from relevant preclinical and clinical investigations. Experimental data suggest that heart rate reduction with ivabradine causes greater increase in duration of diastolic perfusion time and coronary flow compared with β-blockade due to absence of impairing of left ventricular contractility and coronary vasomotion. In consequence, the full benefits of heart rate reduction for improved coronary perfusion could be realized with ivabradine. Following experimental data, clinical studies demonstrated anti-ischaemic and antianginal efficacy of ivabradine in patients with stable coronary artery disease. These clinical benefits have been supported by recent clinical data on improvement of coronary flow reserve, and coronary collateral circulation with ivabradine supports the role of ivabradine as an important anti-ischaemic and antianginal agent in patients with angina in addition to other recommended therapies or revascularization.

Effect of cardiac resynchronisation therapy on coronary blood flow in patients with non-ischaemic dilated cardiomyopathy

Cardiac resynchronisation therapy (CRT) has beneficial effects on cardiac function, exercise tolerance, symptoms, and prognosis. Coronary blood flow impairment has been observed in patients with non-ischaemic dilated cardiomyopathy (DCM) despite angiographically normal coronary arteries. No data are available on coronary blood flow and coronary flow reserve (CFR) measured by intracoronary Doppler in different coronary arteries in patients with DCM and left bundle branch block (LBBB) before and during treatment with CRT. Thus, the major aim of our study was to assess the effect of CRT on coronary blood flow in patients with non-ischaemic DCM and to compare coronary blood flow and CFR measured in the 3 major coronary arteries (left anterior descending [LAD], left circumflex [LCX], and right coronary artery [RCA]). Twenty one patients with DCM and LBBB (mean left ventricular ejection fraction 26 ± 7%, 5 females, mean age 57.8 ± 8.1 years) were studied. Average peak velocity, diastolic/systolic velocity ratio and CFR were measured using intracoronary Doppler before and 6-9 months after implantation of CRT-D or CRT-P. In patients with a clinical improvement (71.4%), CFR increased in LAD. CFR measured in LCX and RCA did not improve either in the overall study group or in patients with a clinical improvement. The observed increase in CFR in LAD correlated only with reduction of QRS duration. In non-ischaemic DCM, CFR is reduced only in LAD. A significant improvement of CFR in LAD after CRT correlates with reduction of QRS duration.

Effects of combination of statin and calcium channel blocker in patients with cardiac syndrome X

Statins and calcium channel blockers have been proven beneficial toward improvement of endothelial function. The aim of this study was to compare the effect of combination therapy of statin and calcium channel blocker with solo treatment in patients with cardiac syndrome X. Sixty-eight patients with cardiac syndrome X were divided randomly into three groups: fluvastatin (40 mg/day, n=23), diltiazem (90 mg/day, n=22), and combination of fluvastatin (40 mg/day) and diltiazem (90 mg/day, n=23). At the end of 90 days, the coronary flow reserve was improved in the three groups (fluvastatin-treated group: 23.2%; diltiazem-treated group: 12.4%; fluvastatin+diltiazem-treated group: 29.1%, all P<0.05). The time to 1 mm ST segment depression increased significantly in the fluvastatin-treated group (from 241±97 to 410±140 s, P<0.05), the diltiazem-treated group (from 258±91 to 392±124 s, P<0.05), and the fluvastatin+diltiazem-treated group (from 250±104 to 446±164 s, P<0.05). The improvement in coronary flow reserve and prolonged time to 1 mm ST segment depression in the combination treatment group were more remarkable than in those who received monotherapy. Combination therapy also induced a significant increase (35.6%, P<0.05) in nitric oxide and an apparent reduction (48.7%, P<0.05) in endothelin-1. Combination treatment with fluvastatin and diltiazem is more effective on endothelial function and exercise tolerance than solo treatment in patients with cardiac syndrome X. The benefits of these drugs may be related to the elevation of nitric oxide and reduction of endothelin-1.

Olmesartan Improves Coronary Flow Reserve of Hypertensive Patients Using Coronary Magnetic Resonance Imaging Compared with Amlodipine

Objectives: Hypertension impairs coronary endothelial cell function, coronary microvascular function and the coronary flow (CF) reserve (CFR). Angiotensin II receptor blockers (ARBs) have been reported to possibly improve coronary endothelial function and coronary microvascular function. The purpose of this study was to determine whether treatment with the ARB olmesartan was more effective for improving CFR than the calcium channel blocker amlodipine. Methods: Twenty patients with untreated essential hypertension (M/F = 13/7, aged 55.6 ± 11.6 years) were randomly assigned to treatment with either olmesartan (n = 10) or amlodipine (n = 10) for 6 months. CF was measured in the proximal left anterior descending artery by magnetic resonance imaging before and during intravenous infusion of adenosine. CFR was calculated as the ratio of the hyperemic to baseline diastolic peak flow before and after 6 months of treatment. Results: The extent of systolic blood pressure reduction was similar in both groups (–40.0 ± 19.1 vs. –48.8 ± 14.7 mm Hg, p = 0.26). The olmesartan group showed significant improvement of CFR (from 1.9 ± 1.0 to 3.1 ± 1.1, p = 0.005), but this did not occur in the amlodipine group. Conclusion: Olmesartan, but not amlodipine, improves CFR in hypertensive patients.