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The brand new 2016 ESC guidelines for the treatment of acute and chronic heart failure continue to give a prominent place to mineralocorticoid receptor antagonists in the treatment of chronic heart failure with reduced ejection fraction (HFrEF). In the prevention of HF hospitalization and death, a class I, level of recommendation A, is given to MRAs for patients with HFrEF, who remain symptomatic despite treatment with an ACE-inhibitor and a beta-blocker and have an LVEF below 35 %. This recommendation is primarily based on two landmark trials, the RALES trial (for spironolactone) and the EMPHASIS-HF trial (for eplerenone). A crucial question is, however, why MRAs are advised only in "third place," i.e., after optimal up-titration of ACE-inhibitors and beta-blockers. We wonder whether MRAs could not or should not be given earlier in the treatment of HFrEF, namely before or together with the up-titration of ACE-inhibitors and beta-blockers. Several arguments to support this plea are described in this short paper. [ABSTRACT FROM AUTHOR]

Cardiac transplant-related vasculopathy remains a leading cause of morbidity and mortality in heart transplant (HTx) recipients. Recently, coronary angiography-derived vessel fractional flow reserve (vFFR) has emerged as a new diagnostic computational tool to functionally evaluate the severity of coronary artery disease. Although vFFR estimates have been shown to perform well against invasive FFR in atherosclerotic coronary artery disease, data on the use of vFFR in heart transplant recipients suffering from cardiac transplant-related arteriopathy are lacking. The aim of the presented study was to validate coronary angiography-derived vessel fractional flow reserve to calculate fractional flow reserve in HTx patients with and without cardiac transplant-related vasculopathy. A prospective, single center study of HTx patients referred for annual check-up, undergoing surveillance coronarography was conducted. Invasive FFR was measured using a motorized device at the speed of 1.0 mm/s in all three major coronary arteries. Angiography-derived pullback FFR was derived from the angiogram and compared with invasive FFR pullback curve. Overall, 18,059 FFR values were extracted from the FFR pullback curves from 23 HTx patients. The mean age was 59.3 ± 9.7 years, the mean time after transplantation was 5.24 years [IQR 1.20, 11.25]. A total of 39 vessels from 23 patients (24 LAD, 11 LCX, 4 RCA) were analyzed. Mean distal vFFR was 0.87 ± 0.14 whereas invasive distal FFR was 0.88 ± 0.17. An excellent correlation was found between invasive distal FFR and vFFR (r = 0.92; p < 0.001). The correlation of the pullback tracing was high, with a correlation coefficient between vFFR and invasive FFR pullback values of 0.72 (95% CI 0.71 to 0.73, p < 0.001). The mean difference between vFFR and invasive FFR pullback values was −0.01 with 0.06 of SD (limits of agreements −0.12 to 0.13). In HTx patients, coronary angiography-derived FFR correlates excellently with invasively measured wire-derived FFR. Therefore, angiography derived FFR could be used as a novel diagnostic tool to quantify the functional severity of graft vasculopathy. [ABSTRACT FROM AUTHOR]

Background: β2-adrenergic receptor Thr164Ile (threonine (Thr) is replaced by an isoleucine (Ile) at codon 164) polymorphism was postulated to contribute to lower exercise tolerance and poor prognosis in patients with congestive heart failure. However, heart failure is associated with several abnormalities of β receptor signalling, and underlying mechanisms are not clear. Objectives: To investigate whether Thr164Ile polymorphism negatively modulates myocardial contractile performance and is associated with adverse long-term prognosis of patients with congestive heart failure. Methods: Among 55 subjects, cardiac contractile response to the 132-adrenergic receptor agonist terbutaline was assessed from the peak myocardial velocity of systolic shortening (Sm) in 18 subjects with the Ile-164 variant and 37 matched controls. In total, 24 subjects had normal left ventricular (LV) function and 31 presented with congestive heart failure due to idiopathic dilated cardiomyopathy. Results: In patients with normal LV function, peak terbutaline-induced increase (~\) in Sm was lower in subjects with the Ile-164 variant than in controls (Δ33% (4%) vs Δ56% (4%), p<0.01). In patients with heart failure, subjects with Ile-164 showed further severe reduction of β2-adrenergic-mediated increase in Sm as compared with controls with heart failure (Δ20% (5%) vs Δ39% (4%), p<0.05). Patients with heart failure with Ile-164 showed a severely blunted force-frequency relationship in response to agonist Stimulation. At 2-years of follow-up, patients with heart failure with the Ile-164 variant showed higher incidence of adverse events than controls with heart failure (75% (6/8)] vs 30% (7/23), p<0.05). Conclusions: The β2-adrenergic Thr164Ile polymorphism directly modulates adrenergic-mediated cardiac responses in patients with normal and failing myocardium. Furthermore, blunted β2 adrenergic-mediated myocardial contractile response in patients with Ile-164 variant seems to adversely modulate the course of congestive heart failure. [ABSTRACT FROM AUTHOR]

Background Impaired vasodilator myocardial blood flow response has been observed in dilated cardiomyopathy (DCMP). However, the mechanisms responsible for this blunted response are not clear. In the present study, we investigated whether the blunted vasodilator flow response is related to indices of left ventricular performance in patients with idiopathic dilated cardiomyopathy.Methods and results Eighteen DCMP patients and 12 healthy subjects (C) underwent transoesophageal echocardiography within 48h from cardiac catheterization. Coronary flow velocity reserve (CFR) was measured in the proximal LAD as the ratio of the peak diastolic coronary flow velocity (Vd-M) after intravenous administration of adenosine to peak baseline diastolic flow velocity (Vd-R). Left ventricular (LV) mass index was positively correlated with baseline coronary diastolic velocity (r=0.415; p=0.043) and inversely correlated with coronary flow reserve (r=−0.570; p=0.003). The baseline coronary diastolic velocity was higher in DCMP vs C (56±13cm/s vs 35±12cm/s; p=0.04). In DCMP pts Vd-R positively correlated with end-diastolic wall stress (r=0.654; p=0.01). Vd increased in both C (96±32cm/s; p<0.05 vs baseline) and DCMP patients (108±20cm/s; p<0.01 vs baseline). The CFR was lower in DCMP patients vs C (1.93±0.78 vs 2.99±1.01; p=0.009). In DCMP pts CFR was negatively correlated with right atrial pressure (r=−0.595; p=0.015), LVEDP (r=−0.576; p=0.015), pulmonary capillary wedge pressure (PCWP: r=−0.772; p<0.001) and positively with ejection fraction (EF: r=0.683; p=0.003).Conclusion Pts with DCMP have lower CFR compared to controls. This blunted CFR is due to higher baseline coronary flow and reflects higher wall stress. The close relation between CFR and EF, PCWP and LVEDP suggests that not only a higher baseline Vd but also compressive forces due to left ventricular dysfunction might be responsible for the observed blunted adenosine-mediated coronary vasodilation. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. 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. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. Background: In diabetic patients with multivessel coronary artery disease, coronary artery bypass grafting (CABG) has shown long-term benefits over percutaneous coronary intervention (PCI). Physiology-guided PCI has shown to improve clinical outcomes in multivessel coronary artery disease, though its impact in diabetic patients has never been investigated. We evaluated long-term clinical outcomes of diabetic patients with multivessel coronary artery disease treated with fractional flow reserve (FFR)–guided PCI compared with CABG. Methods: From 2010 to 2018, 4622 diabetic patients undergoing coronary angiography were screened for inclusion. The inclusion criterion was the presence of at least 2-vessel disease defined as with diameter stenosis ≥50%, in which at least 1 intermediate stenosis (diameter stenosis, 30%–70%) was treated or deferred according to FFR. Inverse probability of treatment weighting analysis was used to account for baseline differences with a contemporary cohort of patients treated with CABG. The primary end point was major adverse cardiovascular and cerebrovascular events, defined as all-cause death, myocardial infarction, revascularization, or stroke. Results: A total of 418 patients were included in the analysis. Among them, 209 patients underwent CABG and 209 FFR-guided PCI. At 5 years, the incidence of major adverse cardiovascular and cerebrovascular events was higher in the FFR-guided PCI versus the CABG group (44.5% versus 31.9%; hazard ratio, 1.60 [95% CI, 1.15–2.22]; P =0.005). No difference was found in the composite of all-cause death, myocardial infarction, or stroke (28.8% versus 27.5%; hazard ratio, 1.05 [95% CI, 0.72–1.53]; P =0.81). Repeat revascularization was more frequent with FFR-guided PCI (24.9% versus 8.2%; hazard ratio, 3.51 [95% CI, 1.93–6.40]; P <0.001). Conclusions: In diabetic patients with multivessel coronary artery disease, CABG was associated with a lower rate of major adverse cardiovascular and cerebrovascular events compared with FFR-guided PCI, driven by a higher rate of repeat revascularization. At 5-year follow-up, no difference was observed in the composite of all-cause death, myocardial infarction, or stroke between CABG and FFR-guided PCI. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. Background—: Fractional flow reserve (FFR)-guided coronary artery bypass graft (CABG) surgery has been associated with lower number of graft anastomoses, lower rate of on-pump surgery, and higher graft patency rate as compared with angiography-guided CABG surgery. However, no clinical benefit has been reported to date. Methods and Results—: Consecutive patients (n=627) treated by CABG between 2006 and 2010 were retrospectively included. In 198 patients, at least 1 stenosis was grafted according to FFR (FFR-guided group), whereas in 429 patients all stenoses were grafted based on angiography (angiography-guided group). The 2 coprimary end points were overall death or myocardial infarction and major adverse cardiovascular events (composite of overall death, myocardial infarction, and target vessel revascularization) up to 6-year follow-up. In the FFR-guided group, patients were significantly younger (66 [57–73] versus 70 [63–76]; P<0.001), more often male (82% versus 72%; P=0.008), and less often diabetic (21% versus 30%; P=0.023). Clinical follow-up (median, 85 [66–104] months) was analyzed in 396 patients after 1:1 propensity-score matching for these 3 variables. The rate of overall death or myocardial infarction was significantly lower in the FFR-guided (n=31 [16%] versus n=49 [25%]; hazard ratio, 0.59 [95% confidence interval, 0.38–0.93]; P=0.020) as compared with the angiography-guided group. Major adverse cardiovascular events rate was also numerically lower in the FFR-guided than in the angiography-guided group (n=42 [21%] versus n=52 [26%]; hazard ratio, 0.77 [95% confidence interval, 0.51–1.16]; P=0.21). Conclusions—: FFR-guided CABG is associated with a significant reduction in the rate of overall death or myocardial infarction at 6-year follow-up as compared with angiography-guided CABG. [ABSTRACT FROM AUTHOR]

Serial transthoracic echocardiographic (TTE) assessment of LVEF and GLS are the gold standard in screening Cancer Therapeutics-Related Cardiac Dysfunction (CTRCD). Non-invasive left-ventricle (LV) pressure–strain loop (PSL) emerged as a novel method to quantify Myocardial Work (MW). This study aims to describe the temporal changes and longitudinal trajectories of MW indices during cardiotoxic treatment. We included 50 breast cancer patients with normal LV function referred for anthracycline therapy w/wo Trastuzumab. Medical therapy, clinical and echocardiographic data were recorded before and 3, 6, and 12 months after initiation of the chemotherapy. MW indices were calculated through PSL analysis. According to ESC guidelines, mild and moderated CTRCD was detected in 10 and 9 patients, respectively (20% CTRCDmild, 18% CTRCDmod), while 31 patients remained free of CTRCD (62% CTRCDneg). Prior to chemotherapy MWI, MWE and CW were significantly lower in CTRCDmod than in CTRCDneg and CTRCDmild. Overt cardiac dysfunction in CTRCDmod at 6 months was accompanied by significant worse values in MWI, MWE and WW compared to CTRCDneg and CTRCDmild. MW features such as low baseline CW, especially when associated with a rise in WW at follow-up, may identify patients at risk for CTRCD. Additional studies are needed to explore the role of MW in CRTCD. [ABSTRACT FROM AUTHOR]

Background: Sodium-glucose co-transporters (SGLT) inhibitors (SGLT2i) showed many beneficial effects at the cardiovascular level. Several mechanisms of action have been identified. However, no data on their capability to act via epigenetic mechanisms were reported. Therefore, this study aimed to investigate the ability of SGLT2 inhibitors (SGLT2i) to induce protective effects at the cardiovascular level by acting on DNA methylation. Methods: To better clarify this issue, the effects of empagliflozin (EMPA) on hyperglycemia-induced epigenetic modifications were evaluated in human ventricular cardiac myoblasts AC16 exposed to hyperglycemia for 7 days. Therefore, the effects of EMPA on DNA methylation of NF-κB, SOD2, and IL-6 genes in AC16 exposed to high glucose were analyzed by pyrosequencing-based methylation analysis. Modifications of gene expression and DNA methylation of NF-κB and SOD2 were confirmed in response to a transient SGLT2 gene silencing in the same cellular model. Moreover, chromatin immunoprecipitation followed by quantitative PCR was performed to evaluate the occupancy of TET2 across the investigated regions of NF-κB and SOD2 promoters. Results: Seven days of high glucose treatment induced significant demethylation in the promoter regions of NF-kB and SOD2 with a consequent high level in mRNA expression of both genes. The observed DNA demethylation was mediated by increased TET2 expression and binding to the CpGs island in the promoter regions of analyzed genes. Indeed, EMPA prevented the HG-induced demethylation changes by reducing TET2 binding to the investigated promoter region and counteracted the altered gene expression. The transient SGLT2 gene silencing prevented the DNA demethylation observed in promoter regions, thus suggesting a role of SGLT2 as a potential target of the anti-inflammatory and antioxidant effect of EMPA in cardiomyocytes. Conclusions: In conclusion, our results demonstrated that EMPA, mainly acting on SGLT2, prevented DNA methylation changes induced by high glucose and provided evidence of a new mechanism by which SGLT2i can exert cardio-beneficial effects. [ABSTRACT FROM AUTHOR]

Introduction: Preliminary studies have suggested a low post-vaccination antibody response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in heart transplant(HTx)recipients. Although many studies have focused on the role of antibodies in vaccine-induced protection against SARS-CoV-2, the role of T cell immunity is less well characterized. To date, data regarding seroconversion and T cell response after mRNA SARS-CoV-2 vaccination in patients undergoing HTx are scarce. Therefore, the present study aimed to assess the specific memory humoral and cellular responses after two doses of the BNT162b2 vaccine in HTx recipients. Methods: Blood was drawn from heart transplant (HTx) recipients at two pre-specified time points after the first and second vaccine doses to measure both the anti-SARS-CoV-2 antibody response against the spike protein and the SARS-CoV-2-reactive T cell response. Results: Our study included 34 SARS-CoV-2 naïve HTx recipients (mean age, 61 ± 11 years). The mean time from transplantation to the first vaccine dose is 10 ± 10 years. Subgroup analysis (n = 21) demonstrated that after the first vaccine dose, only 14% had antibodies and 19% had a SARS-CoV-2-reactive T-cell response, which increased to 41% and 53%, respectively, after the second dose. Interestingly, 20% of patients with no antibodies after the second dose still had a positive SARS-CoV-2-reactive T cell response. The percentage of patients with positive S-IgG antibody titers was significantly higher 5 years after transplantation (18% 0–5 years post-TX vs. 65% 5 years post-TX, p = 0.013). Similarly, 5 years after heart transplantation, the percentage of patients with a T cell response was significantly higher (35% 0–5 years post-TX vs. 71% 5 years post-TX, p = 0.030). Conclusions: In SARS-CoV-2 naïve HTx recipients, post-vaccination antibody titers but also SARS-CoV-2 specific T cell response are low. Therefore, the protection from SARS-CoV-2 that is generally attributed to vaccination should be regarded with caution in HTx recipients. [ABSTRACT FROM AUTHOR]

Background: High glycated-hemoglobin (HbA1c) levels correlated with an elevated risk of adverse cardiovascular outcomes despite renin-angiotensin system (RAS) inhibition in type-2 diabetic (T2DM) patients with reduced ejection fraction. Using the routine biopsies of non-T2DM heart transplanted (HTX) in T2DM recipients, we evaluated whether the diabetic milieu modulates glycosylated ACE2 (GlycACE2) levels in cardiomyocytes, known to be affected by non-enzymatic glycosylation, and the relationship with glycemic control. Objectives: We investigated the possible effects of GlycACE2 on the anti-remodeling pathways of the RAS inhibitors by evaluating the levels of Angiotensin (Ang) 1–9, Ang 1–7, and Mas receptor (MasR), Nuclear-factor of activated T-cells (NFAT), and fibrosis in human hearts. Methods: We evaluated 197 first HTX recipients (107 non-T2DM, 90 T2DM). All patients were treated with angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) at hospital discharge. Patients underwent clinical evaluation (metabolic status, echocardiography, coronary CT-angiography, and endomyocardial biopsies). Biopsies were used to evaluate ACE2, GlycACE2, Ang 1–9, Ang 1–7, MasR, NAFT, and fibrosis. Results: GlycACE2 was higher in T2DM compared tonon-T2DM cardiomyocytes. Moreover, reduced expressions of Ang 1–9, Ang 1–7, and MasR were observed, suggesting impaired effects of RAS-inhibition in diabetic hearts. Accordingly, biopsies from T2DM recipients showed higher fibrosis than those from non-T2DM recipients. Notably, the expression of GlycACE2 in heart biopsies was strongly dependent on glycemic control, as reflected by the correlation between mean plasma HbA1c, evaluated quarterly during the 12-month follow-up, and GlycACE2 expression. Conclusion: Poor glycemic control, favoring GlycACE2, may attenuate the cardioprotective effects of RAS-inhibition. However, the achievement of tight glycemic control normalizes the anti-remodeling effects of RAS-inhibition. Trial registration: https://clinicaltrials.gov/ NCT03546062. [ABSTRACT FROM AUTHOR]

Coronary artery disease (CAD) continues to be the leading cause of mortality and morbidity in developed countries. Assessment of pre-test probability (PTP) based on patient's characteristics, gender and symptoms, help to identify more accurate patient's clinical likelihood of coronary artery disease. Consequently, non-invasive imaging tests are performed more appropriately to rule in or rule out CAD rather than invasive coronary angiography (ICA). Coronary computed tomography angiography (CCTA) is the first-line non-invasive imaging technique in patients with suspected CAD and could be used to plan and guide coronary intervention. Invasive coronary angiography remains the gold-standard method for the identification and characterization of coronary artery stenosis. However, it is recommended in patients where the imaging tests are non-conclusive, and the clinical likelihood is very high, remembering that in clinical practice, approximately 30 to 70% of patients with symptoms and/or signs of ischemia, referred to coronary angiography, have non obstructive coronary artery disease (INOCA). In this contest, physiology and imaging-guided revascularization represent the cornerstone of contemporary management of chronic coronary syndromes (CCS) patients allowing us to focus specifically on ischemia-inducing stenoses. Finally, we also discuss contemporary medical therapeutic approach for secondary prevention. The aim of this review is to provide an updated diagnostic and therapeutic approach for the management of patients with stable coronary artery disease. [ABSTRACT FROM AUTHOR]

The need for a quantitative and operator-independent assessment of coronary microvascular function is increasingly recognized. We propose the theoretical framework of microvascular resistance reserve (MRR) as an index specific for the microvasculature, independent of autoregulation and myocardial mass, and based on operator-independent measurements of absolute values of coronary flow and pressure. In its general form, MRR equals coronary flow reserve (CFR) divided by fractional flow reserve (FFR) corrected for driving pressures. In 30 arteries, pressure, temperature, and flow velocity measurements were obtained simultaneously at baseline (BL), during infusion of saline at 10 mL/min (rest) and 20 mL/min (hyperemia). A strong correlation was found between continuous thermodilution-derived MRR and Doppler MRR (r = 0.88; 95% confidence interval: 0.72-0.93; P < 0.001). MRR was independent from the epicardial resistance, the lower the FFR value, the greater the difference between MRR and CFR. Therefore, MRR is proposed as a specific, quantitative, and operator-independent metric to quantify coronary microvascular dysfunction. [ABSTRACT FROM AUTHOR]