Coronary Collateral Circulation: A New Predictor of Mortality in Heart Transplant Recipients With Allograft Vasculopathy

Background: Coronary collateral arteries (CCAs) are anastomotic channels between vessels; although beneficial in atherosclerosis, their role in heart transplantation (HT) recipients is underinvestigated. CCAs initially develop as microcirculation and cardiac allograft vasculopathy (CAV), promoting immune-dependent proliferative angiogenic response, and play a role in their development. In our hypothesis, ischemia induced by coronary microvascular dysfunction (CMD) triggers the development of CCAs, which are, in turn, less functional as affected by CAV themselves. Methods: One hundred twenty-one patients receiving HT at our institution were retrospectively evaluated and were included if transthoracic echocardiography with coronary flow velocity reserve (CFVR) assessment and coronary angiography were performed. CMD was defined as CFVR of ≤2.5. Patients with CAV were enrolled, and their angiograms were reviewed to evaluate the presence of CCAs. Cardiovascular mortality was assessed as the main clinical outcome. Results: Forty patients were found to have CCAs. Patients with CCAs have lower CFVR than those without CCAs (2.22 ± 0.72 versus 2.69 ± 0.92;P = 0.003), reflecting in different rates of CMD in the 2 groups (72.5% versus 37%; P < 0.001). CMD is associated with higher CAV grades (P < 0.001), which are also associated with CCAs (P < 0.001). Patients with poorly developed CCAs have lower CFVR (P < 0.001). At multivariable analysis, CMD (P = 0.008) and higher CAV grades (P = 0.005) are independent predictors of CCAs. During the median follow-up time of 10.2 (6.6-13.3) y, patients with CCAs have been found to have higher mortality than those without CCAs (57.5% versus 32.1%; P = 0.007). CCAs are associated with a lower probability of survival also in patients with CMD (P < 0.001) and are independent predictors of mortality (P < 0.001). Conclusions: Our results demonstrate an interplay between CAV, CMD, and CCAs. We confirm that CAV is associated with CMD, and we show, for the first time, that CMD is associated with CCAs. CCAs are pathophysiologically associated with more severe graft vasculopathy and independently predict mortality after HT

Antibodies against Angiotensin II Type 1 and Endothelin 1 Type A Receptors in Cardiovascular Pathologies

Angiotensin II receptor type 1 (AT1R) and endothelin-1 receptor type A (ETAR) are G-protein-coupled receptors (GPCRs) expressed on the surface of a great variety of cells: immune cells, vascular smooth cells, endothelial cells, and fibroblasts express ETAR and AT1R, which are activated by endothelin 1 (ET1) and angiotensin II (AngII), respectively. Certain autoantibodies are specific for these receptors and can regulate their function, thus being known as functional autoantibodies. The function of these antibodies is similar to that of natural ligands, and it involves not only vasoconstriction, but also the secretion of proinflammatory cytokines (such as interleukin-6 (IL6), IL8 and TNF-&alpha;), collagen production by fibroblasts, and reactive oxygen species (ROS) release by fibroblasts and neutrophils. The role of autoantibodies against AT1R and ETAR (AT1R-AAs and ETAR-AAs, respectively) is well described in the pathogenesis of many medical conditions (e.g., systemic sclerosis (SSc) and SSc-associated pulmonary hypertension, cystic fibrosis, and allograft dysfunction), but their implications in cardiovascular diseases are still unclear. This review summarizes the current evidence regarding the effects of AT1R-AAs and ETAR-AAs in cardiovascular pathologies, highlighting their roles in heart transplantation and mechanical circulatory support, preeclampsia, and acute coronary syndromes

Coronary Flow Velocity Reserve by Echocardiography: Beyond Atherosclerotic Disease

Coronary flow velocity reserve (CFVR) is defined as the ratio between coronary flow velocity during maximal hyperemia and coronary flow at rest. Gold-standard techniques to measure CFVR are either invasive or require radiation and are therefore inappropriate for large-scale adoption. More than 30 years ago, echocardiography was demonstrated to be a reliable tool to assess CFVR, and its field of application rapidly expanded. Although initially validated to assess the hemodynamic relevance of a coronary stenosis, CFVR by echocardiography was later used to investigate coronary microcirculation. Microvascular dysfunction was detected in many different conditions, ranging from organ transplantation to inflammatory disorders and from metabolic diseases to cardiomyopathies. Moreover, it has been proven that CFVR by echocardiography not only detects coronary microvascular involvement but is also an effective prognostic factor that allows a precise risk stratification of the patients. In this review, we will summarize the many applications of CFVR by echocardiography, focusing on the coronary involvement of systemic diseases

Sex differences in diagnostic modalities of coronary artery disease: Evidence from coronary microcirculation

: Although atherosclerosis is usually considered a disease of the large arteries, risk factors for atherosclerosis also trigger structural and functional abnormalities at a microvascular level. In cardiac disease, microvascular dysfunction is especially relevant in women, among whom the manifestation of ischemic disease due to impaired coronary microcirculation is more common than in men. This sex-specific clinical phenotype has important clinical implications and, given the higher pre-test probability of coronary microvascular dysfunction in females, different diagnostic modalities should be used in women compared to men. In this review, we summarize invasive and non-invasive diagnostic modalities to assess coronary microvascular function, ranging from catheter-based evaluation of endothelial function to Doppler echocardiography and positron emission tomography. Moreover, we discuss different clinical settings in which microvascular disease plays an important role, underlining the importance of choosing the right diagnostic modality depending on the sex of the patients

Coronary Flow Velocity Reserve by Echocardiography: Beyond Atherosclerotic Disease

Coronary flow velocity reserve (CFVR) is defined as the ratio between coronary flow velocity during maximal hyperemia and coronary flow at rest. Gold-standard techniques to measure CFVR are either invasive or require radiation and are therefore inappropriate for large-scale adoption. More than 30 years ago, echocardiography was demonstrated to be a reliable tool to assess CFVR, and its field of application rapidly expanded. Although initially validated to assess the hemodynamic relevance of a coronary stenosis, CFVR by echocardiography was later used to investigate coronary microcirculation. Microvascular dysfunction was detected in many different conditions, ranging from organ transplantation to inflammatory disorders and from metabolic diseases to cardiomyopathies. Moreover, it has been proven that CFVR by echocardiography not only detects coronary microvascular involvement but is also an effective prognostic factor that allows a precise risk stratification of the patients. In this review, we will summarize the many applications of CFVR by echocardiography, focusing on the coronary involvement of systemic diseases

Early detection of ventricular dysfunction in juvenile systemic sclerosis by speckle tracking echocardiography

OBJECTIVE: Cardiac involvement is the most important cause of mortality in juvenile systemic sclerosis (JSSc). Recent reports in adult patients underline that traditional techniques of imaging are inadequate to assess the subclinical cardiac involvement, while speckle tracking echocardiography (STE) is able to identify ventricular dysfunctions in the early stages. The aim of our study was to assess the role of STE in JSSc.METHODS: Demographic, clinical and laboratory data were collected from patients with JSSc. Cardiac investigations performed at baseline (T0) and 18 (T18) and 36months (T36) follow-up included electrocardiography, conventional echocardiography with measurement of the ejection fraction (EF) and STE with assessment of left and right ventricular global longitudinal strain (LV-GLS and RV-GLS). Cardiac parameters have been compared with demographic characteristics and disease severity, assessed by the Juvenile Systemic Sclerosis Severity Score (J4S).RESULTS: A total of 18 patients, 12 (67%) females, entered the study. At T0, electrocardiography was abnormal in three patients, EF was reduced in one, LV-GLS was abnormal in three (16.7%) and RV-GLS was abnormal in five (27.8%). At T18, EF remained stable while at T36 the result decreased in seven of nine patients. At the same time, LV-GLS also worsened (from -21.6% to -18.2%, P=0.01). LV-GLS and RV-GLS at baseline showed a significant correlation with J4S (P=0.012 and P=0.02, respectively).CONCLUSION: STE is more sensitive than standard echocardiography to identify cardiac involvement in JSSc. Over time, we observed a gradual worsening of LV-GLS, a sign of left ventricular dysfunction, that anticipated by several months the decrease of EF

Autoantibodies Targeting G-Protein-Coupled Receptors: Pathogenetic, Clinical and Therapeutic Implications in Systemic Sclerosis

Systemic sclerosis (SSc) is a multifaceted connective tissue disease whose aetiology remains largely unknown. Autoimmunity is thought to play a pivotal role in the development of the disease, but the direct pathogenic role of SSc-specific autoantibodies remains to be established. The recent discovery of functional antibodies targeting G-protein-coupled receptors (GPCRs), whose presence has been demonstrated in different autoimmune conditions, has shed some light on SSc pathogenesis. These antibodies bind to GPCRs expressed on immune and non-immune cells as their endogenous ligands, exerting either a stimulatory or inhibitory effect on corresponding intracellular pathways. Growing evidence suggests that, in SSc, the presence of anti-GPCRs antibodies correlates with specific clinical manifestations. Autoantibodies targeting endothelin receptor type A (ETAR) and angiotensin type 1 receptor (AT1R) are associated with severe vasculopathic SSc-related manifestations, while anti-C-X-C motif chemokine receptors (CXCR) antibodies seem to be predictive of interstitial lung involvement; anti-muscarinic-3 acetylcholine receptor (M3R) antibodies have been found in patients with severe gastrointestinal involvement and anti-protease-activated receptor 1 (PAR1) antibodies have been detected in patients experiencing scleroderma renal crisis. This review aims to clarify the potential pathogenetic significance of GPCR-targeting autoantibodies in SSc, focusing on their associations with the different clinical manifestations of scleroderma. An extensive examination of functional autoimmunity targeting GPCRs might provide valuable insights into the underlying pathogenetic mechanisms of SSc, thus enabling the development of novel therapeutic strategies tailored to target GPCR-mediated pathways

Multiparametric analysis of coronary flow in psoriasis using a coronary flow reserve companion

BACKGROUND Coronary microvascular dysfunction (CMD) is usually evaluated measuring coronary flow velocity reserve (CFVR). A more comprehensive analysis of CFVR including additional consideration of the associated logical companion-CFVR, where hyperemic diastolic coronary flow velocity may act as surrogate, was applied in this study to elucidate the mechanism of CMD in psoriasis. METHODS AND RESULTS Coronary flow velocity reserve was analysed using transthoracic echocardiographs of 127 psoriasis patients (age 36 ± 8 years; 104 males) and of 52 sex- and age-matched healthy controls. CFVR determination was repeated in the patient subgroup (n = 78) receiving anti-inflammatory therapy. Baseline and hyperemic microvascular resistance (MR) were calculated. CMD was defined as CFVR ≤ 2.5. Four endotypes of CMD were identified referring to concordant or discordant impairments of hyperemic flow or CFVR. We evaluated the companion-CFVR, as derived from the quadratic mean of hyperemic and diastolic flow velocity at rest. Coronary flow parameters, including CFVR (p = 0.01), were different among the two endotypes having CFVR > 2.5. Specifically, all 11 (14%) patients with CFVR deterioration despite therapy, belonged to endotype 1, and had higher baseline and hyperemic MR (p < 0.0001, both). Interestingly, while CFVR was comparable in patients with worsened versus those with improved CFVR, the companion-CFVR could discriminate by being lower in patients with worsened CFVR (p = 0.01). CONCLUSIONS The reduced CFVR in psoriasis is driven by decreased companion-CFVR, combined with increased hyperemic MR. Adoption of the mandatory companion-CFVR enables a personalized characterization superior to that achieved by exclusive consideration of CFVR

Spontaneous coronary artery dissection in women with acute myocardial infarction: is there a new role for autoimmunity?

Aims Spontaneous coronary artery dissection (SCAD) is an uncommon cause of acute myocardial infarction in women and has an unclear pathophysiology. Autoantibodies (AAs) targeting angiotensin-II receptor type 1 (AT1R) and endothelin-1 receptor type A (ETAR) have known detrimental effects on endothelial function. We investigated the prevalence of these AAs in SCAD-affected female patients. Methods and results Female patients diagnosed at coronary angiography with myocardial infarction and SCAD were consecutively enrolled. Autoantibodies targeting angiotensin-II receptor type 1 and ETAR-AA titres and seropositivity prevalence were compared between SCAD patients, ST-elevation myocardial infarction (STEMI) patients, and healthy women. Ten women with SCAD and 20 age-matched controls (10 women with STEMI and 10 healthy women) were included. Six out of 10 (60%) women with myocardial infarction and SCAD were seropositive for AT1R-AAs and ETAR-AAs. In contrast, only one (10%) healthy woman and one (10%) STEMI patient were seropositive for AT1R-AAs (P = 0.03 and P = 0.03, respectively). One STEMI patient was seropositive for ETAR-AAs, while none of the healthy women was found to be seropositive (P = 0.03 and P = 0.01, respectively). The median AA titre was significantly higher in SCAD patients than in healthy women (P = 0.01 for AT1R-AAs; P = 0.02 for ETAR-AAs) and STEMI patients (P < 0.001 for AT1R-AAs; P = 0.002 for ETAR-AAs). Conclusion Autoantibodies targeting angiotensin-II receptor type 1 and ETAR-AA seropositivity is significantly higher in SCAD women with myocardial infarction than in healthy women or female patients with STEMI. Our findings, corroborated by previous data in the literature and biological plausibility, suggest a possible role for AT1R-AAs and ETAR-AAs in the pathophysiology of SCAD in women with acute myocardial infarction and should warrant further studies with larger sample sizes

Higher Ventricular-Arterial Coupling Derived from Three-Dimensional Echocardiography Is Associated with a Worse Clinical Outcome in Systemic Sclerosis

Primary myocardial involvement is common in systemic sclerosis (SSc). Ventricular-arterial coupling (VAC) reflecting the interplay between ventricular performance and arterial load, is a key determinant of cardiovascular (CV) performance. We aimed to investigate VAC, VAC-derived indices, and the potential association between altered VAC and survival free from death/hospitalization for major adverse CV events (MACE) in scleroderma. Only SSc patients without any anamnestic and echocardiographic evidence of primary myocardial involvement who underwent three-dimensional echocardiography (3DE) were included in this cross-sectional study and compared with healthy matched controls. 3DE was used for noninvasive measurements of end-systolic elastance (Ees), arterial elastance (Ea), VAC (Ea/Ees) and end-diastolic elastance (Eed); the occurrence of death/hospitalization for MACE was recorded during follow-up. Sixty-five SSc patients (54 female; aged 56 ± 14 years) were included. Ees (p = 0.04), Ea (p = 0.04) and Eed (p = 0.01) were higher in patients vs. controls. Thus, VAC was similar in both groups. Ees was lower and VAC was higher in patients with diffuse cutaneous form (dcSSc) vs. patients with limited form (lcSSc) (p = 0.001 and p = 0.02, respectively). Over a median follow-up of 4 years, four patients died for heart failure and 34 were hospitalized for CV events. In patients with VAC &gt; 0.63 the risk of MACE was higher (HR 2.5; 95% CI 1.13–5.7; p = 0.01) and survival free from death/hospitalization was lower (p = 0.005) than in those with VAC &lt; 0.63. Our study suggests that VAC may be impaired in SSc patients without signs and symptoms of primary myocardial involvement. Moreover, VAC appears to have a prognostic role in SSc