Coronary flow reserve evaluation: basics, techniques and clinical applications.

Coronary flow reserve is a useful physiologic parameter providing information on coronary stenoses severity. To date, the gold standard to evaluate coronary flow reserve consists of fractional flow reserve (FFR) measurement, assessed with a pressure-wire. The FFR has a high lesion specificity, due to insensitivity to patient hemodynamic status and to coronary microvascular resistance; it shows low inter- and intraindividual variability and a well-defined, bound cut-off range values (0.75-0.80). Several reports confirmed that FFR has high reproducibility and feasibility in patients with either single- or multi-vessel coronary artery disease, or with both stable and instable coronary artery disease and that is significantly associated with patient outcome. More recently, the FFR has been used as a sensitive marker of successful percutaneous coronary intervention, since postprocedural FFR value strongly predicts patients event-free survival rate after angioplasty. Moreover, it has been demonstrated that abnormal FFR ratios can be also associated with diffused atherosclerotic coronary artery disease in the absence of unique angiographically detectable stenoses requiring revascularization. There are strong evidences supporting that the FFR provides crucial functional information that could be related with morphological endovascular ultrasound findings, with the possibility to achieve same information in a cheaper, easier and more available manner. This review will focus on the current available literature regarding coronary flow reserve quantification and its clinical validation, suggesting and highlighting its current and future clinical applications.

Coronary stenting early before non-cardiac surgery: is the endothelial progenitor cell capturing coronary stent a solution?

The authors report, for the first time, immediate and mid-term outcome of early antiplatelet therapy discontinuation followed by uneventful non-cardiac surgery and endovascular aortic repair, few days after successful deployment of an endothelial progenitor cell capturing coronary stent, in three consecutive patients.

Endothelial alpha1-adrenoceptors regulate neo-angiogenesis.

BACKGROUND AND PURPOSE: Intact endothelium plays a pivotal role in post-ischaemic angiogenesis. It is a phenomenon finely tuned by activation and inhibition of several endothelial receptors. The presence of alpha(1)-adrenoceptors on the endothelium suggests that these receptors may participate in regenerative phenomena by regulating the responses of endothelial cells involved in neo-angiogenesis. EXPERIMENTAL APPROACH: We evaluated the expression of the subtypes of the alpha(1)-adrenoceptor in isolated endothelial cells harvested from Wistar-Kyoto (WKY) rats. We explored the possibility these alpha(1)-adrenoceptors may influence the pro-angiogenic phenotype of endothelial cells in vitro. In vivo, we used a model of hindlimb ischaemia in WKY rats, to assess the effects of alpha(1) adrenoceptor agonist or antagonist on angiogenesis in the ischaemic hindlimb by laser Doppler blood flow measurements, digital angiographies, hindlimb perfusion with dyed beads and histological evaluation. KEY RESULTS: In vitro, pharmacological antagonism of alpha(1)-adrenoceptors in endothelial cells from WKY rats by doxazosin enhanced, while stimulation of these adrenoceptors with phenylephrine, inhibited endothelial cell proliferation and DNA synthesis, ERK and retinoblastoma protein (Rb) phosphorylation, cell migration and tubule formation. In vivo, we found increased alpha(1)-adrenoceptor density in the ischaemic hindlimb, compared to non-ischaemic hindlimb, suggesting an enhanced alpha(1)-adrenoceptor tone in the ischaemic tissue. Treatment with doxazosin (0.06 mg kg(-1) day(-1) for 14 days) did not alter systemic blood pressure but enhanced neo-angiogenesis in the ischaemic hindlimb, as measured by all our assays. CONCLUSIONS: Our findings support the hypothesis that the alpha(1)-adrenoceptors in endothelial cells provide a negative regulation of angiogenesis.

Micrornas and Cardiovascular Diseases: From Bench to Bedside.

MicroRNAs (microRNAs or miRs) are small, non-coding RNAs that control gene expression by binding to and repressing specific mRNA target and have emered as powerful regulators of many biological processes. Understanding miRNAs-biology and functions may be pivotal to get a better insight into pathophysiological mechanisms responsible for a large number of morbid conditions and may lay the foundations for the development of novel therapeutic interventions. Moreover, besides their intracellular functions, miRs are present in the human circulation in a remarkably stable cell-free form, and their plasmatic levels have been proposed as biomarkers for several pathological conditions. The present review aims to summarize the current evidences with regard to biological role of miRNAs in cardiovascular system and their involvement in the pathogenesis of cardiovascular diseases including atherosclerosis, heart failure and pathological heart and vascular remodelling and to highlight their potential use as novel biomarkers and as therapeutic targets in cardiac and vascular diseases.

Transcatheter Implantable Devices to Monitoring of Elevated Left Atrial Pressures in Patients with Chronic Heart Failure.

Elevated left atrial (LA) pressures are associated with poor prognosis in heart failure (HF). Invasive monitoring of LA-pressures and direct mechanical LA-decompression are associated with functional improvement in patients suffering from HF both with reduced and preserved ejection fraction. We aim to review the current available percutaneously implantable sensors for haemodynamic telemonitoring of LA-pressures (direct LAP sensor device-HeartPOD; right ventricular device-Chronicle; pulmonary artery device-CardioMEMs).

Prediction of high on-treatment platelet reactivity in clopidogrel-treated patients with acute coronary syndromes.

BACKGROUND: About 40% of clopidogrel-treated patients display high platelet reactivity (HPR). Alternative treatments of HPR patients, identified by platelet function tests, failed to improve their clinical outcomes in large randomized clinical trials. A more appealing alternative would be to identify HPR patients a priori, based on the presence/absence of demographic, clinical and genetic factors that affect PR. Due to the complexity and multiplicity of these factors, traditional statistical methods (TSMs) fail to identify a priori HPR patients accurately. The objective was to test whether Artificial Neural Networks (ANNs) or other Machine Learning Systems (MLSs), which use algorithms to extract model-like 'structure' information from a given set of data, accurately predict platelet reactivity (PR) in clopidogrel-treated patients. METHODS: A complete set of fifty-nine demographic, clinical, genetic data was available of 603 patients with acute coronary syndromes enrolled in the prospective GEPRESS study, which showed that HPR after 1month of clopidogrel treatment independently predicted adverse cardiovascular events in patients with Syntax Score >14. Data were analysed by MLSs and TSMs. ANNs identified more variables associated PR at 1month, compared to TSMs. RESULTS: ANNs overall accuracy in predicting PR, although superior to other MLSs was 63% (95% CI 59-66). PR phenotype changed in both directions in 35% of patients across the 3 time points tested (before PCI, at hospital discharge and at 1month). CONCLUSIONS: Despite their ability to analyse very complex non-linear phenomena, ANNs or MLS were unable to predict PR accurately, likely because PR is a highly unstable phenotype.

Bivalirudin in Patients Undergoing PCI: State of Art and Future Perspectives.

Acute coronary syndrome (ACS) represents the most common cause of death worldwide. Percutaneous coronary intervention (PCI) is the management of choice in patients with ACS and occurrence of intra-procedural thrombotic complications are an independent predictor of mortality and other major adverse cardiovascular events in patients undergoing PCI. According to current guideline, anticoagulation therapy is indicated during PCI in order to reduce the risk of thrombotic complications such as stent thrombosis. Among currently available anticoagulant drugs, bivalirudin demonstrates a lower incidence of bleeding risk, despite it is associated with an increased risk of stent thrombosis. The aim of this paper is to discuss the pharmacology of bivalirudin and the clinical evidences of its use in patients undergoing PCI for ACS.

Effect of a single oral dose of milrinone on left ventricular diastolic performance in the failing human heart.

In 14 patients with severe congestive heart failure, left ventricular pressure (measured by tip manometer) and derived variables were measured before and every 10 minutes after administration of oral milrinone (10 mg) for 50 minutes along with measurements of coronary sinus blood flow and drug plasma levels. Arterial and coronary sinus catecholamines were measured only before and 50 minutes after milrinone. Left ventricular pressure, volume (as determined by angiography) and derived indexes were simultaneously assessed at matched atrial paced heart rate before and 60 minutes after milrinone. Three patients who did not achieve a therapeutic plasma level (less than 150 ng/ml) were excluded. Peak negative first derivative of left ventricular pressure (-dP/dt) progressively and significantly increased (10%) together with a decrease in the two exponential time constants of relaxation, namely, Tau 1 (19%) and Tau 2 (22%), which represent the fit for and after the first 40 ms, respectively. Coronary flow significantly increased by 43% within 30 minutes, whereas the decrease (-13%) in coronary vascular resistance failed to be statistically significant. No change occurred in catecholamine concentrations after milrinone. Peak filling rate significantly increased by 15%. Pressure-volume curves showed a leftward and, in four patients, a downward shift; a significant decrease in minimal left ventricular diastolic and end-diastolic pressures (by 55 and 38%, respectively) and in end-diastolic volume (18%) occurred. The constant of elastic chamber stiffness measured by the simple elastic model tended to decrease, but failed to achieve a statistically significant level. Thus, oral milrinone improved left ventricular early relaxation and filling as well as chamber distensibility. This global improvement of diastolic function makes milrinone a potentially useful drug in the oral treatment of heart failure.

Influence of reversible segmental left ventricular dysfunction on heart period variability in patients with one-vessel coronary artery disease.

OBJECTIVES: This study evaluated the relation between reversible segmental left ventricular dysfunction and frequency domain measures of heart period variability in patients with coronary artery disease. BACKGROUND: Heart period variability is frequently reduced in patients with coronary artery disease. However, the mechanisms of this reduction are still unclear. METHODS: Echocardiographic left ventricular wall motion and frequency domain measures of heart period variability were evaluated in 32 patients with one-vessel coronary artery disease before and 16 to 24 days after successful percutaneous transluminal coronary angioplasty. Of these, 12 patients (Group A) had normal and 20 patients (Group B) had abnormal regional wall motion. A control group of 15 healthy subjects (Group C) underwent 24-h Holter recording twice at 2-week intervals to check for spontaneous variations. RESULTS: At baseline, low and high frequency power were lower in Group B than in Groups A and C, whereas no difference was detectable in ultra low and very low frequency and total power. After coronary angioplasty, regional wall motion and frequency domain measures of heart period variability were unchanged in Group A. In Group B the mean (+/- SD) summed segment score improved from 17.1 +/- 3.6 to 12.8 +/- 2.0 (p < 0.01), and mean low and high frequency power (logarithmic units) increased from 6.14 +/- 0.23 to 6.35 +/- 0.34 (p < 0.01) and from 5.43 +/- 0.32 to 5.68 +/- 0.52 (p < 0.01), respectively. Furthermore, low and high frequency power, lower at baseline in Group B than in the other two groups, were comparable in the three groups after coronary angioplasty. CONCLUSIONS: This study demonstrates that segmental left ventricular dysfunction is involved in determining sympathovagal imbalance in patients with one-vessel coronary artery disease; the reversal of left ventricular dysfunction by successful coronary angioplasty improves the heart period power spectrum. Thus, alterations in cardiac geometry influence the discharge of afferent sympathetic mechanoreceptors, contributing to the derangement in autonomic control of heart rate.

Effects of induced asynchrony on left ventricular diastolic function in patients with coronary artery disease.

OBJECTIVES: This study was designed to increase asynchrony with sequential atrioventricular (AV) pacing and to study its effects on left ventricular isovolumetric relaxation, rapid filling and stiffness. BACKGROUND: Left ventricular nonuniformity is a major determinant of diastolic function. METHODS: Thirteen patients with coronary artery disease were studied by simultaneous equilibrium radionuclide angiography and cardiac catheterization during atrial and AV pacing. Ejection fraction and peak filling rate were measured by radionuclide angiography. Regional analysis was obtained by analyzing time-activity curves of four left ventricular sectors; systolic and diastolic asynchrony were evaluated as the coefficient of variation of time to end-systole and, respectively, time to peak filling rate in the four sectors. Cardiac index and left ventricular pressure were measured with high fidelity catheters at cardiac catheterization. The time constant of isovolumetric relaxation was derived from left ventricular pressure. Pressure-volume loops were assembled and constants of chamber stiffness were computed. RESULTS: Atrioventricular pacing led to a decrease in cardiac index (3.7 +/- 0.9 to 3.3 +/- 0.8 liters/min per m2, p = 0.01) and peak filling rate (352 +/- 125 to 287 +/- 141 ml/s, p = 0.03; 2.4 +/- 0.8 to 2.0 +/- 0.8 end-diastolic counts/s, p = 0.02; 4 +/- 1.3 to 3.2 +/- 1.0 stroke counts/s, p = 0.008). The time constant of isovolumetric relaxation increased (57 +/- 10 to 64 +/- 12 ms, p = 0.04) and the global diastolic pressure-volume relation shifted upward. CONCLUSIONS: Atrioventricular pacing induces left ventricular asynchrony, which is associated with a slower rate of isovolumetric relaxation. The isovolumetric relaxation lasts after the filling phase has begun, thereby reducing the rate of rapid filling.

Endovascular procedures in critical leg ischemia of elderly patients.

PURPOSE: Purpose of this study was to evaluate angiographic and clinical results of popliteal, infrapopliteal, and multi-level disease percutaneous transluminal angioplasty (PTA) in over-80 years old patients with chronical clitical leg ischemia. In fact such patients with extensive peripheral vascular disease and critical limb ischemia (CLI) are generally poor surgical candidates. METHODS: Between 1998 and 2003, 37 elderly patients aged 80-89 years old (mean age 83.3) with critical leg ischemia were treated with PTA. All patients were at high surgical risk. 31/37 (81.5%) patients had chronic non-healing wounds, and 14/37 (37%) had multi-level disease of superficial femoral, popliteal and crural arteries. One hundred and two lesions were treated by angioplasty. Immediate angiographic and 1 year clinical results were retrospectively analyzed. RESULTS: The overall procedural success rate was 32/37 (84.2%). There were three major complications (7.9%), but no deaths, and three technical failures, all were of infrapopliteal lesions. After 1 year, 27 patients could be followed, five patients died during the first year of unrelated causes. Twenty-three patients (85.2%), were clinically re-occluded within 1 year, but complete and partial wound healing was achieved in 80% (16/20) and rest pain improvement in 57% (4/7), so that overall limb salvage was 74% (20/27). CONCLUSIONS: Elderly patients with multi-level CCLI have a short patency term following angioplasty of 14.8% after 1 year. Nevertheless, this temporary vascular patency enables wound healing or improvement in 74% of these patients, thus such endovascular interventions are recommended in this age group.

Early surgery after coronary revascularization: a fine line between bleeding and thrombosis.

Management of PCI patients undergoing early surgery is still a matter of debate. Noteworthy, PCI patients require a dual antiplatelet therapy (DAPT), with aspirine and a thienopiridine (clopidogrel, prasugrel, ticagrelor), because of the high risk of stent thrombosis (ST), myocardial infarction (MI) and death, especially within the first month. Indeed, the number of surgical interventions after PCI is actually increasing, and physicians are looking for the best antiplatelet therapy management, in order to reduce both, bleeding and thrombosis risk. In this paper, current guidelines therapy management and new optional strategies to reduce the cardiovascular risk, related to early surgery, are discussed.

Heart Failure in a Dedicated Outpatient Clinic: Results after 58 Month Follow-Up. Can it be Enough?

Incidence of chronic heart failure (HF) is rapidly increasing, approaching a 10 per 1000 rate after 65 years of age. In the last decades, despite pharmacological, interventional and supportive innovations, HF prognosis remained poor, with about 30% of death within one year from the diagnosis. Current guidelines recommend for these patients management programs providing follow-up through dedicated outpatient clinic. Limits of these programs are represented by great difficulties in getting patients adherence, being still too elevated the rate of abandonments. In this paper, we analyzed the impact of 58 months of activity in our dedicated to heart failure outpatient clinic on mortality, hospitalization and abandonment rate. 477 HF patients (346 M, 72.5%, mean age 69.6 years) were enrolled. Mean follow-up and visit were 18.2 and 2.6 months respectively. Total mortality rate was 11.5%, 4% of patients per year. Total hospitalizations for acute HF were 212 and, among all patients left in follow-up, the number of hospitalizations for acute de-compensation significantly decreased from 0.49/patient/year before enrollment to 0.29/patient/year during follow-up (p=0.015). Patients who abandoned outpatient clinic were 94 (19%, 1 abandonment every 23 days), mostly observed over the first months of activity. In conclusion, our patients experienced a major decrease in rates of acute de-compensation and need of in-hospital admissions.

A novel miR-371a-5p-mediated pathway, leading to BAG3 upregulation in cardiomyocytes in response to epinephrine, is lost in Takotsubo cardiomyopathy.

Molecular mechanisms protecting cardiomyocytes from stress-induced death, including tension stress, are essential for cardiac physiology and defects in these protective mechanisms can result in pathological alterations. Bcl2-associated athanogene 3 (BAG3) is expressed in cardiomyocytes and is a component of the chaperone-assisted autophagy pathway, essential for homeostasis of mechanically altered cells. BAG3 ablation in mice results in a lethal cardiomyopathy soon after birth and mutations of this gene have been associated with different cardiomyopathies including stress-induced Takotsubo cardiomyopathy (TTC). The pathogenic mechanism leading to TTC has not been defined, but it has been suggested that the heart can be damaged by excessive epinephrine (epi) spillover in the absence of a protective mechanism. The aim of this study was to provide more evidence for a role of BAG3 in the pathogenesis of TTC. Therefore, we sequenced BAG3 gene in 70 TTC patients and in 81 healthy donors with the absence of evaluable cardiovascular disease. Mutations and polymorphisms detected in the BAG3 gene included a frequent nucleotide change g2252c in the BAG3 3'-untranslated region (3'-UTR) of Takotsubo patients (P<0.05), resulting in loss of binding of microRNA-371a-5p (miR-371a-5p) as evidenced by dual-luciferase reporter assays and argonaute RNA-induced silencing complex catalytic component 2/pull-down assays. Moreover, we describe a novel signaling pathway in cardiomyocytes that leads to BAG3 upregulation on exposure to epi through an ERK-dependent upregulation of miR-371a-5p. In conclusion, the presence of a g2252c polymorphism in the BAG3 3'-UTR determines loss of miR-371a-5p binding and results in an altered response to epi, potentially representing a new molecular mechanism that contributes to TTC pathogenesis.

Evaluation of left ventricular asynchrony by radionuclide angiography: comparison of phase and sector analysis.

UNLABELLED: The aim of this study was to assess the optimal method to evaluate asynchrony in equilibrium radionuclide angiography (RNA). METHODS: We studied 20 patients (14 males and 6 females, age range 25-60 yr) with RNA during atrial and sequential atrioventricular (AV) pacing, which increased left ventricular (LV) asynchrony. Both studies were performed at the same heart rate. Asynchrony was assessed either on phase images, by computing the standard deviation of the phase distribution (SD-P) and by sector analysis. Systolic and diastolic asynchrony were evaluated as the coefficient of variation of time to end systole (CV-TES) and time to peak filling rate (CV-TPFR) in four sectors. In addition, phase values were computed on time-activity curves from the same sectors, and their standard deviation (SD-Psec) was computed. RESULTS: During atrial pacing SD-P was 32.3 degrees +/- 6.7 degrees and did not change during AV pacing (32.1 degrees +/- 5.6 degrees, p = n.s.). Both CV-TES and CV-TPFR had a significant increase during AV pacing (from 7.7% +/- 3.9% to 11.5% +/- 6.4%, p < 0.01, and from 8.4 degrees +/- 5.8 degrees to 12.9 degrees +/- 6.7 degrees, p < 0.001). AV pacing led to a significant increase in SD-Psec (from 6.3 degrees +/- 4.0 degrees to 12.6 degrees +/- 9.7 degrees, p < 0.05). Moreover, reproducibility was assessed in 15 additional age-matched patients. The results of the reproducibility study indicate a better repeatability for CV-TES and CV-TPFR. CONCLUSIONS: The findings of this study suggest that sector analysis with calculation of indices of LV systolic and diastolic asynchrony is better suited for quantitation of LV temporal nonuniformity.

Assessment of left ventricular diastolic function: comparison of contrast ventriculography and equilibrium radionuclide angiography.

Twenty-two patients with coronary artery disease were studied first by radionuclide angiography (RNA) and then by contrast ventriculography. Cardiac medications were discontinued at least 72 hr before study. The patients were studied during atrial pacing at heart rates close to their spontaneous sinus rhythm. Contrast ventriculography was performed at 50 frames/sec in the 30 degrees right anterior oblique projection using 40 ml of a nonionic contrast medium (iopamidol) at a flow rate of 10-12 ml/sec. The contours of the left ventricular silhouette at contrast ventriculography were traced, frame by frame, on a graphic table with a digitizing penlight. Equilibrium 99mTc RNA was performed in the best septal 45 degrees left anterior oblique projection, acquiring 150,000 cts/frame, at 50 frames/sec and with a 5% gate tolerance. Time-activity curves from both end-diastolic and end-systolic ROIs were built and interpolated. Both RNA and contrast ventriculography volume curves were filtered with Fourier five harmonics. A close relationship was found between RNA and contrast ventriculography measurements of peak filling rate normalized to end-diastolic cps (r = 0.87, p less than 0.001) and stroke count (r = 0.87, p less than 0.001), ejection fraction (r = 0.94, p less than 0.001). Thus, in patients with coronary artery disease, LV filling can be accurately assessed using RNA.

Impaired left ventricular filling dynamics during percutaneous transluminal angioplasty for coronary artery disease.

The effects of brief periods of major coronary artery occlusion on global and regional peak left ventricular (LV) filling rates were studied during angioplasty in 10 patients. No patient had had a previous myocardial infarction. High-fidelity LV pressure and volume were determined by angiography before and 20 and 50 seconds after the onset of transluminal coronary occlusion and soon after the last balloon inflation. Segmental wall motion was analyzed frame by frame along 20 hemiaxes. Global peak filling rate decreased significantly both after 20 (29%, p less than 0.05) and 50 seconds (27%, p less than 0.05) from the onset of the occlusion. The term sigma delta t1 was defined as the sum of the absolute values of the time differences from the occurrence of global peak filling rate and the segmental peak filling rate in 20 segments. This variable increased significantly during both periods of transluminal occlusion (by 73% and by 72% [both p less than 0.005], respectively), indicating asynchrony in the occurrence of regional peak filling rate. Simultaneously, the sum of intervals between aortic valve closure (end systole) and occurrence of peak segmental shortening, sigma delta t2, measured in the 20 segments, increased by 63% after 20 seconds and by 87% after 50 seconds (both p less than 0.005), showing major asynchrony in segmental contraction. A significant negative correlation was found between global peak filling rate and both sigma delta t1 and sigma delta t2 (r = 0.64, p less than 0.001 and r = 0.70, p less than 0.0001, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of left ventricular asynchrony on filling in coronary artery disease.

To evaluate whether the extent of left ventricular (LV) asynchrony plays a role in the impairment of LV rapid filling in patients with coronary artery disease (CAD), 48 patients underwent both radionuclide angiography and cardiac catheterization. Patients were divided into group I (n = 33), with normal LV kinesis or only mild hypokinesia, and group II (n = 15), with LV dyskinesia or akinesia. Radionuclide ejection fraction was higher in group I than in group II (62 +/- 12 vs 44 +/- 20%; p less than 0.001). Peak filling rate was significantly lower in group II (1.9 +/- 0.8 vs 2.6 +/- 0.9 end-diastolic counts/s; p less than 0.01). Time to end-systole coefficient of variation, an index of the extent of LV asynchrony, was significantly higher in group II than in group I (43 +/- 10 vs 35 +/- 6; p less than 0.0002). In group I, a highly significant inverse relation was found between this index of asynchrony and peak filling rate (r = 0.71; p less than 0.0001). This correlation was found even when time to end-systole coefficient of variation was normalized to the RR interval (r = 0.49; p less than 0.01) and when peak filling rate was expressed in stroke counts (r = 0.57; p less than 0.001). The correlation between peak filling rate and index of asynchrony was maintained up to an end-systole coefficient of variation value of approximately 35. In group II patients (most with an asynchrony value greater than or equal to 35) no relation was found between time to end-systole coefficient of variation and peak filling rate.