Echocardiographic Biventricular Coupling Index to Predict Precapillary Pulmonary Hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a frequent and detrimental condition. Right heart catheterization (RHC) is the gold standard to identify PH subtype (precapillary from postcapillary PH) and is key for treatment allocation. In this study, the novel echocardiographic biventricular coupling index (BCI), based on the ratio between right ventricular stroke work index and left ventricular E/E' ratio, was tested for the discrimination of PH subtype using RHC as the comparator. METHODS: BCI was derived in 334 consecutive patients who underwent transthoracic echocardiography and RHC for all indications. BCI was then tested in a validation cohort of 1,349 patients. RESULTS: The accuracy of BCI to identify precapillary PH was high in the derivation cohort (area under the curve, 0.82; 95% CI, 0.78-0.88; P < .001; optimal cut point, 1.9). BCI identified patients with precapillary PH with high accuracy also in the validation cohort (area under the curve, 0.87 [95% CI, 0.85-0.89; P < .001]; subgroup with PH: area under the curve, 0.91 [95% CI, 0.89-0.93; P < .001]; cut point, 1.9; sensitivity, 82%; specificity, 89%; positive predictive value, 77%; negative predictive value, 92%). BCI outperformed both the D'Alto score (Z = 3.56; difference between areas = 0.05; 95% CI, 0.02-0.07; P < .001) and the echocardiographic pulmonary-to-left atrial ratio index (Z = 2.88; difference between areas = 0.02; 95% CI, 0.01-0.04; P = .004). CONCLUSIONS: BCI is a novel, noninvasive index based on routinely available echocardiographic parameters that identifies with high accuracy patients with precapillary PH. BCI may be of value in the screening workup of patients with PH.

Feasibility of real-time three-dimensional stress echocardiography: pharmacological and semi-supine exercise.

BACKGROUND: Real time three dimensional (RT3D) echocardiography is an accurate and reproducible method for assessing left ventricular shape and function. AIM: assess the feasibility and reproducibility of RT3D stress echocardiography (SE) (exercise and pharmacological) in the evaluation of left ventricular function compared to 2D. METHODS AND RESULTS: One hundred eleven patients with known or suspected coronary artery disease underwent 2D and RT3DSE. The agreement in WMSI, EDV, ESV measurements was made off-line.The feasibility of RT-3DSE was 67%. The inter-observer variability for WMSI by RT3D echo was higher during exercise and with suboptimal quality images (good: k = 0.88; bad: k = 0.69); and with high heart rate both for pharmacological (HR < 100 bpm, k = 0.83; HR > or = 100 bpm, k = 0.49) and exercise SE (HR < 120 bpm, k = 0.88; HR > or = 120 bpm, k = 0.78). The RT3D reproducibility was high for ESV volumes (0.3 +/- 14 ml; CI 95%: -27 to 27 ml; p = n.s.). CONCLUSIONS: RT3DSE is more vulnerable than 2D due to tachycardia, signal quality, patient decubitus and suboptimal resting image quality, making exercise RT3DSE less attractive than pharmacological stress.

Ticagrelor Enhances Release of Anti-Hypoxic Cardiac Progenitor Cell-Derived Exosomes Through Increasing Cell Proliferation In Vitro.

Despite the widespread clinical use of cardioprotection by long-term direct antagonism of P2Y12 receptor, underlying mechanisms are unclear. Here, we identify how release of pro-survival exosomes from human cardiac-derived mesenchymal progenitor cells (hCPCs) is regulated by clinically relevant dose of ticagrelor (1 µM), an oral selective and reversible non-thienopyridine P2Y12 inhibitor. Ticagrelor-induced enhancement of exosome levels is related to increased mitotic activity of hCPCs. We show a drug-response threshold above which the effects on hCPCs are lost due to higher dose of ticagrelor and larger adenosine levels. While it is known that pan-Aurora kinase inhibitor halts cell proliferation through dephosphorylation of histone H3 residue Ser10, we demonstrate that it also prevents ticagrelor-induced effects on release of cardiac progenitor cell-derived exosomes delivering anti-apoptotic HSP70. Indeed, sustained pre-treatment of cardiomyocytes with exosomes released from explant-derived hCPCs exposed to low-dose ticagrelor attenuated hypoxia-induced apoptosis through acute phosphorylation of ERK42/44. Our data indicate that ticagrelor can be leveraged to modulate release of anti-hypoxic exosomes from resident hCPCs.

Global Right Heart Assessment with Speckle-Tracking Imaging Improves the Risk Prediction of a Validated Scoring System in Pulmonary Arterial Hypertension.

BACKGROUND: Right ventricular (RV) function and right atrial (RA) remodeling are major determinants of outcome in pulmonary arterial hypertension (PAH). Strain echocardiography is emerging as a valuable approach for the study of RV and RA function. We sought to assess the incremental prognostic value of serial combined speckle-tracking examination of right chambers in newly diagnosed therapy-naïve PAH patients. METHODS: The study endpoint was a composite of all-cause mortality, hospitalizations due to worsening PAH, and initiation of parenteral prostanoids. Patients were assessed at baseline and at first revaluation after initiation of treatment. Right ventricular free-wall longitudinal strain (FWLS) and RA peak atrial longitudinal strain (PALS) were used as measures of RV and RA function. RESULTS: Eighty-three patients were included. Mean RV-FWLS and RA-PALS were -13.9% ± 6.1% and 23.1% ± 11.4%. The best performing prognostic score among the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension, French Pulmonary Hypertension Registry, and Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) scores was the REVEAL (area under the curve = 0.79, P < .001). With the identified cutoffs, both RV-FWLS (hazard ratio for RV-FWLS < -13.2% = 0.366; 95% CI, 0.159-0.842; P = .018) and RA-PALS (hazard ratio for RA-PALS > 20% = 0.399; 95% CI, 0.176-0.905; P = .028) were independently associated with the primary outcome after correction for the REVEAL score. The combined assessment of RV-FWLS and RA-PALS in addition to the REVEAL score determined a net improvement in prediction of 0.439 (95% CI, 0.070-0.888, P = .04). At 5 months (interquartile range, 4-8) of follow-up, RV-FWLS and RA-PALS improved significantly only in patients free from the primary outcome (P < .001 and P = .001, respectively). CONCLUSIONS: The combined assessment of RV-FWLS and RA-PALS determined an improvement in outcome prediction of validated prognostic risk scores and should be considered within the multiparametric evaluation of patients with PAH.

Left ventricular ejection fraction for risk stratification in chronic systolic heart failure.

BACKGROUND: Left ventricular ejection fraction (LVEF) represents the most used measure of cardiac systolic function. Different cut-offs have been proposed to classify patients with systolic dysfunction, and to inform therapy decision-making. METHODS: Consecutive outpatients with systolic heart failure (HF; LVEF <50%) were prospectively enrolled and underwent a baseline characterization. The prognostic value of LVEF and LVEF cut-offs was made with regards to the prediction of all-cause and cardiovascular death. RESULTS: Out of 2160 patients, 71% had LVEF <40%, and 61% had ≤35%. Over a 26-month median follow-up (interquartile interval 12-39), patients with LVEF ≤35% (log-rank 31.11 and 59.48, respectively; both p < 0.001) and <40% (log-rank 24.51 and 41.77, respectively; both p < 0.001) had a significantly worse prognosis for all-cause and cardiovascular death. LVEF independently predicted both endpoints in a strong prognostic model including age, sex, ischaemic aetiology, N-terminal fraction of pro-B-type natriuretic peptide, New York Heart Association class III-IV, several comorbidities and therapies. Receiver operating characteristics curves identified LVEF values 32% and 31% as the best cut-offs for the two endpoints. The 40% and lower cut-offs (35%, 32% or 31%) were independent predictors of all-cause and cardiovascular death (p < 0.001 in all cases). The 35% cut-off had a lower Akaike's Information Criterion value than 40%, denoting more accurate risk stratification. CONCLUSIONS: LVEF is an independent predictor of all-cause and cardiovascular mortality in chronic systolic HF. The 35% LVEF cut-off displays a better combination of sensitivity and specificity than the 40% cut-off for outcome prediction, although both hold independent prognostic value.

Statin intolerance in heterozygous familial hypercolesterolemia with cardiovascular disease: After PCSK-9 antibodies what else?

Background Familial hypercholesterolemia is the elective clinical condition that deserves the maximal personalisation in lipid-lowering therapy, especially in the presence of statin intolerance. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represent a promising approach to lower low-density lipoprotein (LDL) cholesterol. Methods We enrolled 18 patients (mean age 62 ± 8 years, 72% men) affected by heterozygous familial hypercholesterolemia and cardiovascular disease, with a history of statin intolerance assigned to PCSK9 inhibitors. Six patients were also on LDL apheresis. Associated Lp(a)-hyperlipoproteinemia (defined as >60 mg/dl) was observed in two out of 18 subjects. PCSK9 inhibitor injectable monoclonal antibodies were administered, every 2 weeks, on top of patient therapy for 12 ± 4 weeks (evolocumab in 15 subjects, alirocumab in three subjects). Results After 3 months (12 ± 4 weeks) of therapy, a decrease in total cholesterol (-35%), LDL cholesterol (-51%) and Lp(a) levels (-20%) was observed. Five out of 18 patients reached LDL cholesterol levels of <70 mg/dl, seven showed LDL cholesterol values between 71 and 100 mg/dl, and six out of 18 still had LDL cholesterol levels above 100 mg/dl. Among the six patients with LDL cholesterol levels >100 mg/dl, three were already on LDL apheresis before the PCSK9 inhibitor treatment, while three were referred to LDL apheresis treatment. Adverse events were reported in two out of 18 patients on evolocumab: one presented with flu-like syndrome and the other reported episodes of mild difficulty in maintaining concentration. Conclusions PCSK9 inhibitors represent a novel therapeutic tool for patients with familial hypercholesterolemia who are intolerant to statins. However, more data are needed before cleaning up the old therapeutic armamentarium, such as LDL apheresis, which is likely to preserve its valuable role also in the new lipid-lowering era.

Stress echo in chest pain unit: the SPEED trial.

BACKGROUND: Emergency room (ER) evaluation of patients with acute chest pain and non-diagnostic electrocardiography (ECG) remains a frequent and difficult problem. AIM: To assess safety and prognostic implications of pharmacological stress echocardiography in the ER chest pain unit (CPU). METHODS: A total of 552 patients (321 males, age 58+/-12.6 years) with acute chest pain, negative serial enzymes and/or troponin, and ECG recordings, and normal/unchanged resting left ventricular function were prospectively enrolled and underwent pharmacological (dipyridamole or dobutamine) stress echo. Six echo labs that had passed the preliminary quality control for stress echo reading entered the study. Follow-up was obtained in all patients after a median period of 13 months. RESULTS: No significant adverse events were observed during the test. Stress echocardiography was negative in 502 patients (91%) and positive in 50 (9%). The 502 patients with negative stress echocardiography were discharged with no or unchanged anti-ischemic medications. While the 50 patients with positive stress echo were admitted to the coronary care unit, 44 of these underwent coronary angiography with the result that 42 out of 44 showed significant coronary artery disease. There were 45 events in the follow-up: six in the 502 patients with negative and 39 in the 50 patients with positive stress echo (1.2% vs. 78%, p<0.001). The negative predictive value of stress echocardiography was 98.8% for all events and 99.6% for hard events. CONCLUSIONS: Stress echocardiography is a feasible, safe, and effective tool for early stratification of patients admitted to the ER with acute chest pain and non-ischemic ECG and resting echo.

Calcified apical cardiomyopathy: a rare form of endomyocardial fibrosis.

Endomyocardial fibrosis is a rare cardiomyopathy characterized by thickening of the endocardium, which leads to a restrictive phenotype. Differential diagnosis with other forms of cardiomyopathy may not always be straightforward and various imaging modalities are frequently necessary. In the present case, we report a patient with heart failure of uncertain origin, in whom, after an in-depth instrumental evaluation, a rare variant of endomyocardial fibrosis was diagnosed.