Clinical assessment of endothelial function in heart failure with preserved ejection fraction: A meta-analysis with meta-regressions.

BACKGROUND: Endothelial dysfunction is a key mechanism in the development of cardiac remodelling and diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF). Flow-mediated (FMD) and nitrate-mediated dilation (NMD) are noninvasive methods to assess endothelial function. We performed a meta-analysis evaluating the impact of HFpEF on FMD and NMD. METHODS: PubMed, Web of Science, Scopus and EMBASE databases were systematically searched according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Differences were expressed as mean difference (MD) with 95% confidence intervals (95%CI). The random effects method was used. RESULTS: A total of seven studies were included in the final analysis, 7 with data on FMD (326 HFpEF patients and 417 controls) and 3 on NMD (185 HFpEF patients and 271 controls). Compared to controls, HFpEF patients showed significantly lower FMD (MD: -1.929; 95%CI: -2.770, -1.088; P < .0001) and NMD values (MD: -2.795; 95%CI: -3.876, -1.715; P < .0001). Sensitivity analyses substantially confirmed results. Meta-regression models showed that increasing differences in E/A ratio (Z-score: -2.002; P = .045), E/E' ratio (Z-score: -2.181; P = .029) and left atrial diameter (Z-score: -1.951; P = .050) were linked to higher differences in FMD values between cases and controls. CONCLUSIONS: Impaired endothelial function can be documented in HFpEF, with the possibility of a direct association between the severity of diastolic and endothelial dysfunction. Targeting endothelial dysfunction through pharmacological and rehabilitation strategies may represent an attractive therapeutic option.

Non-vitamin K vs vitamin K oral anticoagulants in patients aged > 80 year with atrial fibrillation and low body weight.

BACKGROUND: Octogenarian patients are at high risk of both ischaemic and bleeding events, and the low body weight is considered a risk factor for major bleeding in atrial fibrillation (AF) patients on anticoagulation therapy. The aim of our study was to compare the safety and effectiveness of NOACs versus well-controlled VKA therapy among patients aged > 80 year with AF and low body weight in real-life setting. METHODS: Data for this study were sourced from the multicenter prospectively maintained Atrial Fibrillation Research Database (NCT03760874). From this, we selected AF patients aged ≥ 80 years and weighted ≤ 60 kg who received NOACs or VKAs treatment (only those with a time in therapeutic range > 70%). 279 patients (136 in NOAC group and 143 in VKA group) were selected. RESULTS: A total of 71 patients (17 in NOAC vs 54 in VKA group) died during the follow-up. The incidence rate of all-cause mortality was 27.70 per 100 person-years (14.91 in NOAC vs 37.94 in VKA group, adjusted hazard ratio 0.43; 95% CI 0.25 to 0.975; P = .003). 22 patients (9 in NOAC vs 13 in VKA group, P = .6) had major bleeding events. Diabetes mellitus, COPD and age resulted positively associated with death, whereas NOACs, parossistic AF and weight negatively associated with mortality. CONCLUSIONS: Our real-world data might suggest the safe and efficacy use of NOACs in this setting of population, justified by a reduction in overall mortality over VKAs. Further studies are needed to confirm these data.

Global longitudinal strain is a hallmark of cardiac damage in mitral regurgitation: the Italian arm of the European Registry of mitral regurgitation (EuMiClip).

BACKGROUND: The search for reliable cardiac functional parameters is crucial in patients with mitral regurgitation (MR). In the Italian arm of the European Registry of MR, we compared the ability of global longitudinal strain (GLS) and left ventricular (LV) ejection fraction (LVEF) to detect cardiac damage in MR. METHODS: Five hundred four consecutive patients with MR underwent a complete echo-Doppler exam. A total of 431, 53 and 20 patients had degenerative, secondary and mixed MR, respectively. The main echocardiographic parameters, including LV and left atrial (LA) size measurements, pulmonary artery systolic pressure (PASP) and GLS were compared between patients with mild MR (n = 392) vs. moderate to severe MR (n = 112). RESULTS: LVEF and GLS were related one another in the pooled population, and separately in patients with mild and moderate/severe MR (all p < 0.0001). However, a certain number of patients were above the upper or below the lower limits of the 95% confidence interval (CI) of the normal relation in the pooled population and in patients with mild MR. Only 2 patients were below the 95% CI in moderate to severe MR. After adjusting for confounders by separate multivariate models, LVEF and GLS were independently associated with LV and left atrial size in the pooled population and in mild and moderate/severe MR. GLS, but not LVEF, was also independently associated with PASP in patients with mild and moderate to severe MR. CONCLUSIONS: Both LVEF and GLS are independently associated with LV and LA size, but only GLS is related to pulmonary arterial pressure. GLS is a powerful hallmark of cardiac damage in MR.

Layer-specific longitudinal strain in Anderson-Fabry disease at diagnosis: A speckle tracking echocardiography analysis.

BACKGROUND: Speckle tracking advancements make now available the analysis of layer-specific myocardial deformation. This study investigated multilayer longitudinal strain in Anderson-Fabry disease (AFD) patients at diagnosis. METHODS: In a case-control study, 33 newly diagnosed, untreated AFD patients and 33 healthy age- and sex-matched healthy controls underwent a complete echocardiogram, including assessment of left ventricular (LV) transmural global longitudinal strain (GLS), subendocardial longitudinal strain (LSsubendo), subepicardial longitudinal strain (LSsubepi), and strain gradient (LSsubendo-LSsubpepi). RESULTS: Anderson-Fabry disease patients had similar blood pressure, heart rate, and ejection fraction but higher body mass index in comparison with controls. LV mass index, maximal, and relative wall thickness were significantly greater in AFD patients. LSsubendo was significantly higher than LSsubepi in both groups, but GLS (P < 0.0001), LSsubendo (P = 0.003), and particularly LSsubepi (21.4 ± 1.7 vs 18.8 ± 1.4%, P < 0.0001) were lower in AFD patients than in controls. Accordingly, LS gradient was higher in AFD patients (P = 0.003). Three patients symptomatic for dyspnoea presented a combination of LV hypertrophy and reduced LSsubepi. After adjusting for confounders by multivariate analyses, LV mass index or maximal wall thickness were independently and inversely associated with transmural GLS and LSsubepi, but not with LSsubendo in the AFD group. At receiver operating curve curves, LSsubepi best discriminated AFD and normals. CONCLUSIONS: In newly diagnosed, untreated AFD patients, layer-specific strain imaging highlights an impairment of LV longitudinal deformation, mainly involving subepicardial strain and causing increase in longitudinal strain myocardial gradient. These findings could be useful for identifying the mechanisms underlying early LV dysfunction in AFD patients.

Diagnostic performance of multi-organ ultrasound with pocket-sized device in the management of acute dyspnea.

BACKGROUND: The availability of ultra-miniaturized pocket ultrasound devices (PUD) adds diagnostic power to the clinical examination. Information on accuracy of ultrasound with handheld units in immediate differential diagnosis in emergency department (ED) is poor. The aim of this study is to test the usefulness and accuracy of lung ultrasound (LUS) alone or combined with ultrasound of the heart and inferior vena cava (IVC) using a PUD for the differential diagnosis of acute dyspnea (AD). METHODS: We included 68 patients presenting to the ED of "Maurizio Bufalini" Hospital in Cesena (Italy) for AD. All patients underwent integrated ultrasound examination (IUE) of lung-heart-IVC, using PUD. The series was divided into patients with dyspnea of cardiac or non-cardiac origin. We used 2 × 2 contingency tables to analyze sensitivity, specificity, positive predictive value and negative predictive value of the three ultrasonic methods and their various combinations for the diagnosis of cardiogenic dyspnea (CD), comparing with the final diagnosis made by an independent emergency physician. RESULTS: LUS alone exhibited a good sensitivity (92.6%) and specificity (80.5%). The highest accuracy (90%) for the diagnosis of CD was obtained with the combination of LUS and one of the other two methods (heart or IVC). CONCLUSIONS: The IUE with PUD is a useful extension of the clinical examination, can be readily available at the bedside or in ambulance, requires few minutes and has a reliable diagnostic discriminant ability in the setting of AD.

Longitudinal strain of left ventricular basal segments and E/e' ratio differentiate primary cardiac amyloidosis at presentation from hypertensive hypertrophy: an automated function imaging study.

BACKGROUND: Longitudinal strain is an early marker of left ventricular (LV) dysfunction in several cardiac diseases. Our aim was to differentiate cardiac amyloidosis (CA) at diagnosis from hypertensive LV hypertrophy (LVH) by analysis of longitudinal myocardial deformation. METHODS: Thirty healthy controls (C), 30 newly diagnosed, never treated hypertensives with LVH (H-LVH), and 33 patients with CA at diagnosis underwent echo Doppler including speckle tracking-based automated function imaging (AFI). Averaged peak systolic global longitudinal strain (GLS, 18 segments) and basal, middle, and apical longitudinal strain (BLS, MLS, and ALS, respectively, six segments each) were calculated. RESULTS: Left ventricular mass index, relative wall thickness, and ejection fraction did not differ between H-LVH and CA. E/e' ratio was higher in CA than in H-LVH (P<.001) and C (P<.0001). GLS was lower in CA than in C (P<.0001), without difference with H-LVH. ALS did not differ among the three groups, MLS was significantly lower in both CA and H-LVH than in C but BLS was lower in CA compared to both H-LVH and C (both P<.0001). In the pooled population, E/e' was independently associated with BLS (ß=-0.54, P<.0001). At receiver operating curve analysis, CA was predicted by BLS≤-11.3% (sensitivity=63.3%, specificity=100%) and E/e'≥12.3 (sensitivity=69.7%, specificity=83.3%). The best AUC (=0.819) was obtained by the combination E/e'+BLS. CONCLUSIONS: Our findings highlight a real difference of E/e' ratio and longitudinal strain of LV basal segments between hypertensive LVH and CA, which could be used to differentiate the two diseases.

Non-Invasive Assessment of Right Ventricle to Arterial Coupling for Prognosis Stratification of Fibrotic Interstitial Lung Diseases.

Background: The coupling of the right ventricle (RV) to the pulmonary circulation is an indicator of RV performance that can be non-invasively estimated by echocardiography. There are no data about its use in patients affected by fibrotic interstitial lung diseases (f-ILD). Methods: Fifty f-ILD patients, including 27 cases with idiopathic pulmonary fibrosis (IPF) (M = 37; mean age 67 ± 7 years), were studied with standard and speckle-tracking echocardiography and compared with 30 age-matched healthy volunteers. The mean patient follow-up was 70 ± 4 months. Results: Fibrotic ILD patients had a larger right ventricle (RV) and worse diastolic function because the RV global longitudinal strain (GLS) was significantly lower and the systolic pulmonary artery pressure (sPAP) estimates were higher in comparison with those of controls. Conversely, tricuspid annular systolic excursion (TAPSE) did not differ between controls and patients. Median values of TAPSE/sPAP and RV GLS/sPAP were significantly reduced in f-ILD patients (p < 0.0001). Patients with an RV GLS/sPAP below the median value had a shorter survival time (61 vs. 74 months, p = 0.01); this parameter was an independent predictor of a worse outcome. Conclusion: Low estimates of RV GLS/sPAP are predictive of worse outcomes in f-ILD patients. RV coupling seems to be a promising surrogate biomarker of RV performance to discriminate the patient phenotype with significant management and prognosis implications.

Speckle tracking echocardiography in patients with systemic lupus erythematosus: A meta-analysis.

BACKGROUND: Systemic lupus erythematosus (SLE), is characterized by a systemic involvement including myocardial dysfunction. Being standard echocardiography not able at fully detecting subclinical alterations, speckle tracking echocardiography (STE) has recently emerged as a quantitative ultrasound technique to accurately estimate myocardial function. METHODS: We conducted a systematic review with meta-analysis of studies reporting STE parameters in patients with SLE. RESULTS: A total of 9 studies were included in the analysis. Left ventricle global longitudinal strain (GLS) was significantly lower in SLE patients than in non-SLE controls (MD: -2.331, 95% CI: -3.083, -1.580, p < 0.001). In addition, we found significant differences between SLE patients and non-SLE controls in left ventricle GLS rate (MD: -0.115, 95% CI: -0.177 to 0.063, p < 0.001), left ventricle circumferential strain(MD: -1.841, 95% CI: -3.160 to 0.521, p = 0.006) and left ventricle radial strain(MD: -11.03, 95% CI: -13.819 to 8.241, p < 0.001). Right ventricle strain was significantly lower in SLE patients than in non-SLE controls (MD: -5.814, 95% CI: -7.347, -4.281, p < 0.001). Meta-regression models showed a lower difference in left ventricle GLS between SLE cases and controls for studies with a higher prevalence of female gender and higher prevalence of hypertension. CONCLUSIONS: SLE patients have lower STE parameters than controls, thus suggesting the presence of an impaired myocardial function involving both left and right ventricle.

Impaired Right and Left Ventricular Longitudinal Function in Patients with Fibrotic Interstitial Lung Diseases.

Background: Left ventricular (LV) and right ventricular (RV) dysfunction is recognized in idiopathic pulmonary fibrosis (IPF). Little is known about cardiac involvement in non-idiopathic pulmonary fibrosis (no-IPF). This issue can be explored by advanced echocardiography. Methods: Thirty-three clinically stable and therapy-naive fibrotic IPF and 28 no-IPF patients, and 30 healthy controls were enrolled. Exclusion criteria were autoimmune systemic diseases, coronary disease, heart failure, primary cardiomyopathies, chronic obstructive lung diseases, pulmonary embolism, primary pulmonary hypertension. Lung damage was evaluated by diffusion capacity for carbon monoxide (DLCOsb). All participants underwent an echo-Doppler exam including 2D global longitudinal strain (GLS) of both ventricles and 3D echocardiographic RV ejection fraction (RVEF). Results: We observed LV diastolic dysfunction in IPF and no-IPF, and LV GLS but not LV EF reduction only in IPF. RV diastolic and RV GLS abnormalities were observed in IPF versus both controls and no-IPF. RV EF did not differ significantly between IPF and no-IPF. DLCOsb and RV GLS were associated in the pooled pulmonary fibrosis population and in the IPF subgroup (ß = 0.708, p < 0.001), independently of confounders including pulmonary arterial systolic pressure. Conclusion: Our data highlight the unique diagnostic capabilities of GLS in distinguishing early cardiac damage of IPF from no-IPF patients.

Left ventricular diastolic abnormalities other than valvular heart disease in antiphospholipid syndrome: An echocardiographic study.

BACKGROUND: Antiphospholipid syndrome (APS) can be primary or secondary to other autoimmune disorders. Besides valvular heart disease (VHD) and coronary artery disease (CAD), little is known about the impact of APS on left ventricular (LV) function. METHODS: After excluding CAD, relevant VHD and heart failure, 69 patients (mean age = 43.9 years, 40 with primary and 29 with secondary APS) were assessed by echo-Doppler. Sixty-nine heathy controls, matched for age and sex, formed the control group. APS was diagnosed in presence of at least one clinical criteria and one confirmed laboratory criteria, including lupus anticoagulant (LA) titre. The adjusted global APS score (aGAPSS), derived from the combination of risk factors for thrombosis and autoimmune-antibody profile was calculated. RESULTS: Patients had similar blood pressure and heart rate, but higher body mass index (BMI) than controls. LV mass index (p = 0.007) and left atrial volume index (p < 0.01) were greater, while early diastolic velocity (e') was lower (p = 0.003) and E/e' higher (p = 0.007) in APS. Primary APS patients had lower E/A and e' compared to both controls and secondary APS, while E/e' was higher in secondary APS than in controls. APS patients with diastolic dysfunction were older but did not differ for risk factors prevalence from those with normal/indeterminate diastolic function. In the pooled APS, LA positivity was independently associated with e' and E/e' after adjusting for age, BMI and aGAPSS in separate multivariate models. CONCLUSION: In APS, LV diastolic abnormalities are detectable. They are more pronounced in primary APS and independently associated with LA positivity.

Overview of mitral regurgitation in Europe: results from the European Registry of mitral regurgitation (EuMiClip).

Aims: To determine the prevalence of mitral regurgitation (MR) in a large cohort of consecutive patients undergoing clinically indicated echocardiography and to examine the distribution of primary and secondary MR. Methods and results: All patients undergoing an echocardiographic study in 19 European centres within a 3-month period were prospectively included. MR assessment was performed as recommended by the European Association of Cardiovascular Imaging (EACVI). MR was classified according to mechanism as primary or secondary and aetiologies were reported. A total of 63 463 consecutive echocardiographic studies were reviewed. Any degree of MR was described in 15 501 patients. Concomitant valve disease of at least moderate grade was present in 28.5% of patients, being tricuspid regurgitation the most prevalent. In the subgroup of moderate and severe MR (n = 3309), 55% of patients had primary MR and 30% secondary MR. Both mechanisms were described in 14% of the studies. According to Carpentier's classification, 26.7% of MR were classified as I, 19.9% of MR as II, 22.4% of MR as IIIa, and 31.1% of MR as IIIb. Conclusion: To date, this is the largest echocardiography-based study to analyse the prevalence and aetiology distribution of MR in Europe. The burden of secondary MR was higher than previously described, representing 30% of patients with significant MR. In our environment, degenerative disease is the most common aetiology of primary MR (60%), whereas ischaemic is the most common aetiology of secondary MR (51%). Up to 70% of patients with severe primary MR may have a Class I indication for surgery. However, the optimal therapeutic approach for secondary MR remains uncertain.

Obstructive sleep apnoea and right ventricular function: A combined assessment by speckle tracking and three-dimensional echocardiography.

BACKGROUND: Little is known on right ventricular (RV) involvement in obstructive sleep apnoea (OSA). This study aimed at evaluating early RV dysfunction by standard and advanced echocardiography in OSA. METHODS: Fifty-nine OSA patients without heart failure and 29 age-matched controls underwent standard, speckle tracking and real time 3D echocardiography of right ventricle. OSA patients performed lung function tests and overnight cardio-respiratory monitoring with evaluation of apnea-hypopnea index (AHI). RESULTS: OSA had significantly higher body mass index and systolic blood pressure (BP) than controls. RV diameters and systolic pulmonary arterial pressure (sPAP) were significantly higher in OSA, in presence of comparable tricuspid annular plane systolic excursion (TAPSE). OSA showed marginally lower RV global longitudinal strain (GLS) (p<0.05) and RV lateral wall strain (RV LLS) (p=0.04). Three-dimensional RV ejection fraction did not differ between the two groups. By stratifying patients according to sPAP, 18 OSA patients with sPAP≥30mmHg had lower TAPSE (p<0.05), RV GLS and RV LLS (both p<0.001) than 37 patients with normal sPAP. By separate multivariate analyses, RV GLS and RV LLS were independently associated with sPAP (both p<0.0001), AHI (p=0.035 and p=0.015 respectively) and BMI (p<0.05 and p=0.034) but not with age and systolic BP in OSA. CONCLUSIONS: A subclinical RV dysfunction is detectable by speckle tracking in OSA. The impairment of RV GLS and RV LLS is more prominent than that of TAPSE and is evident when RVEF is still normal. GLS is independently associated with sPAP and OSA severity.

Determinants of myocardial mechanics in top-level endurance athletes: three-dimensional speckle tracking evaluation.

AIMS: The determinants of systolic function in the performing heart are not completely understood. Aim of the study was to assess the contributors of left ventricular (LV) strain components, using 3D speckle tracking echocardiography (STE) in endurance athletes. METHODS AND RESULTS: A total of 36 top-level male endurance athletes (AT) and 36 age-matched sedentary normal controls (NC) underwent standard and real-time 3D echocardiography. Global longitudinal strain (GLS), global circumferential strain (GCS), global area strain (GAS), and global radial strain (GRS) were assessed using 3D STE. AT had significantly higher GLS (-22.1 ± 4.4 vs. -18.4 ± 3.5%; P < 0.0001), GCS (-17.9 ± 2.4 vs. -16.0 ± 3.2; P = 0.006), and GAS (-35.5 ± 6.7 vs. -30.2 ± 4.9; P < 0.0001), while GRS did not differ significantly with NC. At separate multiple linear regression analyses, heart rate emerged as independent predictor of GLS (ß = -0.37, P < 0.002), GCS (ß = -0.32, P = 0.007), GAS (ß = -0.37, P < 0.001), and GRS (ß = -0.29, P = 0.019); LV mass was independently associated with GLS (ß = 0.34, P = 0.009) and GAS (ß = 0.41, P < 0.001) but not with GCS and GRS, while diastolic blood pressure predicted GCS (ß = -0.46, P < 0.0001), GAS (ß = -0.28; P = 0.006), and GRS (ß = -0.42, P < 0.001). No independent correlation emerged for body surface area and stroke volume. By replacing LV mass with end-diastolic volume, the latter showed independent association with GCS (ß = -0.65, P = 0.028) and with GRS (ß = -0.60, P < 0.05). CONCLUSION: AT have an increased myocardial function at rest when compared with NC, this being elicited mainly by subendocardial and mid-wall fibres. Sinus bradycardia, LV mass, and afterload are independent determinants of supernormal myocardial deformation at rest.

Aspirin resistance, platelet turnover, and diabetic angiopathy: a 2011 update.

In 2004 an editorial article on the so-called "aspirin resistance" and diabetic angiopathy as related to platelet turnover was published by one of us. An update of this issue is now presented. The evidence of an incomplete inhibition of platelet function by aspirin, despite doses of the drug proved to be clinically effective are employed, was first reported in the '80s, in studies devoted to platelet turnover. Based on this concept, the possibility of monitoring the entry of newly formed platelets into the circulation after aspirin ingestion was documented by measuring the return of thromboxane biosynthesis by platelets challenged in vitro by pairs of aggregating agents. The data obtained showed that platelets with intact cyclooxygenase activity could be detected into the circulation of control individuals as early as 4-6hrs after aspirin ingestion, but at shorter time intervals in diabetic angiopathy. In the latter setting, it was concluded that "schedules of aspirin which may suffice in normals are not effective in patients with diabetic angiopathy, presumably because these patients have a high rate of entry of new platelets into the circulation". As many as 25years after its original publication, the clinical relevance of an accelerated platelet turnover as to "aspirin resistance" has been confirmed and extended to other clinical settings at high risk of ischemic events. Newer aspirin dosing and scheduling, tailored at reducing the individual patient risk related to an incomplete inhibition of platelet function by a standard aspirin dose should now be defined.