Diastolic dysfunction grade in acute coronary syndromes: Application of 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging recommendations.

BACKGROUND: Diagnosis and grading of diastolic dysfunction (DD) is challenging, with different studies using heterogeneous criteria and guidelines not routinely applied in clinical practice. Our aim was to apply the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging classification of DD among a contemporary population of patients with acute coronary syndromes (ACS) by analyzing its correlation with N-terminal pro b-type natriuretic peptide (NT-proBNP) and impact on clinical outcomes. METHODS: Independent investigators blinded to each other and to the clinical history reviewed digitally stored images to apply 2016 and 2009 DD definitions to 380 patients (mean age 66 ± 13 years, 75% men) with ACS admitted to the coronary care unit between January 2016 and March 2018. RESULTS: DD was frequent with both definitions, yet the concordance was weak (kappa =0.21, p < 0.01). Inter-observer reliability was greater by applying the 2016 algorithm (kappa = 0.89, p < 0.001). There was a significant correlation between NT-proBNP and worsening DD (Spearman's rho r = 0.54 for 2016 and r = 0.24 for 2009 algorithms, both p < 0.001). Worse DD was associated with worse clinical presentation and increased risk of events (HR for the cumulative incidence of heart failure and death during follow-up 2.15 [95% CI 1.66-2.78, p < 0.001] and 1.82 [95% CI 1.39-2.40, p < 0.001] for 2016 and 2009 classifications, respectively, all p < 0.001). CONCLUSIONS: The agreement between 2016 and 2009 DD definitions was poor, with newer guidelines having grater interobserver reliability. The positive graded association between 2016 DD classification and NT-proBNP and its association with clinical outcomes provide a validation of the latest guideline algorithm in ACS patients.

Multimodality Imaging of Left Ventricular Clefts in an Asymptomatic Teenager.

Left ventricular clefts (LVCs) are defined as deep, tight blood-filled invaginations within the ventricular myocardium localized predominantly in the basal posterior septum and LV-free wall. Usually, they are asymptomatic and incidentally discovered during diagnostic imaging procedures. LVC has been reported both in healthy volunteers and in patients affected with hypertrophic cardiomyopathy. Clinicians should be able to recognize LVC and to distinguish this entity from other myocardial wall defects with different pathological profile and clinical significance. We describe a case of multimodality imaging of multiple septal myocardial clefts in an asymptomatic teenager.

Increased oxidative stress and platelet activation in patients with hypertension and renovascular disease.

BACKGROUND: Hypertensive patients with renovascular disease (RVD) may be exposed to increased oxidative stress, possibly related to activation of the renin-angiotensin system. METHODS AND RESULTS: We measured the urinary excretion of 8-iso-prostaglandin (PG) F2alpha and 11-dehydro-thromboxane (TX) B2 as indexes of in vivo lipid peroxidation and platelet activation, respectively, in 25 patients with RVD, 25 patients with essential hypertension, and 25 healthy subjects. Plasma renin activity in peripheral and renal veins, angiotensin II in renal veins, cholesterol, glucose, triglycerides, homocysteine, and antioxidant vitamins A, C, and E were also determined. Patients were also studied 6 months after a technically successful angioplasty of the stenotic renal arteries. Urinary 8-iso-PGF2alpha was significantly higher in patients with RVD (median, 305 pg/mg creatinine; range, 124 to 1224 pg/mg creatinine) than in patients with essential hypertension (median, 176 pg/mg creatinine; range, 48 to 384 pg/mg creatinine) or in healthy subjects (median, 123 pg/mg creatinine; range, 58 to 385 pg/mg creatinine). Urinary 11-dehydro-TXB2 was also significantly higher in RVD patients compared with healthy subjects. In RVD patients, urinary 8-iso-PGF2alpha correlated with 11-dehydro-TXB2 (r(s)=0.48; P<0.05) and renal vein renin (r(s)=0.67; P<0.005) and angiotensin II (r(s)=0.65; P=0.005) ratios. A reduction in 8-iso-PGF2alpha after angioplasty was observed in RVD patients with high baseline levels of lipid peroxidation. Changes in 8-iso-PGF2alpha were related to baseline lipid peroxidation (r(s)=-0.73; P<0.001), renal vein angiotensin II (r(s)=-0.70; P<0.01) and renin (r(s)=-0.63; P<0.05) ratios. CONCLUSIONS: Lipid peroxidation is markedly enhanced in hypertensive patients with RVD and is related to activation of the renin-angiotensin system. Moreover, persistent platelet activation triggered or amplified by bioactive isoprostanes may contribute to the progression of cardiovascular and renal damage in this setting.

Long-term effects of intermittent Iloprost infusion on pulmonary arterial pressure in connective tissue disease.

BACKGROUND: Intravenous periodic Iloprost is proven effective in the treatment of Raynaud phenomenon (RP) related to connective tissue disorder (CTD). It's well known that synthetic prostaglandins are effective drugs for the treatment of pulmonary arterial hypertension (PAH), and that PAH is frequently associated with CTD. OBJECTIVE: The aim of the study is to evaluate in the chronic effect of cyclic intravenous Iloprost on pulmonary arterial pressure. METHODS: We studied 17 consecutive patients with CTD (14 systemic sclerosis, 3 mixed CTD) and RP, at the entry and after at least 6months of treatment of RP with cyclic Iloprost. On both occasions, in all patients we performed transthoracic Doppler echocardiography and we determined NT-proBNP plasma levels, NYHA functional class, 6 Minute-Walk Distance (6MWD). RESULTS: At follow-up (8.2±1.9months; range 6-12) mean values of pulmonary arterial systolic pressure (PASP) significantly decreased (from 32.2±9.2 to 29.2±7.6mmHg, p<0.04) and mean values of 6MWD significantly increased (from 407.5±101.5 to 448.3±89.9m, p<0.01). Moreover, we observed a significant direct correlation between PASP and NT-proBNP values and a significant inverse correlation both between NT-proBNP and 6MWD values and between PASP and 6MWD values. CONCLUSION: Our results suggest that cyclic intravenous Iloprost may protect against the development or worsening of PAH in patients with CTD and RP.

[The "Appropriatezza ECO Milano" project. Assessment of appropriateness of indications, prescriptions and clinical utility of two-dimensional Doppler echocardiography among inpatients and outpatients of Milan, Italy]. / Progetto "Appropriatezza ECO Milano". Valutazione basale dell'appropriatezza delle indicazioni, della modalità delle prescrizioni e dell'utilità clinica dell'esame ecocardiografico bidimensionale color Doppler all'interno delle aziende ospedaliere e sul territorio.

BACKGROUND: The value of echocardiography in the diagnosis and follow-up of most cardiovascular diseases is well established, even though the ever-increasing demand for the use of this technique is not always justifiable. The "Appropriatezza ECO Milano" project was developed among hospitals in Milan (Italy) to foster a rational use of echocardiography. The aim of this study was to evaluate and improve appropriateness of requests for two-dimensional color Doppler echocardiography, considering indications, prescription behaviors and clinical utility in both the outpatient and inpatient settings. METHODS: Following several meetings, a consensus was reached whereby a multicenter, observational study would be undertaken. We assessed the value of each request in agreement with the 2003 American College of Cardiology/American Heart Association/American Society of Echocardiography guidelines. An ad hoc Microsoft Access database was developed to collect study data, which refer to May 2007. Eleven hospitals participated in the study. RESULTS: 4130 echocardiographic examinations were considered (2300 performed in men and 1830 performed in women; mean age 64 +/- 16 years); 1701 examinations were performed in hospitalized patients and 2429 in outpatients. The incidence of pathological findings was higher in hospitalized patients (73%) than in outpatients (53%) (Pearson chi2 = 29, p<0.001). A higher additional clinical value was found in hospitalized vs non-hospitalized patients (48 vs. 35%, Pearson chi2 = 99; p <0.001). In both settings, the majority of echocardiographic examinations were requested by cardiologists (inpatients 36%, outpatients 54%). The most appropriate examinations were performed more frequently in class I or class IIA hospitalized patients (73%) than in outpatients (52%) (Pearson chi2 = 277, p<0.001). Furthermore, the least accurate the indication, the less the clinical utility found in examinations requested from hospitals and outpatient clinics (64 vs 61% in class I patients, Pearson chi2 = 413, p<0.001; 5 vs 11% in class III patients, Pearson chi2 = 584, p<0.001). Conclusions. Our data confirm an inadequate level of appropriateness of requests for two-dimensional color Doppler examinations in either inpatients or outpatients. After over 10 years of passively observing and recording this trend, a timely resolution of these issues is topical in order to improve the implementation of criteria and to guarantee cost-effective and high-quality cardiovascular care.

Treatment of atherosclerotic renal artery stenosis.

The increasing prevalence of atherosclerotic renal artery stenosis (ARAS) has prompted in recent years a more aggressive treatment of this condition for reducing BP and for preserving the jeopardized renal function. Percutaneous transluminal renal angioplasty (PTRA), alone or in conjunction with stent implantation, may be useful for both these goals. However, despite the methodological improvements that make this procedure much safer than surgery, caution must be applied before PTRA is extended to all patients with ARAS. Indeed, PTRA is associated with a 23% rate of major/minor complications and with a 20% rate of restenosis, even in arteries implanted with stent. Moreover the cure rate of hypertension achievable with PTRA is, at best, around 10%, with a 40% rate of improvements. Even for rescuing the ischemic kidney, PTRA/stent implantation are not always effective; only 35% of patients with ARAS have some improvement in renal function. These data indicate that there is an urgent need of rigorous criteria for selecting among the many patients with ARAS those who may actually benefit from the dilation procedure.

L-type Ca2+ channel and ryanodine receptor cross-talk in frog skeletal muscle.

The dihydropyridine receptors (DHPRs)/L-type Ca2+ channels of skeletal muscle are coupled with ryanodine receptors/Ca2+ release channels (RyRs/CRCs) located in the sarcoplasmic reticulum (SR). The DHPR is the voltage sensor for excitation-contraction (EC) coupling and the charge movement component q gamma has been implicated as the signal linking DHPR voltage sensing to Ca2+ release from the coupled RyR. Recently, a new charge component, qh, has been described and related to L-type Ca2+ channel gating. Evidence has also been provided that the coupled RyR/CRC can modulate DHPR functions via a retrograde signal. Our aim was to investigate whether the newly described qh is also involved in the reciprocal interaction or cross-talk between DHPR/L-type Ca2+ channel and RyR/CRC. To this end we interfered with DHPR/L-type Ca2+ channel function using nifedipine and 1-alkanols (heptanol and octanol), and with RyR/CRC function using ryanodine and ruthenium red (RR). Intramembrane charge movement (ICM) and L-type Ca2+ current (ICa) were measured in single cut fibres of the frog using the double-Vaseline-gap technique. Our records showed that nifedipine reduced the amount of q gamma and qh moved by approximately 90% and approximately 55%, respectively, whereas 1-alkanols completely abolished them. Ryanodine and RR shifted the transition voltages of q gamma and qh and of the maximal conductance of ICa by approximately 4-9 mV towards positive potentials. All these interventions spared q beta. These results support the hypothesis that only q gamma; and qh arise from the movement of charged particles within the DHPR/L-type Ca2+ channel and that these charge components together with ICa are affected by a retrograde signal from RyR/CRC.

Sphingosine 1-phosphate induces Ca2+ transients and cytoskeletal rearrangement in C2C12 myoblastic cells.

In many cell systems, sphingosine 1-phosphate (SPP) increases cytosolic Ca2+ concentration ([Ca2+]i) by acting as intracellular mediator and extracellular ligand. We recently demonstrated (Meacci E, Cencetti F, Formigli L, Squecco R, Donati C, Tiribilli B, Quercioli F, Zecchi-Orlandini S, Francini F, and Bruni P. Biochem J 362: 349-357, 2002) involvement of endothelial differentiation gene (Edg) receptors (Rs) specific for SPP in agonist-mediated Ca2+ response of a mouse skeletal myoblastic (C2C12) cell line. Here, we investigated the Ca2+ sources of SPP-mediated Ca2+ transients in C2C12 cells and the possible correlation of ion response to cytoskeletal rearrangement. Confocal fluorescence imaging of C2C12 cells preloaded with Ca2+ dye fluo 3 revealed that SPP elicited a transient Ca2+ increase propagating as a wave throughout the cell. This response required extracellular and intracellular Ca2+ pool mobilization. Indeed, it was significantly reduced by removal of external Ca2+, pretreatment with nifedipine (blocker of L-type plasma membrane Ca2+ channels), and inositol 1,4,5-trisphosphate [Ins(1,4,5)P3]-mediated Ca2+ pathway inhibitors. Involvement of EdgRs was tested with suramin (specific inhibitor of Edg-3). Fluorescence associated with Ins(1,4,5)P3Rs and L-type Ca2+ channels was evident in C2C12 cells. SPP also induced C2C12 cell contraction. This event, however, was unrelated to [Ca2+]i increase, because the two phenomena were temporally shifted. We propose that SPP may promote C2C12 cell contraction through Ca2+-independent mechanisms.

Effects of sphingosine 1-phosphate on excitation-contraction coupling in mammalian skeletal muscle.

Sphingosine 1-phosphate (S1P) activates a subset of plasma membrane receptors of the endothelial differentiation gene family (EdgRs) in many cell types. In C2C12 myoblasts, exogenous S1P elicits Ca2+ transients by activating voltage-independent plasma membrane Ca2+ channels and intracellular Ca2+-release channels. In this study, we investigated the effects of exogenous S1P on voltage-dependent L-type Ca2+ channels in skeletal muscle fibers from adult mice. To this end, intramembrane charge movements (ICM) and L-type Ca2+ current (I(Ca)) were measured in single cut fibers using the double Vaseline-gap technique. Our data showed that submicromolar concentrations of S1P (100 nM) caused a approximately 10-mV negative shift of the voltage threshold and transition voltages of q(gamma) and q(h) components of ICM, and of I(Ca) activation and inactivation. Biochemical studies showed that EdgRs are expressed in skeletal muscles. The involvement of EdgRs in the above S1P effects was tested with suramin, a specific inhibitor of Edg-3Rs. Suramin (200 microM) significantly reduced, by approximately 90%, the effects of S1P on ICM and I(Ca), suggesting that most of S1P action occurred via Edg-3Rs. Moreover, SIP at concentration above 10 microM elicited intracellular Ca2+ transients in muscle fibers loaded with the fluorescent Ca2+ dye Fluo-3, as detected by confocal laser scanning microscopy.