Association of ADP-Induced Whole-Blood Platelet Aggregation with Serum Low-Density Lipoprotein Cholesterol in Patients with Coronary Artery Disease When Receiving Maintenance Ticagrelor-Based Dual Antiplatelet Therapy.

The degree of platelet inhibition in patients undergoing dual antiplatelet therapy (DAPT) affects cardiovascular outcomes after acute coronary syndromes (ACS) and/or percutaneous coronary intervention. Our aim was to search for correlates of residual ex vivo platelet reactivity and circulating soluble P-selectin (sP-selectin), an index of in vivo platelet activation, in patients being treated by DAPT with ticagrelor. Adenosine diphosphate (ADP)-induced platelet aggregability (by multiple electrode aggregometry) and plasma sP-selectin were estimated in 62 stable post-ACS subjects (46 men and 16 women; mean age: 64 ± 10 years; 30 with type 2 diabetes (T2DM)) undergoing maintenance DAPT with ticagrelor and aspirin. These patients did not exhibit heart failure or other relevant coexistent diseases except for properly controlled T2DM, mild renal insufficiency, and hypertension. We also assessed this in 64 subjects on clopidogrel-based DAPT matched for age, sex, and T2DM status. ADP-induced platelet aggregation was below the optimal levels (190-460 arbitrary units (AU) * min) in most patients receiving ticagrelor-based DAPT, especially in those with below-median (<1.9 mmol/L) serum concentrations of low-density lipoprotein cholesterol (LDL-c) (128 ± 61 vs. 167 ± 73 AU * min for below-median and above-median LDL-c, respectively, p = 0.025). In contrast, platelet reactivity did not differ by LDL-c on clopidogrel-based DAPT (246 ± 101 vs. 268 ± 108 AU * min for below-median and above-median LDL-c, respectively, p > 0.4). Plasma sP-selectin was found to be unrelated to serum LDL-c when receiving DAPT with ticagrelor (p > 0.4) or clopidogrel (p > 0.8). In conclusion, our preliminary observational study suggests the association of lower residual ex vivo platelet aggregability with better LDL-c control in patients undergoing ticagrelor-based maintenance DAPT, which does not appear to be reflected by plasma sP-selectin. Whether the serum LDL-c level should be considered among the factors affecting the degree of platelet inhibition for those treated with ticagrelor-based DAPT needs to be investigated in larger studies.

MicroRNA composition of plasma extracellular vesicles: a harbinger of late cardiotoxicity of doxorubicin.

BACKGROUND: The use of doxorubicin is associated with an increased risk of acute and long-term cardiomyopathy. Despite the constantly growing number of cancer survivors, little is known about the transcriptional mechanisms which progress in the time leading to a severe cardiac outcome. It is also unclear whether long-term transcriptomic alterations related to doxorubicin use are similar to transcriptomic patterns present in patients suffering from other cardiomyopathies. METHODS: We have sequenced miRNA from total plasma and extracellular vesicles (EVs) from 66 acute lymphoblastic leukemia (ALL) survivors and 61 healthy controls (254 samples in total). We then analyzed processes regulated by differentially expressed circulating miRNAs and cross-validated results with the data of patients with clinically manifested cardiomyopathies. RESULTS: We found that especially miRNAs contained within EVs may be informative in terms of cardiomyopathy development and may regulate pathways related to neurotrophin signaling, transforming growth factor beta (TGFß) or epidermal growth factor receptors (ErbB). We identified vesicular miR-144-3p and miR-423-3p as the most variable between groups and significantly correlated with echocardiographic parameters and, respectively, for plasma: let-7g-5p and miR-16-2-3p. Moreover, vesicular miR-144-3p correlates with the highest number of echocardiographic parameters and is differentially expressed in the circulation of patients with dilated cardiomyopathy. We also found that distribution of particular miRNAs between of plasma and EVs (proportion between compartments) e.g., miR-184 in ALL, is altered, suggesting changes within secretory and miRNA sorting mechanisms. CONCLUSIONS: Our results show that transcriptomic changes resulting from doxorubicin induced myocardial injury are reflected in circulating miRNA levels and precede development of the late onset cardiomyopathy phenotype. Among miRNAs related to cardiac function, we found vesicular miR-144-3p and miR-423-3p, as well as let-7g-5p and miR-16-2-3p contained in the total plasma. Selection of source for such studies (plasma or EVs) is of critical importance, as distribution of some miRNA between plasma and EVs is altered in ALL survivors, in comparison to healthy people, which suggests that doxorubicin-induced changes include miRNA sorting and export to extracellular space.

Endothelial biomarkers and platelet reactivity on ticagrelor versus clopidogrel in patients after acute coronary syndrome with and without concomitant type 2 diabetes: a preliminary observational study.

BACKGROUND: Pleiotropic effects have been implicated in clinical benefits of ticagrelor compared to thienopyridine P2Y12 antagonists. There are conflicting data regarding effects of ticagrelor vs. thienopyridine P2Y12 blockers on endothelial function. Our aim was to compare endothelial biomarkers and their relations with platelet reactivity in real-world patients after acute coronary syndrome (ACS) on maintenance dual antiplatelet therapy (DAPT) with ticagrelor or clopidogrel stratified by diabetes status. METHODS: Biochemical indices of endothelial dysfunction/activation and platelet reactivity by multiple electrode aggregometry were compared in 126 stable post-ACS subjects (mean age: 65 ± 10 years, 92 men and 34 women), including patients with (n = 61) or without (n = 65) coexistent type 2 diabetes (T2DM) on uneventful maintenance DAPT with either ticagrelor (90 mg b.d.) or clopidogrel (75 mg o.d.) in addition to low-dose aspirin. Exclusion criteria included a complicated in-hospital course, symptomatic heart failure, left ventricular ejection fraction < 40% and relevant coexistent diseases except for well-controlled diabetes, mild renal insufficiency or hypertension. RESULTS: Clinical characteristics were similar in patients on ticagrelor (n = 62) and clopidogrel (n = 64). The adenosine diphosphate-induced platelet aggregation and circulating soluble P-selectin (sP-selectin) were decreased in ticagrelor users irrespective of T2DM status (p < 0.001 and p < 0.01 for platelet reactivity and sP-selectin, respectively). Plasma levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) were lower in T2DM subjects on ticagrelor vs. clopidogrel (758 ± 162 vs. 913 ± 217 µg/L, p < 0.01). In contrast, plasma sVCAM-1 was similar in non-diabetic patients on ticagrelor and clopidogrel (872 ± 203 vs. 821 ± 210 µg/L, p > 0.7). The concentrations of sE-selectin, monocyte chemoattractant protein-1 and asymmetric dimethylarginine did not differ according to the type of P2Y12 antagonist regardless of T2DM status. Platelet reactivity was unrelated to any endothelial biomarker in subjects with or without T2DM. CONCLUSIONS: Our preliminary findings may suggest an association of ticagrelor-based maintenance DAPT with favorable endothelial effects compared to clopidogrel users in stable post-ACS patients with T2DM. If proven, this could contribute to more pronounced clinical benefits of ticagrelor in diabetic subjects.

Impaired Left Ventricular Circumferential Midwall Systolic Performance Appears Linked to Depressed Preload, but Not Intrinsic Contractile Dysfunction or Excessive Afterload, in Paradoxical Low-Flow/Low-Gradient Severe Aortic Stenosis.

Paradoxical low-flow/low-gradient aortic stenosis (P-LFLG-AS) occurs in about one-third of patients with severe AS and preserved left ventricular (LV) ejection fraction (EF). Our aim was to differentiate between altered LV loading conditions and contractility as determinants of subtle LV systolic dysfunction in P-LFLG-AS. We retrospectively analyzed medical records of patients with isolated severe degenerative AS and preserved EF (30 subjects with P-LFLG-AS and 30 patients with normal-flow/high-gradient severe AS (NFHG-AS)), without relevant coexistent diseases (e.g., diabetes, coronary artery disease and chronic kidney disease) or any abnormalities which could account for a low-flow state. Patients with P-LFLG-AS and NFHG-AS did not differ in aortic valve area index and most clinical characteristics. Compared to NFHG-AS, subjects with P-LFLG-AS exhibited smaller LV end-diastolic diameter (LVd) (44 ± 5 vs. 54 ± 5 mm, p < 0.001) (consistent with lower LV preload) with pronounced concentric remodeling, higher valvulo-arterial impedance (3.8 ± 1.1 vs. 2.2 ± 0.5 mmHg per mL/m2, p < 0.001) and diminished systemic arterial compliance (0.45 ± 0.11 vs. 0.76 ± 0.23 mL/m2 per mmHg, p < 0.001), while circumferential end-systolic LV midwall stress (cESS), an estimate of afterload at the LV level, was similar in P-LFLG-AS and NFHG-AS (175 ± 83 vs. 198 ± 69 hPa, p = 0.3). LV midwall fractional shortening (mwFS) was depressed in P-LFLG-AS vs. NFHG-AS (12.3 ± 3.5 vs. 14.7 ± 2.9%, p = 0.006) despite similar EF (61 ± 6 vs. 59 ± 8%, p = 0.4). By multiple regression, the presence of P-LFLG-AS remained a significant predictor of lower mwFS compared to NFHG-AS upon adjustment for cESS (ß ± SEM: −2.35 ± 0.67, p < 0.001); however, the significance was lost after further correction for LVd (ß = −1.10 ± 0.85, p = 0.21). In conclusion, the association of P-LFLG-AS with a lower cESS-adjusted mwFS, an index of afterload-corrected LV circumferential systolic function at the midwall level, appears secondary to a smaller LV end-diastolic cavity size according to the Frank−Starling law. Thus, low LV preload, not intrinsic contractile dysfunction or excessive afterload, may account for impaired LV circumferential midwall systolic performance in P-LFLG-AS.

Safety and Efficacy of Four Different Diagnostic Catheter Curves Dedicated to One-Catheter Technique of Transradial Coronaro-Angiography-Prospective, Randomized Pilot Study. TRACT 1: Trans RAdial CoronaryAngiography Trial 1.

Transradial coronaro-angiography (TRA) can be performed with one catheter. We investigate the efficacy of four different DxTerity catheter curves dedicated to the single-catheter technique and compare this method to the standard two-catheter approach. For this prospective, single-blinded, randomized pilot study, we enrolled 100 patients. In groups 1, 2, 3, and 4, the DxTerity catheters Trapease, Ultra, Transformer and Tracker Curve, respectively, were used. In group 5 (control), standard Judkins catheters were used. The study endpoints were the percentage of optimal stability, proper ostial artery engagement and a good quality angiogram, the duration of each procedure stage, the amount of contrast, and the radiation dose. The highest rate of optimal stability was observed in groups 2 (90%) and 5 (95%). Suboptimal results with at least one episode of catheter fallout from the ostium were most frequent in group 1 (45%). The necessity of using another catheter was observed most frequently in group 4. The analysis of time frames directly depending on the catheter type revealed that the shortest time for catheter introduction and for searching coronary ostia was achieved in group 2 (Ultra). There were no differences in contrast volume and radiation dose between groups. DxTerity catheters are suitable tools to perform TRA coronary angiography. The Ultra Curve catheter demonstrated an advantage over other catheters in terms of its ostial stability rate and procedural time.

Thyroid Hormones-An Underestimated Player in Dilated Cardiomyopathy?

Dilated cardiomyopathy (DCM) is the most prevalent cardiomyopathy, typified by left ventricular dilation and systolic dysfunction. Many patients with DCM have altered thyroid status, especially lower levels of free triiodothyronine (T3) and elevated levels of thyroid-stimulating hormone. Moreover, growing evidence indicates that even subtle changes in thyroid status (especially low T3) are linked with a worse long-term prognosis and a higher risk of mortality. Notably, recent discoveries have shown that not only local myocardial thyroid hormones (THs) bioavailability could be diminished due to impaired expression of the activating deiodinase, but virtually all genes involved in TH biosynthesis are also expressed in the myocardium of DCM patients. Importantly, some studies have suggested beneficial effects of TH therapy in patients suffering from DCM. Our aim was to discuss new insights into the association between TH status and prognosis in DCM, abnormal expression of genes involved in the myocardial synthesis of TH in DCM, and the potential for TH use in the future treatment of DCM.

Diagonal Earlobe Crease (Frank's Sign) for Diagnosis of Coronary Artery Disease: A Systematic Review of Diagnostic Test Accuracy Studies.

Coronary artery disease is a global challenge for healthcare systems. Early diagnosis is a key issue to improve quality of life and reduce morbidity and mortality. Diagonal earlobe crease, a wrinkle extending obliquely across the earlobe, was linked by many authors to various atherosclerotic diseases. This systematic review aimed at summarizing the diagnostic accuracy of diagonal earlobe crease for diagnosis of chronic and acute coronary syndromes in adults. Cochrane's recommendations for systematic reviews of diagnostic test accuracy studies were followed. The protocol was registered on PROSPERO. Seven electronic databases were searched up to April 2021. The risk of bias and applicability were assessed using the QUADAS-2 tool. Meta-analysis was not performed. Finally, 13 cross-sectional studies evaluating 3951 patients were analyzed, all of which focused on chronic coronary syndromes defined as anatomically significant coronary stenosis. Invasive coronary angiography was used as a reference in most studies, except one which utilized computed tomography angiography. Sensitivity ranged from 26% to 90%, and specificity from 32% to 96%. Positive likelihood ratios varied from 1.11 to 7.03, but most results were below 2. Negative likelihood ratios were from 0.84 to 0.30, but most values exceeded 0.5. Diagnostic accuracy of diagonal earlobe crease for the detection of chronic coronary syndromes is insufficient. It only slightly changes pre-test probability, and its mere presence or absence should not affect the clinical management of the patients. However, for its feasibility and easy interpretation, Frank's sign could be considered as a part of physical examination.

Diagnostic Ability of Peguero-Lo Presti Electrocardiographic Left Ventricular Hypertrophy Criterion in Severe Aortic Stenosis.

Traditional electrocardiographic (ECG) criteria for left ventricular hypertrophy (LVH), introduced in the pre-echocardiographic era of diagnosis, have a relatively low sensitivity (usually not exceeding 25-40%) in detecting LVH. A novel Peguero-Lo Presti ECG-LVH criterion was recently shown to exhibit a higher sensitivity than the traditional ECG-LVH criteria in hypertension. Our aim was to test the diagnostic ability of the novel Peguero-Lo Presti ECG-LVH criterion in severe aortic stenosis. We retrospectively analyzed 12-lead ECG tracings and echocardiographic records from the index hospitalization of 50 patients with isolated severe aortic stenosis (mean age: 77 ± 10 years; 30 women and 20 men). Exclusion criteria included QRS > 120 ms, bundle branch blocks or left anterior fascicular block, a history of myocardial infarction, more than mild aortic or mitral regurgitation, and significant LV dysfunction by echocardiography. We compared the agreement of the novel Peguero-Lo Presti criterion and traditional ECG-LVH criteria with echocardiographic LVH (LV mass index > 95 g/m2 in women and >115 g/m2 in men). Echocardiographic LVH was found in 32 out of 50 study patients. The sensitivity of the Peguero-Lo Presti criterion in detecting LVH was improved (55% vs. 9-34%) at lower specificity (72% vs. 78-100%) in comparison to 8 single traditional ECG-LVH criteria. Additionally, the positive predictive value (77% vs. 72%), positive likelihood ratio (2.0 vs. 1.5), and odds ratio (3.2 vs. 2.4) were higher for the Peguero-Lo Presti criterion versus the presence of any of these 8 traditional ECG-LVH criteria. Cohen's Kappa, a measure of concordance between ECG and echocardiography with regard to LVH, was 0.24 for the Peguero-Lo Presti criterion, -0.01-0.13 for single traditional criteria, and 0.20 for any traditional criterion. However, by the receiver operating characteristics (ROC) curve analysis, the overall ability to discriminate between patients with and without LVH was insignificantly lower for the Peguero-Lo Presti versus Cornell voltage as a continuous variable (area under the ROC curve: 0.65 (95% CI, 0.48-0.81) vs. 0.71 (0.55-0.86), p = 0.5). In conclusion, our preliminary results suggest a slightly better, albeit still low, agreement of the novel Peguero-Lo Presti ECG criterion compared to the traditional ECG-LVH criteria with echocardiographic LVH in severe aortic stenosis.

Electrocardiographic Versus Echocardiographic Left Ventricular Hypertrophy in Severe Aortic Stenosis.

Although ECG used to be a traditional method to detect left ventricular hypertrophy (LVH), its importance has decreased over the years and echocardiography has emerged as a routine technique to diagnose LVH. Intriguingly, an independent negative prognostic effect of the "electrical" LVH (i.e., by ECG voltage criteria) beyond echocardiographic LVH was demonstrated both in hypertension and aortic stenosis (AS), the most prevalent heart valve disorder. Our aim was to estimate associations of the ECG-LVH voltage criteria with echocardiographic LVH and indices of AS severity. We retrospectively manually analyzed ECG tracings of 50 patients hospitalized in our center for severe isolated aortic stenosis, including 32 subjects with echocardiographic LVH. The sensitivity of single traditional ECG-LVH criteria in detecting echocardiographic LVH was 9-34% and their respective specificity averaged 78-100%. The ability to predict echocardiographic LVH was higher for S-waves than R-waves (mean area under the receiver operating curve (AUC): 0.62-0.70 vs. 0.58-0.65). Among combinations of R- and S-waves, the discriminating ability was highest for the Cornell voltage (AUC: 0.71) compared to the Sokolow-Lyon, Romhilt and Gubner-Ungerleider voltage (AUC: 0.62-0.68). By multiple regression, peak aortic pressure gradient was positively related to the Sokolow-Lyon (ß = 1.7 ± 0.5, p = 0.002) and Romhilt voltage (ß = 1.3 ± 0.5, p = 0.01), but not Cornell (0.5 ± 0.3, p = 0.2) or Gubner-Ungerleider voltage (ß = 0.0 ± 0.5, p > 0.9), regardless of LV mass index. In conclusion, echocardiographic LVH and stenosis severity appear to have distinct associations with traditional ECG-LVH criteria in AS. A moderate diagnostic superiority of the Cornell voltage criterion with regard to anatomic LVH might result from its unique ability to include depolarization vectors in both the frontal and horizontal plane with consequent lesser sensitivity to the confounding effect of obesity.

Depressed Cardiac Mechanical Energetic Efficiency: A Contributor to Cardiovascular Risk in Common Metabolic Diseases-From Mechanisms to Clinical Applications.

Cardiac mechanical energetic efficiency is the ratio of external work (EW) to the total energy consumption. EW performed by the left ventricle (LV) during a single beat is represented by LV stroke work and may be calculated from the pressure-volume loop area (PVLA), while energy consumption corresponds to myocardial oxygen consumption (MVO2) expressed on a per-beat basis. Classical early human studies estimated total mechanical LV efficiency at 20-30%, whereas the remaining energy is dissipated as heat. Total mechanical efficiency is a joint effect of the efficiency of energy transfer at three sequential stages. The first step, from MVO2 to adenosine triphosphate (ATP), reflects the yield of oxidative phosphorylation (i.e., phosphate-to-oxygen ratio). The second step, from ATP split to pressure-volume area, represents the proportion of the energy liberated during ATP hydrolysis which is converted to total mechanical energy. Total mechanical energy generated per beat-represented by pressure-volume area-consists of EW (corresponding to PVLA) and potential energy, which is needed to develop tension during isovolumic contraction. The efficiency of the third step of energy transfer, i.e., from pressure-volume area to EW, decreases with depressed LV contractility, increased afterload, more concentric LV geometry with diastolic dysfunction and lower LV preload reserve. As practical assessment of LV efficiency poses methodological problems, De Simone et al. proposed a simple surrogate measure of myocardial efficiency, i.e., mechano-energetic efficiency index (MEEi) calculated from LV stroke volume, heart rate and LV mass. In two independent cohorts, including a large group of hypertensive subjects and a population-based cohort (both free of prevalent cardiovascular disease and with preserved ejection fraction), low MEEi independently predicted composite adverse cardiovascular events and incident heart failure. It was hypothesized that the prognostic ability of low MEEi can result from its association with both metabolic and hemodynamic alterations, i.e., metabolic syndrome components, the degree of insulin resistance, concentric LV geometry, LV diastolic and discrete systolic dysfunction. On the one part, an increased reliance of cardiomyocytes on the oxidation of free fatty acids, typical for insulin-resistant states, is associated with both a lower yield of ATP per oxygen molecule and lesser availability of ATP for contraction, which might decrease energetic efficiency of the first and second step of energy transfer from MVO2 to EW. On the other part, concentric LV remodeling and LV dysfunction despite preserved ejection fraction can impair the efficiency of the third energy transfer step. In conclusion, the association of low MEEi with adverse cardiovascular outcome might be related to a multi-step impairment of energy transfer from MVO2 to EW in various clinical settings, including metabolic syndrome, diabetes, hypertension and heart failure. Irrespective of theoretical considerations, MEEi appears an attractive simple tool which couldt improve risk stratification in hypertensive and diabetic patients for primary prevention purposes. Further clinical studies are warranted to estimate the predictive ability of MEEi and its post-treatment changes, especially in patients on novel antidiabetic drugs and subjects with common metabolic diseases and concomitant chronic coronary syndromes, in whom the potential relevance of MEE can be potentiated by myocardial ischemia.

Endothelial Dysfunction: A Contributor to Adverse Cardiovascular Remodeling and Heart Failure Development in Type 2 Diabetes beyond Accelerated Atherogenesis.

Endothelial dysfunction, associated with depressed nitric oxide (NO) bioavailability, is awell-recognized contributor to both accelerated atherogenesis and microvascular complications intype 2 diabetes (DM). However, growing evidence points to the comorbidities-driven endothelialdysfunction within coronary microvessels as a key player responsible for left ventricular (LV)diastolic dysfunction, restrictive LV remodeling and heart failure with preserved ejection fraction(HFpEF), the most common form of heart failure in DM. In this review we have described: (1)multiple cellular pathways which may link depressed NO bioavailability to LV diastolicdysfunction and hypertrophy; (2) hemodynamic consequences and prognostic effects of restrictiveLV remodeling and combined diastolic and mild systolic LV dysfunction on cardiovascularoutcomes in DM and HFpEF, with a focus on the clinical relevance of endothelial dysfunction; (3)novel therapeutic strategies to improve endothelial function in DM. In summary, beyondassociations with accelerated atherogenesis and microvascular complications, endothelialdysfunction supplements the multiple interwoven pathways affecting cardiomyocytes, endothelialcells and the extracellular matrix with consequent LV dysfunction in DM patients. The associationamongst impaired endothelial function, reduced coronary flow reserve, combined LV diastolic anddiscrete systolic dysfunction, and low LV stroke volume and preload reserve-all of which areadverse outcome predictors-is a dangerous constellation of inter-related abnormalities, underlyingthe development of heart failure. Nevertheless, the relevance of endothelial effects of novel drugsin terms of their ability to attenuate cardiovascular remodeling and delay heart failure onset in DMpatients remains to be investigated.

Novel antidiabetic drugs in diabetic kidney disease accompanying type 2 diabetes - a minireview.

Intensive hypoglycemic treatment is the strongest preventive strategy against the development of microvascular complications of type 2 diabetes (T2DM), including diabetic nephropathy. However, some antidiabetic drugs, i.e. sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP1-RA) have an additional renoprotective effect beyond glucose control by itself. Similar, both SGLT-2i and GLP1-RA have been demonstrated to decrease the risk of adverse cardiovascular (CV) events in CV outcome trials. Nevertheless, there are relevant differences in CV and renal effects of SGLT-2i and GLP1-RA. First, SGLT2i reduced the incidence and progression of albuminuria and prevented loss of kidney function, while predominant renal benefits of GLP1-RA were driven by albuminuria outcomes. Second, the risk of heart failure (HF) hospitalizations decreased on SGLT2i but not on GLP1-RA, which gives priority to SGLT2i in T2DM and HF, especially with depressed EF. Third, either GLP1-RA (reducing predominantly atherosclerosis-dependent events) or SGLT-2i, should be used in T2DM and established atherosclerotic CV disease (ASCVD) or other indicators of high CV risk. In this review, we have briefly compared clinical practice guidelines of the American Diabetes Association (2020 and 2021 versions), Polish Diabetes Association (2020) and the European Society of Cardiology/European Association for the Study of Diabetes (2019), with a focus on the choice between SGLT-2i and GLP1-RA in patients with diabetic kidney disease.

Cranial Irradiation in Childhood Acute Lymphoblastic Leukemia Is Related to Subclinical Left Ventricular Dysfunction and Reduced Large Artery Compliance in Cancer Survivors.

Long-term survivors of acute lymphoblastic leukemia (ALL), the most common childhood malignancy, are at remarkably increased risk of heart failure (HF) in middle age, most likely due anthracycline cardiotoxicity. The role of cranial radiation therapy (CRT) in the development of left ventricular (LV) dysfunction, a predecessor of overt HF, remains unclear. Our aim was to compare LV function and systemic arterial properties according to past CRT in young adult survivors of anthracycline-treated ALL. We studied young adult survivors of childhood ALL at a median of 16 years from diagnosis treated with anthracycline-based chemotherapy, with (n = 12) or without (n = 30) CRT. In addition to fractional shortening (FS) and ejection fraction (EF), LV function was quantified by tissue Doppler imaging of the mitral annulus. Aortic strain/distensibility and arterial compliance were derived from echocardiography and simultaneously recorded pulse pressure. Despite similar FS and EF, peak mitral annular systolic velocity (median (interquartile range): 9.0 (7.5-10.0) vs. 10.0 (8.8-11.5) cm/s, p = 0.05), and early diastolic velocity (13.8 (13.0-14.8) vs. 15.5 (14.0-17.3), p = 0.01) were decreased after chemotherapy combined with CRT compared to chemotherapy without CRT. Systemic arterial compliance was lower in post-CRT subjects (1.0 (0.8-1.2 vs. 1.4 (1.1-1.7) mL/mmHg, p = 0.002). Aortic strain and distensibility were similar regardless of prior CRT. In conclusion, lower arterial compliance and subclinical LV dysfunction may be possible late consequences of past CRT in adult survivors of childhood ALL. Whether arterial stiffening is associated with future HF development in CRT-exposed ALL survivors remains to be investigated.

Better Myocardial Function in Aortic Stenosis with Low Left Ventricular Mass: A Mechanism of Protection against Heart Failure Regardless of Stenosis Severity?

About one-tenth to one-third of patients with severe aortic stenosis (AS) do not develop left ventricular hypertrophy (LVH). Intriguingly, the absence of LVH despite severe AS is associated with lower prevalence of heart failure (HF), which challenges the classical notion of LVH as a beneficial compensatory response. Notably, the few studies that have attempted to characterize AS subjects with inadequately low left ventricular (LV) mass relative to LV afterload (i-lowLVM) described better prognosis and enhanced LV performance in AS associated with i-lowLVM, but those reports were limited to severe AS. Our aim was to compare myocardial function between moderate and severe AS with i-lowLVM. We retrospectively analyzed in-hospital records of 225 clinically stable nondiabetic patients with isolated moderate or severe degenerative AS in sinus rhythm, free of coexistent diseases. Subjects with i-lowLVM were compared to those with appropriate or excessive LVM (a/e-LVM), defined on the basis of the ratio of a measured LVM to the LVM predicted from an individual hemodynamic load. Patients with i-lowLVM and a/e-LVM did not differ in aortic valve area, LV end-diastolic diameter (LVd, a measure of LV preload), and circumferential end-systolic LV wall stress (cESS), an estimate of LV afterload. Compared to a/e-LVM, patients with i-lowLVM had increased LV ejection fraction (EF) and especially higher LV midwall fractional shortening (a better index of LV myocardial function than EF in concentric LV geometry) (p < 0.001-0.01), in both moderate and severe AS. LVd and cESS were similar in the four subgroups of the study subjects, i.e., moderate AS with i-lowLVM, moderate AS with a/e-LVM, severe AS with i-lowLVM, and severe AS with a/e-LVM (p > 0.6). Among patients with i-lowLVM, LVM did not differ significantly between moderate and severe AS (p > 0.4), while in those with a/e-LVM, LVM was increased in severe versus moderate AS (p < 0.001). In conclusion, the association of the low-LVM phenotype with better myocardial contractility may already develop in moderate AS. Additionally, cESS appears to be a controlled variable, which is kept constant over AS progression irrespective of LVM category, but even when controlled (by increasing LVM), is not able to prevent deterioration of LV function. Whether improved myocardial performance contributes to favorable prognosis and the preventive effect against HF in AS without LVH, remains to be studied.

Depressed systemic arterial compliance and impaired left ventricular midwall performance in aortic stenosis with concomitant type 2 diabetes: a retrospective cross-sectional study.

BACKGROUND: Degenerative aortic stenosis (AS), a disease of the elderly, frequently coexists with concomitant diseases, including type 2 diabetes (T2DM) which amplifies the cardiovascular (CV) risk. T2DM affects left ventricular (LV) structure and function via hemodynamic and metabolic factors. In concentric LV geometry, typical for AS, indices of LV midwall mechanics are better estimates of LV function than ejection fraction (EF). Effects of T2DM coexisting with AS on circumferential LV midwall systolic function and large artery properties have not been reported so far. Our aim was to compare characteristics of AS patients with and without T2DM, with a focus on LV midwall systolic function and arterial compliance. METHODS: Medical records of 130 electively hospitalized patients with moderate or severe isolated degenerative AS were retrospectively analyzed. Exclusion criteria included clinical instability, atrial fibrillation, coronary artery disease and relevant non-cardiac diseases. From in-hospital echocardiography and blood pressure, we calculated LV midwall fractional shortening (mwFS), circumferential end-systolic LV wall stress (cESS) and valvulo-arterial impedance (Zva), estimates of LV afterload, as well as systemic arterial compliance. RESULTS: Patients with (n = 50) and without T2DM (n = 80) did not differ in age, AS severity, LV mass and LV diastolic diameter. T2DM patients exhibited elevated cESS (247 ± 105 vs. 209 ± 84 hPa, p = 0.025) and Zva (5.8 ± 2.2 vs. 5.1 ± 1.8 mmHg per mL/m2, p = 0.04), and lower stroke volume index (33 ± 10 vs. 38 ± 12 mL/m2, p = 0.01) and systemic arterial compliance (0.53 ± 0.16 vs. 0.62 ± 0.22 mL/m2 per mmHg, p = 0.01). mwFS (11.9 ± 3.9 vs. 14.1 ± 3.7%, p = 0.001), but not EF (51 ± 14 vs. 54 ± 13%, p = n.s.), was reduced in T2DM. mwFS and cESS were inversely interrelated in patients both with (r = - 0.59, p < 0.001) and without T2DM (r = - 0.53, p < 0.001) By multiple regression, higher cESS (p < 0.001) and T2DM (p = 0.02) were independent predictors of depressed mwFS. CONCLUSIONS: In AS, coexistent T2DM appears associated with reduced systemic arterial compliance and LV dysfunction at the midwall level, corresponding to slightly depressed myocardial contractility.

Distinct associations between plasma osteoprotegerin, homoarginine and asymmetric dimethylarginine in chronic kidney disease male patients with coronary artery disease.

High plasma osteoprotegerin (OPG) and asymmetric dimethylarginine (ADMA) and low homoarginine (hArg) predict adverse renal and cardiovascular (CV) outcomes. In patients with chronic kidney disease and stable coronary artery disease, plasma OPG correlated with hArg (r = - 0.37, P = 0.03) and the hArg/ADMA molar ratio (r = - 0.46, P = 0.009), which was maintained upon adjustment for renal function. Elevated OPG levels and decreased hArg/ADMA ratios independently predicted 4-year composite CV and renal endpoints (CV death or progression to dialysis). Thus, high OPG and low hArg/ADMA ratio, albeit interrelated, appear to independently contribute to adverse clinical outcome.