Marco Canepa

Longitudinal Trajectories of Arterial Stiffness and the Role of Blood Pressure: The Baltimore Longitudinal Study of Aging

Carotid-femoral pulse wave velocity (PWV), a marker of arterial stiffness, is an established independent cardiovascular risk factor. Little information is available on the pattern and determinants of the longitudinal change in PWV with aging. Such information is crucial to elucidating mechanisms underlying arterial stiffness and the design of interventions to retard it. Between 1988 and 2013, we collected 2 to 9 serial measures of PWV in 354 men and 423 women of the Baltimore Longitudinal Study of Aging, who were 21 to 94 years of age and free of clinically significant cardiovascular disease. Rates of PWV increase accelerated with advancing age in men more than women, leading to sex differences in PWV after the age of 50 years. In both sexes, not only systolic blood pressure (SBP) ≥140 mm Hg but also SBP of 120 to 139 mm Hg was associated with steeper rates of PWV increase compared with SBP<120 mm Hg. Furthermore, there was a dose-dependent effect of SBP in men with marked acceleration in PWV rate of increase with age at SBP ≥140 mm Hg compared with SBP of 120 to 139 mm Hg. Except for waist circumference in women, no other traditional cardiovascular risk factors predicted longitudinal PWV increase. In conclusion, the steeper longitudinal increase of PWV in men than women led to the sex difference that expanded with advancing age. Age and SBP are the main longitudinal determinants of PWV, and the effect of SBP on PWV trajectories exists even in the prehypertensive range.

p38 MAPK and JNK Antagonistically Control Senescence and Cytoplasmic p16INK4A Expression in Doxorubicin-Treated Endothelial Progenitor Cells

Patients treated with low-dose anthracyclines often show late onset cardiotoxicity. Recent studies suggest that this form of cardiotoxicity is the result of a progenitor cell disease. In this study we demonstrate that Cord Blood Endothelial Progenitor Cells (EPCs) exposed to low, sub-apoptotic doses of doxorubicin show a senescence phenotype characterized by increased SA-b-gal activity, decreased TRF2 and chromosomal abnormalities, enlarged cell shape, and disarrangement of F-actin stress fibers accompanied by impaired migratory ability. P16 INK4A localizes in the cytoplasm of doxorubicin-induced senescent EPCs and not in the nucleus as is the case in EPCs rendered senescent by different stimuli. This localization together with the presence of an arrest in G2, and not at the G1 phase boundary, which is what usually occurs in response to the cell cycle regulatory activity of p16INK4A, suggests that doxorubicin-induced p16 INK4A does not regulate the cell cycle, even though its increase is closely associated with senescence. The effects of doxorubicin are the result of the activation of MAPKs p38 and JNK which act antagonistically. JNK attenuates the senescence, p16 INK4A expression and cytoskeleton remodeling that are induced by activated p38. We also found that conditioned medium from doxorubicin-induced senescent cardiomyocytes does not attract untreated EPCs, unlike conditioned medium from apoptotic cardiomyocytes which has a strong chemoattractant capacity. In conclusion, this study provides a better understanding of the senescence of doxorubicin-treated EPCs, which may be helpful in preventing and treating late onset cardiotoxicity.

Relationship between inter-arm difference in systolic blood pressure and arterial stiffness in community-dwelling older adults.

A significant inter‐arm difference in systolic blood pressure (IADSBP) has recently been associated with worse cardiovascular outcomes. The authors hypothesized that part of this association is mediated by arterial stiffness, and examined the relationship between significant IADSBP and carotid‐femoral pulse wave velocity (CF‐PWV) in a sample from the Baltimore Longitudinal Study of Aging. Of 1045 participants, 50 (4.8%) had an IADSBP ≥10 mm Hg at baseline, and 629 had completed data from ≥2 visits (for a total of 1704 visits during 8 years). CF‐PWV was significantly higher in patients with an IADSBP ≥10 mm Hg (7.3±1.9 vs 8.2±2, P=.002). Compared with others, patients with IADSBP ≥10 mm Hg also had higher body mass index, waist circumference, and triglycerides; higher prevalence of diabetes; and lower high‐density lipoprotein (HDL) cholesterol (P<.001 for all). A significant association with IADSBP ≥10 mm Hg was observed for CF‐PWV in both cross‐sectional (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.06–1.87; P=.01) and longitudinal (OR, 1.15; 95% CI, 1.03–1.29; P=.01) multivariate analyses. Female sex, Caucasian race, high body mass index (plus diabetes and low HDL cholesterol only cross‐sectionally) were other independent correlates of IADSBP ≥10 mm Hg. Significant IADSBP is associated with increased arterial stiffness in community‐dwelling older adults.

Testosterone Antagonizes Doxorubicin-Induced Senescence of Cardiomyocytes

Background Chronic cardiotoxicity is less common in male than in female patients receiving doxorubicin and other anthracyclines at puberty and adolescence. We hypothesized that this sex difference might be secondary to distinct activities of sex hormones on cardiomyocyte senescence, which is thought to be central to the development of long‐term anthracycline cardiomyopathy. Methods and Results H9c2 cells and neonatal mouse cardiomyocytes were exposed to doxorubicin with or without prior incubation with testosterone or 17β‐estradiol, the main androgen and estrogen, respectively. Testosterone, but not 17β‐estradiol, counteracted doxorubicin‐elicited senescence. Downregulation of telomere binding factor 2, which has been pinpointed previously as being pivotal to doxorubicin‐induced senescence, was also prevented by testosterone, as were p53 phosphorylation and accumulation. Pretreatment with the androgen receptor antagonist flutamide, the phosphatidylinositol 3 kinase inhibitor LY294002, and the nitric oxide synthase inhibitor L‐NG‐nitroarginine methyl ester abrogated the reduction in senescence and the normalization of telomere binding factor 2 levels attained by testosterone. Consistently, testosterone enhanced the phosphorylation of AKT and nitric oxide synthase 3. In H9c2 cells, doxorubicin‐stimulated senescence was still observed up to 21 days after treatment and increased further when cells were rechallenged with doxorubicin 14 days after the first exposure to mimic the schedule of anthracycline‐containing chemotherapy. Remarkably, these effects were also inhibited by testosterone. Conclusions Testosterone protects cardiomyocytes against senescence caused by doxorubicin at least in part by modulating telomere binding factor 2 via a pathway involving the androgen receptor, phosphatidylinositol 3 kinase, AKT, and nitric oxide synthase 3. This is a potential mechanism by which pubescent and adolescent boys are less prone to chronic anthracycline cardiotoxicity than girls.

Comparison of Outcomes in Patients With Nonobstructive, Labile-Obstructive, and Chronically Obstructive Hypertrophic Cardiomyopathy

Patients with nonobstructive hypertrophic cardiomyopathy (HC) are considered low risk, generally not requiring aggressive intervention. However, nonobstructive and labile-obstructive HC have been traditionally classified together, and it is unknown if these 2 subgroups have distinct risk profiles. We compared cardiovascular outcomes in 293 patients HC (96 nonobstructive, 114 labile-obstructive, and 83 obstructive) referred for exercise echocardiography and magnetic resonance imaging and followed for 3.3 ± 3.6 years. A subgroup (34 nonobstructive, 28 labile-obstructive, 21 obstructive) underwent positron emission tomography. The mean number of sudden cardiac death risk factors was similar among groups (nonobstructive: 1.4 vs labile-obstructive: 1.2 vs obstructive: 1.4 risk factors, p = 0.2). Prevalence of late gadolinium enhancement (LGE) was similar across groups but more non-obstructive patients had late gadolinium enhancement ≥20% of myocardial mass (23 [30%] vs 19 [18%] labile-obstructive and 8 [11%] obstructive, p = 0.01]. Fewer labile-obstructive patients had regional positron emission tomography perfusion abnormalities (12 [46%] vs nonobstructive 30 [81%] and obstructive 17 [85%], p = 0.003]. During follow-up, 60 events were recorded (36 ventricular tachycardia/ventricular fibrillation, including 30 defibrillator discharges, 12 heart failure worsening, and 2 deaths). Nonobstructive patients were at greater risk of VT/VF at follow-up, compared to labile obstructive (hazed ratio 0.18, 95% confidence interval 0.04 to 0.84, p = 0.03) and the risk persisted after adjusting for age, gender, syncope, family history of sudden cardiac death, abnormal blood pressure response, and septum ≥3 cm (p = 0.04). Appropriate defibrillator discharges were more frequent in nonobstructive (8 [18%]) compared to labile-obstructive (0 [0%], p = 0.02) patients. In conclusion, nonobstructive hemodynamics is associated with more pronounced fibrosis and ischemia than labile-obstructive and is an independent predictor of VT/VF in HC.

The human amniotic fluid stem cell secretome effectively counteracts doxorubicin-induced cardiotoxicity.

The anthracycline doxorubicin (Dox) is widely used in oncology, but it may cause a cardiomyopathy with bleak prognosis that cannot be effectively prevented. The secretome of human amniotic fluid-derived stem cells (hAFS) has previously been demonstrated to significantly reduce ischemic cardiac damage. Here it is shown that, following hypoxic preconditioning, hAFS conditioned medium (hAFS-CM) antagonizes senescence and apoptosis of cardiomyocytes and cardiac progenitor cells, two major features of Dox cardiotoxicity. Mechanistic studies with mouse neonatal ventricular cardiomyocytes (mNVCM) reveal that hAFS-CM inhibition of Dox-elicited senescence and apoptosis is associated with decreased DNA damage, nuclear translocation of NF-kB, and upregulation of the NF-kB controlled genes, Il6 and Cxcl1, promoting mNVCM survival. Furthermore, hAFS-CM induces expression of the efflux transporter, Abcb1b, and Dox extrusion from mNVCM. The PI3K/Akt signaling cascade, upstream of NF-kB, is potently activated by hAFS-CM and pre-treatment with a PI3K inhibitor abrogates NF-kB accumulation into the nucleus, modulation of Il6, Cxcl1 and Abcb1b, and prevention of Dox-initiated senescence and apoptosis in response to hAFS-CM. These results support the concept that hAFS are a valuable source of cardioprotective factors and lay the foundations for the development of a stem cell-based paracrine treatment of chemotherapy-related cardiotoxicity.

Role of bone mineral density in the inverse relationship between body size and aortic calcification: Results from the Baltimore Longitudinal Study of Aging

OBJECTIVE There is a J-shaped relationship between body mass index (BMI) and cardiovascular outcomes in elderly patients (obesity paradox). Whether low BMI correlates with aortic calcification (AC) and whether this association is accounted for by bone demineralization is uncertain. METHODS Presence of AC was evaluated in 687 community-dwelling individuals (49% male, mean age 67 ± 13 years) using CT images of the thoracic, upper and lower abdominal aorta, and scored from 0 to 3 according to number of sites that showed any calcification. Whole-body bone mineral density (BMD) was evaluated by dual-energy X-ray absorptiometry. Predictors of AC were assessed by logistic regression, and the role of BMD using mediation analysis. RESULTS Age and cardiovascular risk factors were positively associated while both BMI (r = -0.11, p < 0.01) and BMD (r = -0.17, p < 0.0001) were negatively associated with AC severity. In multivariate models, lower BMI (OR 0.96, 95%CI 0.92-0.99, p = 0.01), older age, higher systolic blood pressure, use of lipid-lowering drugs and smoking were independent predictors of AC. A nonlinear relationship between BMI and AC was noticed (p = 0.03), with decreased AC severity among overweight participants. After adjusting for BMD, the coefficient relating BMI to AC was reduced by 14% and was no longer significant, whereas BMD remained negatively associated with AC (OR 0.82, 95%CI 0.069-0.96, p = 0.01), with a trend for a stronger relationship in older participants. CONCLUSION Low BMI is associated with increased AC, possibly through calcium mobilization from bone, resulting in low BMD. Prevention of weight loss and bone demineralization with aging may help reducing AC.

Prevalence and Prognostic Impact of Chronic Obstructive Pulmonary Disease in Patients with Chronic Heart Failure: Data from the GISSI-HF Trial

Objectives: Chronic obstructive pulmonary disease (COPD) is a common comorbidity in patients with heart failure (HF). We aimed to assess its prevalence, characterization and long-term prognostic impact in the GISSI-HF population. Methods: The study randomized 6,975 ambulatory HF patients to either n-3 polyunsaturated fatty acids or placebo. We performed a retrospective analysis of clinical characteristics and outcomes of the 1,533 patients diagnosed with COPD (22%). Results: COPD was associated with a worse clinical presentation and an increased burden of comorbidities. At a median follow-up of 3.9 years, COPD was found to be an independent predictor of both predefined primary study end points, including all-cause mortality (HR 1.28, 95% CI 1.15-1.43, p < 0.0001) and all-cause mortality or hospitalization for cardiovascular reasons (HR 1.19, 95% CI 1.10-1.30, p < 0.0001). Both cardiovascular (HR 1.20, 95% CI 1.05-1.36, p = 0.007) and noncardiovascular mortality (HR 1.56, 95% CI 1.26-1.94, p < 0.0001) were significantly increased in COPD-HF patients, as well as hospitalizations for any reason (HR 1.23, 95% CI 1.14-1.34, p < 0.0001), for cardiovascular reasons (HR 1.16, 95% CI 1.06-1.27, p = 0.002) and for HF (HR 1.27, 95% CI 1.14-1.43, p < 0.0001). Conclusions: COPD is an independent predictor of mortality and hospitalizations in ambulatory HF patients. Increased awareness and improved management of COPD may reduce the burden of this morbidity to patients with HF.

Indoxyl Sulfate: A Candidate Target for the Prevention and Treatment of Cardiovascular Disease in Chronic Kidney Disease

The awareness that chronic kidney disease (CKD) is a condition of dramatically increased cardiovascular risk has prompted an intense research activity, aimed at identifying factors that are specifically involved in the development of cardiovascular complications of CKD and that can be delayed or reduced by novel pharmacological approaches. This may be the case with indoxyl sulfate (IS). IS is an endogenous molecule derived from indole, a product of protein metabolism by intestinal bacteria, which acts via the aryl hydrocarbon receptor (AhR). IS accumulates early in CKD and exerts proinflammatory and other detrimental effects on the cardiovascular system, in particular promoting atherosclerosis and atherosclerosis-related arterial remodeling. Furthermore, IS also contributes to renal damage, thereby fueling a vicious circle. Dialysis is poorly effective in removing IS, but its levels can be lowered by preventing the bacterial generation of indole or by absorbing this latter within the intestine. More intriguing, although still theoretical, is the possibility of inhibiting the action of IS at the cell level, by antagonizing the binding to AhR or IS intracellular signaling. Therefore, IS targeting might become an option for reducing the cardiovascular burden of CKD.

What can we learn from pulmonary function testing in heart failure

Pulmonary diseases frequently coexist in heart failure (HF), thus posing diagnostic and therapeutic challenges to cardiologists evaluating patients with overlapping symptoms and implementing recommended HF treatments. There is a growing body of evidence suggesting that pulmonary function testing might provide useful information for the best management of these patients. The availability of portable devices, allowing the measurement of spirometry and lung diffusion capacity for carbon monoxide outside of hospital‐based pulmonary lung function laboratories, provides an opportunity for a more widespread use of these measures in the cardiology community, but their interpretation can be challenging. In this work, after a brief review of the methodologies, we discuss the interpretation of pulmonary function testing in patients with HF alone or associated with pulmonary diseases, and its contribution in differentiating cardiac and pulmonary symptoms and preventing acute cardiac decompensation. In addition, we examined recent evidence suggesting how the use of pulmonary function testing may provide independent prognostic information in HF patients with and without pulmonary disorders, and help therapeutic decisions to fill the treatment gap that still exists in HF patients with concomitant pulmonary diseases.