Good performance in the management of acute heart failure in cardiogeriatric departments: the ICREX-94 experience.

CONTEXT: A growing number of elderly patients hospitalized for Acute Heart Failure (AHF) are being managed in cardiogeriatrics departments, but their characteristics and prognosis are poorly known. This study aimed to investigate the profile and outcome (rehospitalization at 90 days) of patients hospitalized for AHF in cardiogeriatrics departments in the Val-de-Marne area in the suburbs of Paris, and to compare them to AHF patients hospitalized in cardiology departments in the same area. METHODS: Observational study, ICREX-94, conducted in seven cardiology departments in France and three specific cardiogeriatrics departments in Val-de-Marne. RESULTS: A total of 308 patients were hospitalized for AHF between October 2017 and January 2019. During the 90 days following discharge, 29.6% patients were readmitted to the hospital. Compared with patients hospitalized in cardiology departments, patients in cardiogeriatrics departments were older (p < 0.001), less independent (living more often alone or in an institution) (p < 0.001), more often depressed (p < 0.001), had more often major neurocognitive disorder (p < 0.001), had a higher Human Development Index (HDI, p < 0.001), and were less often diagnosed with amyloidosis (p < 0.001). There was no difference in outcome whether patients were discharged from cardiology or cardiogeriatrics departments. The most frequent precipitating factors underlying AHF decompensation between the first and second hospitalization were arrhythmia and infection. CONCLUSION: AHF patients discharged from cardiogeriatrics departments, compared to cardiology departments, showed clinical differences but had the same prognosis regarding AHF rehospitalization at 90 days.

Concomitant systolic and diastolic alterations during chronic hypertension in pig.

The mechanical and cellular relationships between systole and diastole during left ventricular (LV) dysfunction remain to be established. LV contraction-relaxation coupling was examined during LV hypertrophy induced by chronic hypertension. Chronically instrumented pigs received angiotensin II infusion for4weeks to induce chronic hypertension (133 ±â€¯7 mmHg vs 98 ±â€¯5 mmHg for mean arterial pressure at Day 28 vs 0, respectively) and LV hypertrophy. LV function was investigated with the instrumentation and echocardiography for LV twist-untwist assessment before and after dobutamine infusion. The cellular mechanisms were investigated by exploring the intracellular Ca2+ handling. At Day 28, pigs exhibited LV hypertrophy with LV diastolic dysfunction (impaired LV isovolumic relaxation, increased LV end-diastolic pressure, decreased and delayed LV untwisting rate) and LV systolic dysfunction (impaired LV isovolumic contraction and twist) although LV ejection fraction was preserved. Isolated cardiomyocytes exhibited altered shortening and lengthening. Interestingly, contraction-relaxation coupling remained preserved both in vivo and in vitro during LV hypertrophy. LV systolic and diastolic dysfunctions were associated to post-translational remodeling and dysfunction of the type 2 cardiac ryanodine receptor/Ca2+ release channel (RyR2), i.e., PKA hyperphosphorylation of RyR2, depletion of calstabin 2 (FKBP12.6), RyR2 leak and hypersensitivity of RyR2 to cytosolic Ca2+ during both contraction and relaxation phases. In conclusion, LV contraction-relaxation coupling remained preserved during chronic hypertension despite LV systolic and diastolic dysfunctions. This implies that LV diastolic dysfunction is accompanied by LV systolic dysfunction. At the cellular level, this is linked to sarcoplasmic reticulum Ca2+ leak through PKA-mediated RyR2 hyperphosphorylation and depletion of its stabilizing partner.

Haematological determinants of cardiac involvement in adults with sickle cell disease.

AIMS: Cardiac involvement is common in sickle cell disease (SCD). Studies are needed to establish haematological determinants of this involvement and prognostic markers. The aim of the study was to identify haematological factors associated with cardiac involvement in SCD and their impact on prognosis. METHODS AND RESULTS: This longitudinal observational study was performed on 1780 SCD patients with SS or S-ß(0)-thalassemia referred to our centre. Six hundred fifty-six met our inclusion criteria (availability of a blood-workup and echocardiogram obtained <1 year apart, no heart valve surgery and no current pregnancy). Median age was 31 (interquartile range, 25-40) years, and median haemoglobin (Hb) was 87 (80-95)g/L. Left ventricular (LV) dilation, left atrial dilation, cardiac index (CI) >4 L/min/m(2), LV ejection fraction <55%, and tricuspid regurgitant velocity (TRV) ≥2.5 m/s were found in 35, 78, 23, 8.5, and 17% of patients, respectively. Compared with other patients, those in the fourth quartiles (Q4) of LV end-diastolic dimension index (LVEDDind) and left atrial dimension index (LADind) and those with high CI had significantly lower Hb, % foetal Hb (HbF), and red blood cell (RBC) counts; and significantly higher lactate dehydrogenase, bilirubin, and %dense RBCs. Independent haematologic determinants of Q4 LVEDDind and LADind were low RBC count and %HbF; high %dense RBCs were associated with LADind. Low %HbF and RBC count were associated with high CI. High %dense RBCs or no α-thalassemia gene deletion was associated with greater severity of anaemia and cardiac dilation and with higher CI. During the median follow-up of 48 (32-59) months, 50 (7.6%) patients died. Tricuspid regurgitant velocity ≥ 2.5 m/s was a predictor of mortality. The risk of death increased four-fold when left ventricular ejection fraction <55% was present also (P = 0.0001). CONCLUSION: Cardiac dilation and CI elevation in patients with SCD are associated with haematologic variables reflecting haemolysis, RBC rigidity, and blood viscosity. Tricuspid regurgitant velocity ≥ 2.5 and LV dysfunction (even mild) predict mortality.

Improvement of left ventricular filling by ivabradine during chronic hypertension: involvement of contraction-relaxation coupling.

Chronic hypertension is associated with left ventricular (LV) hypertrophy and LV diastolic dysfunction with impaired isovolumic relaxation and abnormal LV filling. Increased heart rate (HR) worsens these alterations. We investigated whether the I f channel blocker ivabradine exerts beneficial effects on LV filling dynamic. In this setting, we also evaluated the relationship between LV filling and isovolumic contraction as a consequence of contraction-relaxation coupling. Therefore, hypertension was induced by a continuous infusion of angiotensin II during 28 days in 10 chronically instrumented pigs. LV function was investigated after stopping angiotensin II infusion to offset the changes in loading conditions. In the normal heart, LV relaxation filling, LV early filling, LV peak early filling rate were positively correlated to HR. In contrast, these parameters were significantly reduced at day 28 vs. day 0 (18, 42, and 26 %, respectively) despite the increase in HR (108 ± 6 beats/min vs. 73 ± 2 beats/min, respectively). These abnormalities were corrected by acute administration of ivabradine (1 mg/kg, iv). Ivabradine still exerted these effects when HR was controlled at 150 beats/min by atrial pacing. Interestingly, LV relaxation filling, LV early filling and LV peak early filling were strongly correlated with both isovolumic contraction and relaxation. In conclusion, ivabradine improves LV filling during chronic hypertension. The mechanism involves LV contraction-relaxation coupling through normalization of isovolumic contraction and relaxation as well as HR-independent mechanisms.

[18F]-NaF PET/CT imaging in cardiac amyloidosis.

Cardiac amyloidosis (CA) is recognized as a common cause of restrictive cardiomyopathy and heart failure due to the deposition of insoluble proteins in the myocardial interstitium. We emphasize the role of [18F]-sodium fluoride (NaF) PET/CT as a potential noninvasive tool to identify and differentiate the transthyretin-related cardiac amyloidosis from the light-chain cardiac amyloidosis. We report cases of a 73-year-old man and a 75-year-old woman followed in our center for congestive heart failure with marked alteration of the left ventricular ejection fraction due to familial transthyretin Val122Ile cardiac amyloidosis and light-chain cardiac amyloidosis, respectively, confirmed on endomyocardial biopsy.

Nanotubular crosstalk with distressed cardiomyocytes stimulates the paracrine repair function of mesenchymal stem cells.

Mesenchymal stem cells (MSC) are known to repair broken heart tissues primarily through a paracrine fashion while emerging evidence indicate that MSC can communicate with cardiomyocytes (CM) through tunneling nanotubes (TNT). Nevertheless, no link has been so far established between these two processes. Here, we addressed whether cell-to-cell communication processes between MSC and suffering cardiomyocytes and more particularly those involving TNT control the MSC paracrine regenerative function. In the attempt to mimic in vitro an injured heart microenvironment, we developed a species mismatch coculture system consisting of terminally differentiated CM from mouse in a distressed state and human multipotent adipose derived stem cells (hMADS). In this setting, we found that crosstalk between hMADS and CM through TNT altered the secretion by hMADS of cardioprotective soluble factors such as VEGF, HGF, SDF-1α, and MCP-3 and thereby maximized the capacity of stem cells to promote angiogenesis and chemotaxis of bone marrow multipotent cells. Additionally, engraftment experiments into mouse infarcted hearts revealed that in vitro preconditioning of hMADS with cardiomyocytes increased the cell therapy efficacy of naïve stem cells. In particular, in comparison with hearts treated with stem cells alone, those treated with cocultured ones exhibited greater cardiac function recovery associated with higher angiogenesis and homing of bone marrow progenitor cells at the infarction site. In conclusion, our findings established the first relationship between the paracrine regenerative action of MSC and the nanotubular crosstalk with CM and emphasize that ex vivo manipulation of these communication processes might be of interest for optimizing current cardiac cell therapies.

Development of a Human Model for the Study of Effects of Hypoxia, Exercise, and Sildenafil on Cardiac and Vascular Function in Chronic Heart Failure.

BACKGROUND: Pulmonary hypertension is associated with poor outcome in patients with chronic heart failure (CHF) and may be a therapeutic target. Our aims were to develop a noninvasive model for studying pulmonary vasoreactivity in CHF and characterize sildenafil's acute cardiovascular effects. METHODS AND RESULTS: In a crossover study, 18 patients with CHF participated 4 times [sildenafil (2 × 20 mg)/or placebo (double-blind) while breathing air or 15% oxygen] at rest and during exercise. Oxygen saturation (SaO2) and systemic vascular resistance were recorded. Left and right ventricular (RV) function and transtricuspid systolic pressure gradient (RVTG) were measured echocardiographically. At rest, hypoxia caused SaO2 (P = 0.001) to fall and RVTG to rise (5 ± 4 mm Hg; P = 0.001). Sildenafil reduced SaO2 (-1 ± 2%; P = 0.043), systemic vascular resistance (-87 ± 156 dyn·s·cm; P = 0.034), and RVTG (-2 ± 5 mm Hg; P = 0.05). Exercise caused cardiac output (2.1 ± 1.8 L/min; P < 0.001) and RVTG (19 ± 11 mm Hg; P < 0.0001) to rise. The reduction in RVTG with sildenafil was not attenuated by hypoxia. The rise in RVTG with exercise was not substantially reduced by sildenafil. CONCLUSIONS: Sildenafil reduces SaO2 at rest while breathing air, this was not exacerbated by hypoxia, suggesting increased ventilation-perfusion mismatching due to pulmonary vasodilation in poorly ventilated lung regions. Sildenafil reduces RVTG at rest and prevents increases caused by hypoxia but not by exercise. This study shows the usefulness of this model to evaluate new therapeutics in pulmonary hypertension.

Accurate quantification of cardiovascular biomarkers in serum using Protein Standard Absolute Quantification (PSAQ™) and selected reaction monitoring.

Development of new biomarkers needs to be significantly accelerated to improve diagnostic, prognostic, and toxicity monitoring as well as therapeutic follow-up. Biomarker evaluation is the main bottleneck in this development process. Selected Reaction Monitoring (SRM) combined with stable isotope dilution has emerged as a promising option to speed this step, particularly because of its multiplexing capacities. However, analytical variabilities because of upstream sample handling or incomplete trypsin digestion still need to be resolved. In 2007, we developed the PSAQ™ method (Protein Standard Absolute Quantification), which uses full-length isotope-labeled protein standards to quantify target proteins. In the present study we used clinically validated cardiovascular biomarkers (LDH-B, CKMB, myoglobin, and troponin I) to demonstrate that the combination of PSAQ and SRM (PSAQ-SRM) allows highly accurate biomarker quantification in serum samples. A multiplex PSAQ-SRM assay was used to quantify these biomarkers in clinical samples from myocardial infarction patients. Good correlation between PSAQ-SRM and ELISA assay results was found and demonstrated the consistency between these analytical approaches. Thus, PSAQ-SRM has the capacity to improve both accuracy and reproducibility in protein analysis. This will be a major contribution to efficient biomarker development strategies.

Relationship between recommended chronic heart failure treatments and mortality over 8 years in real-world conditions: a pharmacoepidemiological study.

PURPOSE: We previously reported that chronic heart failure (CHF) treatments reduce the duration of hospitalisation, even in elderly patients. The present study aimed to determine whether CHF treatment also provides long-term benefits in terms of reduced mortality at 8 years. METHODS: A cohort of 281 patients who were admitted to a French teaching hospital with a main diagnosis of CHF were followed through the health insurance databases for 1 year and through the national mortality database for 8 years. RESULTS: Diuretics (236 patients, 84 %) and angiotensin-converting enzyme (ACE) inhibitors (193 patients, 69 %) were the most-frequently prescribed medications. The median duration of survival was 46 months. Mortality rates were significantly lower for patients administered beta-blockers (59 %) and statins (56 %) than for patients not exposed to these drugs (82 %, p < 0.001 and 78 %, p = 0.001 respectively). No significant differences in mortality were observed for spironolactone, diuretics or ACE inhibitors. After adjustment, beta-blocker treatment remained associated with a significantly lower risk of mortality (hazard ratio, HR = 0.54 [0.34-0.84]). After adjustment, the use of two or three CHF drugs was associated with longer survival (HR = 0.53 [0.36-0.77]) than the use of zero or one CHF drug. Statins were also associated with longer survival after adjustment (HR = 0.53 [0.31-0.89]). In patients 75 years of age or older (n = 73), only beta-blocker treatment was associated with a significantly lower risk of mortality (HR = 0.31 [0.16-0.63]) in multivariate analysis. CONCLUSIONS: The use of beta-blockers was associated with better survival rates. The use of statins was also associated with better survival at 8 years. Randomised controlled trials are required to confirm these observations.

Spatial and Temporal Non-Uniform Changes in Left Ventricular Myocardial Strain in Dogs with Duchenne Muscular Dystrophy.

BACKGROUND: Understanding and effectively treating dystrophin-deficient cardiomyopathy is of high importance for Duchenne muscular dystrophy (DMD) patients due to their prolonged lifespan. We used two-dimensional speckle tracking echocardiography to analyze more deeply the non-uniformity of myocardial strain within the left ventricle during the progression of cardiomyopathy in golden retriever muscular dystrophy (GRMD) dogs. METHODS: The circumferential strain (CS) and longitudinal strain (LS) of left ventricular (LV) endocardial, middle and epicardial layers were analyzed from three parasternal short-axis views and three apical views, respectively, in GRMD (n = 22) and healthy control dogs (n = 7) from 2 to 24 months of age. RESULTS: In GRMD dogs, despite normal global systolic function (normal LV fractional shortening and ejection fraction), a reduction in systolic CS was detected in the three layers of the LV apex but not in the LV middle-chamber and base at 2 months of age. This spatial heterogeneity in CS progressed with age, whereas a decrease in systolic LS could be detected early at 2 months of age in the three layers of the LV wall from three apical views. CONCLUSIONS: Analyzing the evolution of myocardial CS and LS in GRMD dogs reveals spatial and temporal non-uniform alterations of LV myocardial strain, providing new insights into the progression of dystrophin-deficient cardiomyopathy in this relevant model of DMD.

Comparison of cardiac involvement, extracardiac manifestations and outcomes between homozygote and heterozygote transthyretin p.Val142Ile (V122I) variant in patients with hereditary transthyretin amyloidosis: a cohort study.

BACKGROUND: Hereditary transthyretin (ATTRv) p.Val142Ile (V122I) mutation is the most common inherited cause of cardiac amyloidosis and little is known about the phenotype and outcome of the rare homozygotic genotype. This study aimed to compare phenotypic characteristics and outcomes between heterozygous and homozygous patients with ATTRv V122I amyloidosis. MATERIAL AND METHODS: This monocentric, observational, retrospective study conducted at the French National Referral Centre for Cardiac Amyloidosis (Henri Mondor Hospital, Créteil), described clinical, electrocardiographic, cardiac imaging features and prognostic data for patients with ATTRv V122I amyloidosis. RESULTS: Among 185 ATTRv V122I patients identified, 161 were heterozygous and 24 were homozygous. The homozygous frequency was 13%. Onset occured significantly earlier in the homozygotes compared to heterozygotes with earlier median age at diagnosis (67[63-71] years vs 76[70-79] years, p < .001), age at first cardiac symptom (66[61-71] years vs 74[68-78] years, p < .001) and age at first extracardiac symptom (59[52-70] years vs 69[62-75] years, p = .003). Homozygous ATTRv V122I was also associated with greater disease burden with earlier events (death, transplant or hospitalisation for acute heart failure) compared with heterozygotes (71[67-74] vs 78[76-79] years, p = .018). CONCLUSION: This rare, homozygous V122I cohort confirmed the earlier age of onset, death and cardiac events in this population.

Patients with cardiac amyloidosis are at a greater risk of mortality and hospital readmission after acute heart failure.

AIMS: Cardiac amyloidosis (CA) is an under-diagnosed cause of heart failure (HF) and has a worse prognosis than other forms of HF. The frequency of death or rehospitalization following discharge for acute heart failure (AHF) in CA (relative to other causes) has not been documented. The study aims to compare hospital readmission and death rates 90 days after discharge for AHF in patients with vs. without CA and to identify risk factors associated with these events in each group. METHODS AND RESULTS: Patients with HF and CA (HF + CA+) were recruited from the ICREX cohort, after screening of their medical records. The cases were matched 1:5 by sex and age with control HF patients without CA (HF + CA-). There were 27 HF + CA + and 135 HF + CA- patients from the ICREX cohort included in the study. Relative to the HF + CA- group, HF + CA+ patients had a higher heart rate (P = 0.002) and N-terminal prohormone of brain natriuretic peptide levels (P < 0.001) and lower blood pressure (P < 0.001), weight, and body mass index values (P < 0.001) on discharge. Ninety days after discharge, the HF + CA+ group displayed a higher death rate, a higher all-cause hospital readmission rate, and a higher hospital readmission rate for AHF. Death and hospital readmissions occurred sooner after discharge in the HF + CA+ group than in the HF + CA- group. CONCLUSIONS: The presence of CA in patients with HF was associated with a three-fold greater risk of death and a two-fold greater risk of all-cause hospital readmission 90 days after discharge. These findings emphasize the importance of close, active management of patients with CA and AHF.

Real-Life Evaluation of an Algorithm for the Diagnosis of Cardiac Amyloidosis.

OBJECTIVE: To evaluate the real-life use of a modified Gillmore algorithm with a "one-stop-shop" approach, bone scintigraphy (BS), a monoclonal gammopathy test (GT), a salivary gland biopsy (SGB), and genetic testing performed at the same time for the diagnosis of cardiac amyloidosis at the French National Reference Centre for Cardiac Amyloidosis (Henri Mondor Hospital, Créteil, France). METHODS: This retrospective cohort study included a total of 1222 patients with suspected amyloidosis who underwent BS and GT between June 2008 and May 2019. RESULTS: Of 1222 patients, 349 had no cardiac uptake on BS and negative GT (BS-/GT-), 276 were BS-/GT positive (GT+), 420 patients were BS+/GT-, and 177 were BS+/GT+. Our one-stop-shop check-up enabled us to diagnose 892 (72.9%) patients; 330 (27.0%) patients required additional examinations, such as mass spectrometry and/or a cardiac biopsy. This subset notably included 112 patients with amyloid light chain amyloidosis. More than 64% of the patients with transthyretin amyloidosis or another type of amyloidosis were diagnosed during the one-stop shop visit. Sensitivity and specificity of BS for transthyretin amyloidosis diagnosis was 99% and 96%, respectively. For amyloid light chain diagnosis, sensitivity and specificity were 100% and 76%, respectively, for GT and 54% and 100%, respectively, for SGB. Of 910 transthyretin genetic tests, 205 (17%) detected mutations. CONCLUSION: The results of our real-life cohort study confirmed the ability of a one-stop-shop approach with a modified Gillmore algorithm to diagnose cardiac amyloidosis and the interest of simultaneous testing for earlier diagnosis. The SGB has diagnostic value because it is easy, quick, and less invasive than a cardiac biopsy.

Amylo-AFFECT-QOL, a self-reported questionnaire to assess health-related quality of life and to determine the prognosis in cardiac amyloidosis.

Background and aims: Self-reported questionnaires are useful for estimating the health-related quality of life (HR-QoL), impact of interventions, and prognosis. To our knowledge, no HR-QoL questionnaire has been developed for cardiac amyloidosis (CA). This study aimed to validate Amylo-AFFECT-QOL questionnaire to assess HR-QoL and its prognostic value in CA. Methods: A self-reported questionnaire, "Amylo-AFFECT" had been designed and validated for CA symptoms evaluation and screening by physicians. It was adapted here to assess HR-QoL (Amylo-AFFECT-QOL) and its prognostic value in CA. To validate the theoretical model, internal consistency and convergent validity were assessed, particularly correlations between Amylo-AFFECT-QOL and the HR-QoL Minnesota Living Heart Failure (MLHF) questionnaire. Results: Amylo-AFFECT-QOL was completed by 515 patients, 425 of whom (82.5%) had CA. Wild-type and hereditary transthyretin amyloidosis (ATTRwt and ATTRv) and immunoglobulin light-chain amyloidosis (AL) were diagnosed in 47.8, 14.7, and 18.8% of cases, respectively. The best HR-QoL evaluation was obtained with five dimensions: "Heart failure," "Vascular dysautonomia," "Neuropathy," "Ear, gastrointestinal, and urinary dysautonomia," and "Skin or mucosal involvement." The global Amylo-AFFECT-QOL and MLHF scores showed significant positive correlations (rs = 0.72, p < 0.05). Patients with a final diagnosis of CA had a global Amylo-AFFECT-QOL score significantly higher than the control group composed by patients with other diagnoses (22.2 ± 13.6 vs. 16.2 ± 13.8, respectively, p-value < 0.01). According to the Amylo-AFFECT-QOL global results, ATTRv patients' QoL was more affected than AL patients' QoL or ATTRwt patients' QoL. Patients with a higher HR-QoL score had a greater risk of death or heart transplant after 1 year of follow-up (log-rank < 0.01). Conclusion: Amylo-AFFECT-QOL demonstrates good psychometric properties and is useful for quantifying HR-QoL and estimating CA prognosis. Its use may help to improve overall management of patients with CA.

Changes in amyloidosis phenotype over 11 years in a cardiac amyloidosis referral centre cohort in France.

BACKGROUND: Early cardiac amyloidosis (CA) diagnosis enables patients to access effective treatments for better long-term outcomes, yet it remains under-recognised, misdiagnosed and inadequately managed. AIM: To reduce diagnostic delays, we aimed to describe the epidemiological and clinical characteristics and changes over an 11-year period. METHODS: This was a retrospective, observational cohort study of all patients referred to the Henri-Mondor Hospital for suspected CA. RESULTS: Overall, 3194 patients were identified and 3022 were included and analysed. Our patients came from varied ethnic backgrounds, and more than half (55.2%) had confirmed CA. Over 11 years, referrals increased 4.4-fold, mostly from cardiologists. Notably, wild-type transthyretin amyloidosis (ATTRwt) became the predominant diagnosis, with referrals increasing 15-fold from 20 in 2010-2012 to 308 in 2019-2020. The number of amyloid light chain (AL) diagnoses increased, whilst variant transthyretin amyloidosis (ATTRv) numbers remained relatively stable. Concerning disease severity, AL patients presented more frequently with severe cardiac involvement whereas an increasing number of ATTRwt patients presented with National Amyloid Centre stage I (22.0% in 2013-2014 to 45.9% in 2019-2020). Lastly, among patients diagnosed with ATTRv in 2019-2020, 83.9% had ATTR Val122Ile cardiac phenotype. CONCLUSIONS: This study shows that increasing cardiologist awareness and referrals have increased CA diagnoses. With improved awareness and non-invasive diagnostic techniques, more patients with ATTRwt with milder disease and more ATTRv Val122Ile mutations are being referred and diagnosed. Although more AL cases are being recognised, patients are diagnosed with severe cardiac involvement.

Impaired left ventricular function in the presence of preserved ejection in chronic hypertensive conscious pigs.

Systolic function is often evaluated by measuring ejection fraction and its preservation is often assimilated with the lack of impairment of systolic left ventricular (LV) function. Considering the left ventricle as a muscular pump, we explored LV function during chronic hypertension independently of increased afterload conditions. Fourteen conscious and chronically instrumented pigs received continuous infusion of either angiotensin II (n = 8) or saline (n = 6) during 28 days. Hemodynamic recordings were regularly performed in the presence and 1 h after stopping angiotensin II infusion to evaluate intrinsic LV function. Throughout the protocol, the mean arterial pressure steadily increased by 55 ± 4 mmHg in angiotensin II-treated animals. There were no significant changes in stroke volume, LV fractional shortening or LV wall thickening, indicating the lack of alterations in LV ejection. In contrast, we observed maladaptive changes with (1) the lack of reduction in isovolumic contraction and relaxation durations with heart rate increases, (2) abnormally blunted isovolumic contraction and relaxation responses to dobutamine and (3) a linear correlation between isovolumic contraction and relaxation durations. None of these changes were observed in saline-infused animals. In conclusion, we provide evidence of impaired LV function with concomitant isovolumic contraction and relaxation abnormalities during chronic hypertension while ejection remains preserved and no sign of heart failure is present. The evaluation under unloaded conditions shows intrinsic LV abnormalities.

Vascular endothelial dysfunction in Duchenne muscular dystrophy is restored by bradykinin through upregulation of eNOS and nNOS.

Little is known about the vascular function and expression of endothelial and neuronal nitric oxide synthases (eNOS and nNOS) in Duchenne muscular dystrophy (DMD). Bradykinin is involved in the regulation of eNOS expression induced by angiotensin-converting enzyme inhibitors. We characterized the vascular function and eNOS and nNOS expression in a canine model of DMD and evaluated the effects of chronic bradykinin treatment. Vascular function was examined in conscious golden retriever muscular dystrophy (GRMD) dogs with left ventricular dysfunction (measured by echocardiography) and in isolated coronary arteries. eNOS and nNOS proteins in carotid arteries were measured by western blot and cyclic guanosine monophosphate (cGMP) content was analyzed by radioimmunoassay. Compared with controls, GRMD dogs had an impaired vasodilator response to acetylcholine. In isolated coronary artery, acetylcholine-elicited relaxation was nearly absent in placebo-treated GRMD dogs. This was explained by reduced nNOS and eNOS proteins and cGMP content in arterial tissues. Chronic bradykinin infusion (1 µg/min, 4 weeks) restored in vivo and in vitro vascular response to acetylcholine to the level of control dogs. This effect was NO-mediated through upregulation of eNOS and nNOS expression. In conclusion, this study is the first to demonstrate that DMD is associated with NO-mediated vascular endothelial dysfunction linked to an altered expression of eNOS and nNOS, which can be overcome by bradykinin.

Prevalence of, associations with, and prognostic value of tricuspid annular plane systolic excursion (TAPSE) among out-patients referred for the evaluation of heart failure.

BACKGROUND: Prevalence, predictors, and prognostic value of right ventricular (RV) function measured by the tricuspid annular plane systolic excursion (TAPSE) in patients with chronic heart failure (CHF) symptoms with a broad range of left ventricular ejection fraction (LVEF) are unknown. METHODS AND RESULTS: Of 1,547 patients, mean (±SD) age was 71 ± 11 years, 48% were women, median (interquartile range [IQR]) TAPSE was 18.5 (14.0-22.7) mm, mean LVEF was 47 ± 16%, 47% had LVEF ≤45% and 67% were diagnosed with CHF, defined as systolic (S-HF) if LVEF was ≤45% and as heart failure with preserved ejection fraction (HFPEF) if LVEF was >45% and treated with a loop diuretic. During a median (IQR) follow-up of 63 (41-75) months, mortality was 34%. In multivariable analysis, increasing age, N-terminal pro-B-type natriuretic peptide (NT-proBNP), New York Heart Association functional class, right atrial volume index, and transtricuspid pressure gradient; lower TAPSE, diastolic blood pressure, and hemoglobin; and atrial fibrillation (AF) or COPD were associated with an adverse prognosis. Receiver operating characteristic curve analysis identified a TAPSE of 15.9 mm as the best prognostic threshold (P = .0001); 47% of S-HF and 20% of HFPEF had a TAPSE of <15.9 mm. The main associations with a TAPSE <15.9 mm were higher NT-proBNP, presence of atrial fibrillation and presence of LV systolic dysfunction. CONCLUSIONS: In patients with CHF, low values for TAPSE are common, especially in those with reduced LVEF. TAPSE, unlike LVEF, was an independent predictor of outcome.

Prognostic significance and normal values of 2D strain to assess right ventricular systolic function in chronic heart failure.

BACKGROUND: Normal values and the prognostic significance of right ventricle (RV)-2D strain in chronic heart failure (CHF) patients are unknown. METHODS AND RESULTS: Between 2005 and 2010, we prospectively enrolled 43 controls and 118 stable CHF patients. Standard echocardiographic variables, tricuspid annular plane systolic excursion, peak systolic velocity of tricuspid annular motion using tissue Doppler imaging, and RV and left ventricle (LV) 2D-strain were measured. The primary outcome was death or emergency transplantation or emergency ventricular assist device implantation or acute heart failure. RV-2D strain was measurable in 39 controls (58±17 years, 50% men), whose median value was 30% (95% confidence interval [95%CI], 39%; 20%); and in 104 CHF patients (80% men, mean age 57±11 years, and mean LV ejection fraction 29%±8%), whose median value was 19% (95%CI, 34%; 9%). During the mean follow-up of 37±14 months, 44 experienced the primary outcome. By Cox proportional hazards multivariate analysis, only RV-2D strain and log B-type natriuretic peptide independently predicted experiencing the primary outcome within the first year. The best RV-2D strain cut-off by receiver-operating characteristics analysis was 21%, and patients with values >21% were at greatest risk (χ(2)-log-rank test=14.1, P<0.0001). CONCLUSIONS: RV-2D strain is a strong independent predictor of severe adverse events in patients with CHF and may be superior to other systolic RV or LV echocardiographic variables.

Prevalence and determinants of iron deficiency in cardiac amyloidosis.

AIMS: Iron deficiency (ID) is common in patient with chronic heart failure (HF) and has been widely studied. In contrast, data concerning ID in cardiac amyloidosis (CA) are limited. Amyloidosis is a severe and fatal systemic disease, characterized by an accumulation of amyloid fibrils in various tissues/organs, including nerves, kidneys, gastrointestinal tract, and heart. Amyloid deposits in the heart eventually cause HF. The main subtypes of CA are light chain (AL), hereditary transthyretin (ATTRv), and wild-type transthyretin (ATTRwt). We performed this study to determine the prevalence, clinical outcome (all-cause mortality), and determinants of ID among the three main subtypes of CA. METHODS AND RESULTS: Iron deficiency status were analysed in 816 CA patients enrolled at the French Referral Centre for Cardiac Amyloidosis: 271 (33%) had AL, 164 (20%) ATTRv, and 381 (47%) ATTRwt. ID affected 49% of CA patients, 45% with AL, 58% with ATTRv, and 48% with ATTRwt. We identified ATTR status (ATTRv P = 0.003, ATTRwt P = 0.037), diabetes (P = 0.003), aspirin treatment (P = 0.009), haemoglobin levels (P = 0.006), and altered global longitudinal strain (P = 0.02) as independent ID determinants. There is no difference in all-cause mortality considering ID status. CONCLUSIONS: Iron deficiency is common in patients with CA, irrespective of the subtype. Patients seem more likely to have ID if diagnosed with ATTR, if diabetic, and/or treated with aspirin. In CA, the benefit of intravenous iron therapy, for ID, on morbidity and mortality needs further study.