Amyloid myopathy: expanding the clinical spectrum of transthyretin amyloidosis-case report and literature review.

We identified two patients with transthyretin (ATTR) amyloid myopathy (one ATTR variant amyloidosis, ATTRv; one wild-type ATTR amyloidosis, ATTRwt). Myopathy was the initial manifestation in ATTRwt, whereas it followed neuropathy and cardiomyopathy in ATTRv. The ATTRwt patient showed muscular tracer uptake on 99mTc-DPD planar scintigraphy at the time of initial diagnosis, consistent with ATTR amyloid myopathy. The ATTRv patient underwent heart transplantation because of progressive heart failure. Within the next two years, progressive myopathic symptoms and extracardiac tracer uptake on 99mTc-DPD planar scintigraphy were documented, attributable to ATTR amyloid myopathy. Interstitial amyloid deposits were confirmed by muscle biopsy in both patients, with a particularly high amyloid burden in the adipose tissue. This case report highlights the frequent concomitant presence of cardiac ATTR amyloidosis and ATTR amyloid myopathy. ATTR amyloid myopathy may precede cardiac manifestation in ATTRwt or occur after heart transplantation in ATTRv. Due to the high diagnostic accuracy of 99mTc-DPD scintigraphy for detecting ATTR amyloid myopathy and the emergence of novel therapeutics, it is important to increase the awareness of its presence.

Smooth Muscle Specific Ablation of CXCL12 in Mice Downregulates CXCR7 Associated with Defective Coronary Arteries and Cardiac Hypertrophy.

The chemokine CXCL12 plays a fundamental role in cardiovascular development, cell trafficking, and myocardial repair. Human genome-wide association studies even have identified novel loci downstream of the CXCL12 gene locus associated with coronary artery disease and myocardial infarction. Nevertheless, cell and tissue specific effects of CXCL12 are barely understood. Since we detected high expression of CXCL12 in smooth muscle (SM) cells, we generated a SM22-alpha-Cre driven mouse model to ablate CXCL12 (SM-CXCL12-/-). SM-CXCL12-/- mice revealed high embryonic lethality (50%) with developmental defects, including aberrant topology of coronary arteries. Postnatally, SM-CXCL12-/- mice developed severe cardiac hypertrophy associated with fibrosis, apoptotic cell death, impaired heart function, and severe coronary vascular defects characterized by thinned and dilated arteries. Transcriptome analyses showed specific upregulation of pathways associated with hypertrophic cardiomyopathy, collagen protein network, heart-related proteoglycans, and downregulation of the M2 macrophage modulators. CXCL12 mutants showed endothelial downregulation of the CXCL12 co-receptor CXCR7. Treatment of SM-CXCL12-/- mice with the CXCR7 agonist TC14012 attenuated cardiac hypertrophy associated with increased pERK signaling. Our data suggest a critical role of smooth muscle-specific CXCL12 in arterial development, vessel maturation, and cardiac hypertrophy. Pharmacological stimulation of CXCR7 might be a promising target to attenuate adverse hypertrophic remodeling.

Pharmacokinetics of trimethoprim/sulfametrole in critically ill patients on continuous renal replacement therapy.

OBJECTIVES: We investigated the effect of continuous renal replacement therapy (CRRT) on the pharmacokinetics of trimethoprim and sulfametrole. PATIENTS AND METHODS: We enrolled critically ill adults undergoing CRRT and critically ill adults with normal or slightly impaired renal function (plasma creatinine concentration <1.5 mg/dL, control group). All patients received trimethoprim/sulfametrole at standard doses. Pharmacokinetics were determined after the first dose and at steady-state. In addition, a population pharmacokinetic model using plasma data was built. We also assessed the renal clearance (CLR) and the extracorporeal clearance in patients undergoing CRRT. RESULTS: Twelve patients were enrolled in the CRRT group and 12 patients in the control group. There was no statistically significant difference in trimethoprim pharmacokinetics between the two groups. In patients on CRRT, total plasma clearance (CLtot) and V of sulfametrole were significantly higher than in the control group. However, sulfametrole exposure was not significantly altered during CRRT. The population pharmacokinetic analysis indicated that neither CRRT intensity nor residual diuresis were significant covariates on trimethoprim or sulfametrole CL. Median CL by continuous venovenous haemofiltration accounted for about one-third of CLtot of trimethoprim and for about one-half of CLtot of sulfametrole. In patients on CRRT, CLR of trimethoprim and sulfametrole were <5% of CLtot. CONCLUSIONS: During CRRT, standard doses of trimethoprim/sulfametrole appear to be adequate.

High Body Mass Index is Associated with Elevated Blood Levels of Progerin mRNA.

Obesity is a well-described risk factor resulting in premature aging of the cardiovascular system ultimately limiting longevity. Premature cardiac death and aging is the hallmark of Hutchinson-Gilford syndrome (HGPS), a disease caused by defined mutations in the lamin A gene leading to a shortened prelamin A protein known as progerin. Since small amounts of progerin are expressed in healthy individuals we aimed to investigate the association of Body-Mass-Index (BMI) with respect to expression of progerin mRNA in blood samples of patient with known cardiovascular disease. In this cross-sectional retrospective analysis, 111 patients were consecutively included of which 46 were normal (BMI < 25 kg/m2) and 65 overweight (BMI ≥ 25.0 kg/m2). Blood samples were analyzed for quantitative expression of progerin mRNA. Progerin as well as high-sensitive C-Reactive Protein (hs-CRP) levels were significantly upregulated in the overweight group. Linear regression analyses showed a significant positive correlation of BMI and progerin mRNA (n = 111; r = 0.265, p = 0.005), as well as for hs-CRP (n = 110; r = 0.300, p = 0.001) and for Hb1Ac (n = 110; r = 0.336, p = 0.0003). Our data suggest that BMI strongly correlates with progerin mRNA expression and inflammation. Progerin might contribute to well described accelerated biologic aging in obese individuals.

Evaluation of right ventricular function by coronary computed tomography angiography using a novel automated 3D right ventricle volume segmentation approach: a validation study.

OBJECTIVES: To evaluate right ventricle (RV) function by coronary computed tomography angiography (CTA) using a novel automated three-dimensional (3D) RV volume segmentation tool in comparison with clinical reference modalities. METHODS: Twenty-six patients with severe end-stage heart failure [left ventricle (LV) ejection fraction (EF) <35%] referred to CTA were enrolled. A specific individually tailored biphasic contrast agent injection protocol was designed (80%/20% high/low flow) was designed. Measurement of RV function [EF, end-diastolic volume (EDV), end-systolic volume (ESV)] by CTA was compared with tricuspid annular plane systolic excursion (TAPSE) by transthoracic echocardiography (TTE) and right heart invasive catheterisation (IC). RESULTS: Automated 3D RV volume segmentation was successful in 26 (100%) patients. Read-out time was 3 min 33 s (range, 1 min 50s-4 min 33s). RV EF by CTA was stronger correlated with right atrial pressure (RAP) by IC (r = -0.595; p = 0.006) but weaker with TAPSE (r = 0.366, p = 0.94). When comparing TAPSE with RAP by IC (r = -0.317, p = 0.231), a weak-to-moderate non-significant inverse correlation was found. Interobserver correlation was high with r = 0.96 (p < 0.001), r = 0.86 (p < 0.001) and r = 0.72 (p = 0.001) for RV EDV, ESV and EF, respectively. CT attenuation of the right atrium (RA) and right ventricle (RV) was 196.9 ± 75.3 and 217.5 ± 76.1 HU, respectively. CONCLUSIONS: Measurement of RV function by CTA using a novel 3D volumetric segmentation tool is fast and reliable by applying a dedicated biphasic injection protocol. The RV EF from CTA is a closer surrogate of RAP than TAPSE by TTE. KEY POINTS: • Evaluation of RV function by cardiac CTA by using a novel 3D volume segmentation tool is fast and reliable. • A biphasic contrast agent injection protocol ensures homogenous RV contrast attenuation. • Cardiac CT is a valuable alternative modality to CMR for the evaluation of RV function.

Aetiology, ejection fraction and mortality in chronic heart failure: a mediation analysis.

OBJECTIVE: Clinical decision making in chronic heart failure (CHF) is based primarily on left ventricular ejection fraction (LVEF), and only secondarily on aetiology of the underlying disease. Our aim was to investigate the mediating role of LVEF in the relationship between aetiology and mortality. METHODS: Using data of 2056 Austrian patients with CHF (mean age 57.2 years; mean follow-up 8.8 years), effects of aetiology on LVEF and overall mortality were estimated using multivariable-adjusted linear and Cox regression models. In causal mediation analyses, we decomposed the total effect of aetiology on mortality into direct and indirect (mediated through LVEF) effects. RESULTS: For the analysed aetiologies (dilated (DCM, n=1009) and hypertrophic (HCM, n=89) cardiomyopathy; ischaemic (IHD, n=529) and hypertensive (HHD, n=320) heart disease; cardiac amyloidosis (CA, n=109)), the effect of LVEF on mortality was similar (HR5%-points lower LVEF=1.07, 95% CI 1.04 to 1.10; pinteraction=0.718). HCM and CA were associated with significantly higher, and IHD and DCM with significantly lower LVEF compared with other aetiologies. Compared with respective other aetiologies, the corresponding total effect HRs for mortality were 0.77 (95% CI 0.67 to 0.89), 0.47 (95% CI 0.25 to 0.88), 1.40 (95% CI 1.21 to 1.62), 0.79 (95% CI 0.67 to 0.95) and 2.36 (95% CI 1.81 to 3.08) for DCM, HCM, IHD, HHD and CA, respectively. CA had the highest mortality despite a HRindirect effect of 0.74 (95% CI 0.65 to 0.83). For all other aetiologies, <20% of the total mortality effects were mediated through LVEF. CONCLUSIONS: The direct effect of aetiology on mortality dominates the indirect effect through LVEF. Therefore, clarification of aetiology is as important as measurement of LVEF.

Imbalance of Iron Availability and Demand in Patients With Acute and Chronic Heart Failure.

BACKGROUND: Iron deficiency (ID) is a frequent comorbidity in patients with acute (AHF) and chronic heart failure (CHF) associated with morbidity and death. We aimed to better characterize iron homeostasis in patients with heart failure applying different biomarkers and to evaluate the accuracy of current ID definition by the European Society of Cardiology/American College of Cardiology/American Heart Association to indicate tissue iron availability and demand. METHODS AND RESULTS: We performed a retrospective cohort study investigating 277 patients with AHF and 476 patients with CHF between February 2021 and May 2022. Patients with AHF had more advanced ID than patients with CHF, reflected by increased soluble transferrin receptor and soluble transferrin receptor-ferritin index, and lower ferritin, serum iron, transferrin saturation, hepcidin, and reticulocyte hemoglobin. Decreased iron availability or increased tissue iron demand, reflected by increased soluble transferrin receptor-ferritin index and decreased reticulocyte hemoglobin, was found in 84.1% (AHF) and 28.0% (CHF) with absolute ID and in 50.0% (AHF) and 10.5% (CHF) with combined ID according to the current European Society of Cardiology/American College of Cardiology/American Heart Association-based ID definition. Low hepcidin expression as an indicator of systemic ID was found in 91.1% (AHF) and 80.4% (CHF) of patients with absolute ID and in 32.3% (AHF) and 18.8% (CHF) of patients with combined ID. ID definitions with higher specificity reduce the need for iron supplementation by 25.5% in patients with AHF and by 65.6% in patients with CHF. CONCLUSIONS: Our results suggest that the current European Society of Cardiology/American College of Cardiology/American Heart Association-based ID definition might overestimate true ID, particularly in CHF. More stringent thresholds for ID could more accurately identify patients with heart failure with reduced tissue iron availability who benefit from intravenous iron supplementation.

Roxadustat Attenuates Adverse Remodeling Following Myocardial Infarction in Mice.

Activation of the CXCL12/CXCR4/ACKR3 axis is known to aid myocardial repair through ischemia-triggered hypoxia-inducible factor-1α (HIF-1α). To enhance the upregulation of HIF-1α, we administered roxadustat, a novel prolyl hydroxylase inhibitor (PHI) clinically approved by the European Medicines Agency 2021 for the treatment of renal anemia, with the purpose of improving LV function and attenuating ischemic cardiomyopathy. METHODS: We evaluated roxadustat's impact on HIF-1 stimulation, cardiac remodeling, and function after MI. Therefore, we analyzed nuclear HIF-1 expression, the mRNA and protein expression of key HIF-1 target genes (RT-PCR, Western blot), inflammatory cell infiltration (immunohistochemistry), and apoptosis (TUNEL staining) 7 days after MI. Additionally, we performed echocardiography in male and female C57BL/6 mice 28 days post-MI. RESULTS: We found a substantial increase in nuclear HIF-1, associated with an upregulation of HIF-1α target genes like CXCL12/CXCR4/ACKR3 at the mRNA and protein levels. Roxadustat increased the proportion of myocardial reparative M2 CD206+ cells, suggesting beneficial alterations in immune cell migration and a trend towards reduced apoptosis. Echocardiography showed that roxadustat treatment significantly preserved ejection fraction and attenuated subsequent ventricular dilatation, thereby reducing adverse remodeling. CONCLUSIONS: Our findings suggest that roxadustat is a promising clinically approved treatment option to preserve myocardial function by attenuating adverse remodeling.

Correlation of 99mTc-DPD bone scintigraphy with histological amyloid load in patients with ATTR cardiac amyloidosis.

BACKGROUND: The significance of measuring 99mTc-labelled-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) in transthyretin (ATTR) cardiac amyloidosis has not been adequately studied. This single-centre observational study evaluated the correlation between 99mTc-DPD scintigraphy and histological amyloid load in endomyocardial biopsy (EMB). METHODS: Twenty-eight patients with biopsy-proven ATTR amyloidosis and concomitantly available 99mTc-DPD scintigraphy were included. Visual Perugini scoring, and (semi-)quantitative analysis of cardiac 99mTc-DPD uptake by planar whole-body imaging and single photon emission computed tomography (SPECT/CT) using regions of interest (ROI) were performed. From this, heart-to-whole-body ratio (H/WB) and heart-to-contralateral-chest ratio (H/CL) were calculated. The histological amyloid load was quantified using two different staining methods. RESULTS: Increased cardiac tracer uptake was documented in all patients (planar: ROImean 129 ± 37 cps; SPECT/CT: ROImean 369 ± 142 cps). Histological amyloid load (19 ± 13%) significantly correlated with Perugini score (r = 0.69, p < .001) as well as with cardiac 99mTc-DPD uptake (planar: r = 0.64, p < .001; H/WB: r = 0.50, p = .014; SPECT/CT: r = 0.53, p = .008; H/CL: r = 0.43, p = .037) (results are shown for correlations with Congo Red-staining). CONCLUSION: In ATTR, cardiac 99mTc-DPD uptake significantly correlated with histological amyloid load in EMB. Further studies are needed to implement thresholds in cardiac 99mTc-DPD uptake measurements for risk stratification and guidance of therapy.

Granulocyte colony-stimulating factor treatment plus dipeptidylpeptidase-IV inhibition augments myocardial regeneration in mice expressing cyclin D2 in adult cardiomyocytes.

AIMS: Although pharmacological interventions that mobilize stem cells and enhance their homing to damaged tissue can limit adverse post-myocardial infarction (MI) remodelling, cardiomyocyte renewal with this approach is limited. While experimental cell cycle induction can promote cardiomyocyte renewal following MI, this process must compete with the more rapid processes of scar formation and adverse remodelling. The current study tested the hypothesis that the combination of enhanced stem cell mobilization/homing and cardiomyocyte cell cycle induction would result in increased myocardial renewal in injured hearts. METHODS AND RESULTS: Myocardial infarction was induced by coronary artery ligation in adult MHC-cycD2 transgenic mice (which exhibit constitutive cardiomyocyte cell cycle activity) and their non-transgenic littermates. Mice were then treated with saline or with granulocyte colony-stimulating factor (G-CSF) plus the dipeptidylpeptidase-IV (DPP-IV) inhibitor Diprotin A (DipA) for 7 days. Infarct thickness and cardiomyocyte number/infarct/section were significantly improved in MHC-cycD2 mice with G-CSF plus DipA treatment when compared with MHC-cycD2 transgene expression or G-CSF plus DipA treatment alone. Echocardiographic analyses revealed that stem cell mobilization/homing and cardiomyocyte cell cycle activation had an additive effect on functional recovery. CONCLUSION: These data strongly suggest that G-CSF plus DPP-IV inhibition, combined with cardiomyocyte cell cycle activation, leads to enhanced myocardial regeneration following MI. The data are also consistent with the notion that altering adverse post-injury remodelling renders the myocardium more permissive for cardiomyocyte repopulation.

Eosinophilic myocarditis complicated by permanent atrioventricular nodal block: a case report.

Background: Eosinophilic myocarditis (EM) is a rare disease with different clinical pictures and disease courses. Little literature is available on the various courses of the disease. Case summary: A previously healthy 44-year-old male patient presented with acute heart failure and developed complete atrioventricular (AV) block requiring pacing. Acute heart failure was managed with inotropic support, non-invasive ventilation, and implantation of a permanent AV-sequential pacemaker. Cardiac magnetic resonance imaging was suggestive of myocarditis and endomyocardial biopsy diagnosed EM histologically. Endomyocardial biopsy was essential for definite aetiologic assignment, thus dispelling initial reservations about immunosuppressive therapy. Final treatment strategy consisted of steroids and Azathioprine. Discussion: Endomyocardial biopsy is essential to establish diagnosis and targeted treatment in EM, which can rapidly lead to life-threatening conditions. Left ventricular function recovered within 2 weeks in response to immunosuppression and the patient was consistently well during follow-up. Despite the otherwise good response to immunosuppression, complete AV block continued over time.

Cardio-oncology in Austria: cardiotoxicity and surveillance of anti-cancer therapies : Position paper of the Heart Failure Working Group of the Austrian Society of Cardiology.

Survival in cancer is continuously improving due to evolving oncological treatment. Therefore, cardiovascular short-term and long-term side effects gain crucial importance for overall outcome. Cardiotoxicity not only presents as heart failure, but also as treatment-resistant hypertension, acute coronary ischemia with plaque rupture or vasospasm, thromboembolism, arrhythmia, pulmonary hypertension, diastolic dysfunction, acute myocarditis and others. Recent recommendations have proposed baseline cardiac risk assessment and surveillance strategies. Major challenges are the availability of monitoring and imaging resources, including echocardiography with speckle tracking longitudinal strain (GLS), serum biomarkers such as natriuretic peptides (NT-proBNP) and highly sensitive cardiac troponins. This Austrian consensus encompasses cardiotoxicity occurrence in frequent antiproliferative cancer drugs, radiotherapy, immune checkpoint inhibitors and cardiac follow-up considerations in cancer survivors in the context of the Austrian healthcare setting. It is important to optimize cardiovascular risk factors and pre-existing cardiac diseases without delaying oncological treatment. If left ventricular ejection fraction (LVEF) deteriorates during cancer treatment (from >10% to <50%), or myocardial strain decreases (>15% change in GLS), early initiation of cardioprotective therapies (angiotensin-converting enzyme inhibitors, angiotensin or beta receptor blockers) is recommended, and LVEF should be reassessed before discontinuation. Lower LVEF cut-offs were recently shown to be feasible in breast cancer patients to enable optimal anticancer treatment. Interdisciplinary cardio-oncology cooperation is pivotal for optimal management of cancer patients.

Cardiomyogenic potential of C-kit(+)-expressing cells derived from neonatal and adult mouse hearts.

BACKGROUND: C-kit is a receptor tyrosine kinase family member expressed in hematopoietic stem cells. C-kit is also transiently expressed in cardiomyocyte precursors during development and in a rare cell population in the normal adult heart. In the present study, the cardiomyogenic potential of c-kit(+) cells isolated from normal neonatal, normal adult, and infarcted adult mouse hearts was evaluated. METHODS AND RESULTS: Magnetic activated cell sorting was used to prepare c-kit(+) cells from the hearts of ACT-EGFP/MHC-nLAC double transgenic mice. These animals exhibit widespread enhanced green fluorescent protein (EGFP) expression and cardiomyocyte-restricted nuclear beta-galactosidase activity, thus permitting simultaneous tracking of cell survival and differentiation. A subset of the c-kit(+) cells from double transgenic neonatal hearts acquired a cardiomyogenic phenotype when cocultured with fetal cardiomyocytes (2.4% of all EGFP(+) cells screened) but rarely when cultured alone or when cocultured with mouse fibroblasts (0.03% and 0.05% of the EGFP(+) cells screened, respectively). In contrast, c-kit(+) cells from normal adult double transgenic hearts failed to undergo cardiomyogenic differentiation when cocultured with nontransgenic fetal cardiomyocytes (>18 000 EGFP(+) cells screened) or when transplanted into normal or infarcted adult mouse hearts (14 EGFP(+) grafts examined). A single c-kit(+) cell from an infarcted double transgenic adult heart was observed to acquire a cardiomyogenic phenotype in coculture (>37 000 EGFP(+) cells screened). CONCLUSIONS: These data suggest that the ability of cardiac-resident c-kit(+) cells to acquire a cardiomyogenic phenotype is subject to temporal limitations or, alternatively, that the cardiomyogenic population is lost. Elucidation of the underlying molecular basis may permit robust cardiomyogenic induction in adult-derived cardiac c-kit(+) cells.

Erythropoietin administration after myocardial infarction in mice attenuates ischemic cardiomyopathy associated with enhanced homing of bone marrow-derived progenitor cells via the CXCR-4/SDF-1 axis.

Mobilization of bone marrow-derived stem cells (BMCs) was shown to have protective effects after myocardial infarction (MI). However, the classical mobilizing agent, granulocyte-colony stimulating factor (G-CSF) relapsed after revealing an impaired homing capacity. In the search for superior cytokines, erythropoietin (EPO) appears to be a promising agent. Therefore, we analyzed in a murine model of surgically induced MI the influence of EPO treatment on survival and functional parameters as well as BMC mobilization, homing, and effect on resident cardiac stem cells (CSCs). Human EPO was injected intraperitoneally after ligation of the left anterior descendens (LAD) for 3 days with a total dose of 5000 IU/kg 6 and 30 days after MI, and pressure volume relationships were investigated in vivo. Cardiac tissues were analyzed by histology. To show the effect on BMCs and CSCs, FACS analyses were performed. Homing factors were analyzed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and ELISA. EPO-treated animals showed a significant improvement of survival post-MI (62 vs. 36%). At days 6 and 30, all hemodynamic parameters associated with attenuated remodeling, enhanced neovascularization, and diminished apoptotic cells in the peri-infarct area were improved. BMC subpopulations (CD31(+), c-kit(+), and Sca-1(+) cells) were mobilized, and homing of Sca-1(+) and CXCR4(+) BMCs toward an SDF-1 gradient into the ischemic myocardium was enhanced. However, there was no beneficial effect on CSCs. We have shown that EPO application after MI shows cardioprotective effects. This may be explained by mobilization of BMCs, which are homing via the CXCR-4/SDF-1 axis. However, EPO has no beneficial effects on resident CSCs. Therefore, new treatment regimes using EPO together with other agents may combine complementary beneficial effects preventing ischemic cardiomyopathy.

ZMPSTE24 Is Associated with Elevated Inflammation and Progerin mRNA.

Lamins are important filaments forming the inner nuclear membrane. Lamin A is processed by zinc metalloproteinase (ZMPSTE24). Failure to cleave a truncated form of prelamin A-also called progerin-causes Hutchinson-Gilford progeria syndrome a well-known premature aging disease. Minor levels of progerin are readily expressed in the blood of healthy individuals due to alternative splicing. Previously, we found an association of increased progerin mRNA with overweight and chronic inflammation (hs-CRP). Here, we aimed to elucidate correlations of ZMPSTE24, lamin A/C and progerin with the inflammatory marker hs-CRP. In this retrospective, cross-sectional study we analyzed blood samples from 110 heart failure patients for quantitative mRNA expression of ZMPSTE24, lamin A/C, progerin and hs-CRP protein. Spearman correlations and linear regression analyses including adjustments for age, gender and ejection fraction showed a significant positive correlation of lnprogerin with lnZMPSTE24 (n = 110; r = 0.33; p = 0.0004) and lnlamin A/C (n = 110; r = 0.82, p < 0.0001), whereas no association was observed between lnlamin A/C and lnZMPSTE24 expression. Further analyses showed a significant positive correlation of lnhs-CRP with lnZMPSTE24 (n = 110; r = 0.21; p = 0.01) and lnlamin A/C (n = 110; r = 0.24; p = 0.03). We conclude that chronic inflammation is associated with increased expression of ZMPSTE24 and lamin A/C mRNA. Both markers also positively correlate with increased expression of the premature aging marker progerin which may be linked to cardiovascular aging.

Heart failure from ATTRwt amyloid cardiomyopathy is associated with poor prognosis.

AIMS: Amyloid cardiomyopathy is an underappreciated cause of morbidity and mortality. Recent evidence suggests that ATTR wild-type cardiomyopathy (ATTRwt-CM) is probably much more common than widely appreciated. So far, no data are available on comparison of mortality from ATTRwt-CM and other heart failure aetiologies. METHODS AND RESULTS: This was a retrospective, observational, cohort study of 2251 patients and their data collected prospectively from May 2000 to June 2018. Long-term mortality was the main outcome measure. Underlying cardiomyopathies were classified as amyloid CM (6.1%) [ATTRwt 3.0%; light-chain amyloidosis (AL) 3.1%], dilated CM (dCMP) (46.4%), ischaemic heart disease (IHD) (24.4%), hypertensive heart disease (HHD) (14.6%), hypertrophic CM (HCM) (5.1%), and valvular heart disease (VHD) (3.4%). Median duration of follow-up was 7.1 years (interquartile range 3.4-11.3). Five-year overall survival in the whole cohort was 80.1%. In multivariate analysis, individuals with amyloid CM were 3.74 times [95% confidence interval (CI) 2.72-5.14; P < 0.001] more likely to die of any reason than were individuals with dCMP. Mortality was higher in AL-CM compared with ATTRwt-CM [hazard ratio (HR) 2.88; 95% CI 1.48-5.58; P = 0.002]. Mortality rates in patients with ATTRwt-CM were higher than in patients with dCMP (HR 1.96; 95% CI 1.24-3.22; P = 0.007), HCM (HR 2.94; 95% CI 1.28-6.67; P = 0.011), HHD (HR 2.08; 95% CI 1.27-3.45; P = 0.004), VHD (HR 2.38; 95% CI 1.30-4.35; P = 0.005), or left ventricular ejection fraction ≥ 40% (HR 1.99; 95% CI 1.12-3.52; P = 0.018). CONCLUSIONS: Our study demonstrates that amyloid CM is independently associated with poor survival among patients with various causes of heart failure. ATTRwt-CM had a better long-term prognosis than did AL-CM, but was associated with higher mortality than were dCMP, HCM, HHD, VHD, and heart failure with preserved or mid-range ejection fraction.

Diagnosis and treatment of cardiac amyloidosis: an interdisciplinary consensus statement.

The prevalence and significance of cardiac amyloidosis have been considerably underestimated in the past; however, the number of patients diagnosed with cardiac amyloidosis has increased significantly recently due to growing awareness of the disease, improved diagnostic capabilities and demographic trends. Specific therapies that improve patient prognosis have become available for certain types of cardiac amyloidosis. Thus, the earliest possible referral of patients with suspicion of cardiac amyloidosis to an experienced center is crucial to ensure rapid diagnosis, early initiation of treatment, and structured patient care. This requires intensive collaboration across several disciplines, and between resident physicians and specialized centers. The aim of this consensus statement is to provide guidance for the rapid and efficient diagnosis and treatment of light-chain amyloidosis and transthyretin amyloidosis, which are the most common forms of cardiac amyloidosis.

Parathyroid hormone effectively induces mobilization of progenitor cells without depletion of bone marrow.

OBJECTIVE: Cytokine-mediated mobilization of hematopoietic stem cells has become an established method in the field of autologous and allogenic stem cell transplantation. Furthermore, it presents a new concept in tissue repair and regenerative medicine. In the present study, we explored the potency of parathyroid hormone (PTH) compared to granulocyte colony-stimulating factor (G-CSF) for mobilization of stem cells and its regenerative capacity on bone marrow. MATERIALS AND METHODS: Healthy mice were either treated with PTH, G-CSF, or saline. Laboratory parameters were analyzed using a hematological cell analyzer. Hematopoietic stem cells characterized by lin(-)/Sca-1(+)/c-kit(+), as well as subpopulations (CD31(+), c-kit(+), Sca-1(+), CXCR4(+)) of CD45(+)/CD34(+) and CD45(+)/CD34(-) cells were measured by flow cytometry. Immunohistology as well as fluorescein-activated cell sorting analyses were utilized to determine the composition and cell-cycle status of bone marrow cells. Serum levels of distinct cytokines (G-CSF, vascular endothelial growth factor [VEGF]) were determined by enzyme-linked immunosorbent assay. Further, circulating cells were measured after PTH treatment in combination with G-CSF or a G-CSF antibody. RESULTS: Stimulation with PTH showed a significant increase of all characterized subpopulations of bone marrow-derived progenitor cells (BMCs) in peripheral blood (1.5- to 9.8-fold) similar to G-CSF. In contrast to G-CSF, PTH treatment resulted in an enhanced cell proliferation with a constant level of lin(-)/Sca-1(+)/c-kit(+) cells and CD45(+)/CD34(+) subpopulations in bone marrow. Interestingly, PTH application was associated with increased serum levels of G-CSF (2.8-fold), whereas VEGF showed no significant changes. Blocking endogenous G-CSF with an antibody significantly reduced the number of circulating cells after PTH treatment. A combination of PTH and G-CSF showed slight additional effects compared to PTH or G-CSF alone. CONCLUSION: PTH induces mobilization of progenitor cells effectively, which can be related to an endogenous release of G-CSF. In contrast to G-CSF treatment, PTH does not result in a depletion of bone marrow, which may be mediated by an activation of PTH receptor on osteoblasts. The novel function of PTH on mobilization and regeneration of BMCs may pave the way for new therapeutic options in bone marrow and stem cell transplantation as well as in the field of ischemic disorders.

G-CSF treatment after myocardial infarction: impact on bone marrow-derived vs cardiac progenitor cells.

OBJECTIVE: Besides its classical function in the field of autologous and allogenic stem cell transplantation, granulocyte colony-stimulating factor (G-CSF) was shown to have protective effects after myocardial infarction (MI) by mobilization of bone marrow-derived progenitor cells (BMCs) and in addition by activation of multiple signaling pathways. In the present study, we focused on the impact of G-CSF on migration of BMCs and the impact on resident cardiac cells after MI. MATERIALS AND METHODS: Mice (C57BL/6J) were sublethally irradiated, and BM from green fluorescent protein (GFP)-transgenic mice was transplanted. Coronary artery ligation was performed 10 weeks later. G-CSF (100 microg/kg) was daily injected for 6 days. Subpopulations of enhanced GFP(+) cells in peripheral blood, bone marrow, and heart were characterized by flow cytometry. Growth factor expression in the heart was analyzed by quantitative real-time polymerase chain reaction. Perfusion was investigated in vivo by gated single photon emission computed tomography (SPECT). RESULTS: G-CSF-treated animals revealed a reduced migration of c-kit(+) and CXCR-4(+) BMCs associated with decreased expression levels of the corresponding growth factors, namely stem cell factor and stromal-derived factor-1 alpha in ischemic myocardium. In contrast, the number of resident cardiac Sca-1(+) cells was significantly increased. However, SPECT-perfusion showed no differences in infarct size between G-CSF-treated and control animals 6 days after MI. CONCLUSION: Our study shows that G-CSF treatment after MI reduces migration capacity of BMCs into ischemic tissue, but increases the number of resident cardiac cells. To optimize homing capacity a combination of G-CSF with other agents may optimize cytokine therapy after MI.