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BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and acute myocardial infarction (AMI) have common pathological links. This study investigates the prognostic impact of NAFLD assessed as hepatic steatosis (HS) by computed tomography (CT) in AMI patients and explores the mechanistic role of NAFLD in cardiovascular (CV) events using coronary angioscopy (CAS). METHODS: We retrospectively examined 342 AMI patients who underwent CT followed by primary percutaneous coronary intervention (PCI) between January 2014 and December 2019. HS was defined as a hepatic to spleen attenuation ratio of <1.0 on CT scans. Major cardiac events (MCE) included cardiac death, non-fatal myocardial infarction, target-vessel revascularization, and target-lesion revascularization. RESULTS: HS was identified in 88 patients (26â¯%). Patients with HS were significantly younger, had a higher body mass index, and higher hemoglobin A1c, triglyceride, and malondialdehyde low-density lipoprotein levels (all pâ¯<â¯0.05). MCE occurred more frequently [27 (30.7â¯%) vs. 39 (15.4â¯%), pâ¯=â¯0.001] in the HS group than in the non-HS group. In the multivariate analysis, the presence of HS was an independent predictor of MCE after adjusting for metabolic risk factor and liver function markers. Among the 74 patients who underwent CAS for a median of 15â¯days after primary PCI, 51 (69â¯%) had intrastent thrombus, which was strongly associated with the presence of HS [18 (35â¯%) vs. 1 (4â¯%), pâ¯=â¯0.005]. CONCLUSIONS: AMI patients with NAFLD detected by CT often had CAS-derived intrastent thrombi and were at a high risk for CV events. Therefore, these patients should be carefully monitored.
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Infarto do Miocárdio , Hepatopatia Gordurosa não Alcoólica , Intervenção Coronária Percutânea , Humanos , Estudos Retrospectivos , Resultado do Tratamento , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/etiologia , TomografiaRESUMO
Objective Sodium-glucose co-transporter-2 inhibitors (SGLT2is), such as dapagliflozin, have a diuretic effect, and their early initiation to treat acute heart failure (AHF) may improve outcomes; however, the significance of the timing of starting dapagliflozin after hospital admission remains unclear. Methods We performed a post hoc analysis of a prospective, observational registry. Participants were divided into the early (E) group and late (L) group using the median time to the initiation of dapagliflozin (6 days) as the cut-off. We evaluated the relationship between the time to the initiation of dapagliflozin after hospital admission and patient characteristics and the length of the hospital stay. Patients Study subjects were 118 patients with AHF admitted between January 2021 and April 2022 who were started on dapagliflozin treatment (10 mg/day). Results Patients were divided into the E group (n=63) and L group (n=55). The HF severity as evaluated by the New York Heart Association class and the N-terminal pro-brain natriuretic peptide level was not significantly different between the groups. The time to the initiation of dapagliflozin and length of hospital stay showed a significant positive correlation (p<0.001, r=0.46). The hospital stay was significantly shorter in group E [median, 16.5 days; interquartile range (IQR): 13-22 days] than in group L (median, 22 days; IQR: 17-27 days; p=0.002). A multivariate logistic regression analysis showed that the early initiation of dapagliflozin was independently associated with a shorter hospital stay, even after multiple adjustments. Conclusion Early initiation of dapagliflozin after hospital admission is associated with a shorter hospital stay, suggesting it is a key factor for shortening hospital stays.
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Insuficiência Cardíaca , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Tempo de Internação , Estudos Prospectivos , Hospitalização , Insuficiência Cardíaca/complicações , Compostos Benzidrílicos/uso terapêutico , Compostos Benzidrílicos/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Hospitais , Volume SistólicoRESUMO
BACKGROUND: Chronological changes in ablation lesions after cryoballoon ablation (CBA) and hot balloon ablation (HBA) of atrial fibrillation (AF) remain unclear. METHODS: Of 90 patients who underwent initial balloon-based catheter ablation of AF and cardiac magnetic resonance imaging (cMRI) 3 months after ablation, data from 48 propensity score-matched patients (24 per group; 34 males; age 62±10 years) were analyzed. High-density pulmonary vein-left antrum (PV-LA) voltage mapping was performed after PV isolation, and low voltage areas around the PV ostia were defined as the total acute ablation lesion area (cm2). cMRI-derived dense fibrotic tissue localized around PVs was defined as the total chronic ablation lesion area (cm2). The percentage of total ablation lesion areas to total PV-LA surface area (%ablation lesion) was calculated during each phase, and %acute ablation lesion and %chronic ablation lesion areas were compared in patients who had undergone CBA and HBA. RESULTS: The %acute ablation lesion area was larger for the CBA group than for the HBA group (30.8±5.8% vs. 23.0±5.5%, p < 0.001). There was no difference in %chronic cMRI-derived ablation lesion area (24.8±10.8% vs. 21.1±11.6%, p = 0.26) between groups. The rates of chronic AF recurrence were 12.5% and 8.3%, respectively (p = 0.45; log-rank test). LA volume and LA surface area were strongly associated with AF recurrence, but %chronic ablation lesion area was not (27±8% vs. 23±12%, p = 0.39). CONCLUSION: Large acute ablation lesions after CBA were smaller during the chronic phase. The size of chronic ablation lesions and the rate of AF recurrence were both similar for CBA and HBA.
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Fibrilação Atrial , Ablação por Cateter , Criocirurgia , Masculino , Humanos , Pessoa de Meia-Idade , Idoso , Criocirurgia/métodos , Resultado do Tratamento , Frequência Cardíaca , Imageamento por Ressonância Magnética/métodos , Ablação por Cateter/métodos , RecidivaRESUMO
Background: The possibility of permanent cardiovascular damage causing cardiovascular long COVID has been suggested; however, data are insufficient. This study investigated the prevalence of cardiovascular disorders, particularly in patients with cardiovascular long COVID using multi-modality imaging. Methods: A total of 584 patients admitted to the hospital due to COVID-19 between January 2020 and September 2021 were initially considered. Upon outpatient follow-up, 52 (9%) were suspected to have cardiovascular long COVID, had complaints of chest pain, dyspnea, or palpitations, and were finally enrolled in this study. This study is registered with the Japanese University Hospital Medical Information Network (UMIN 000047978). Results: Of 52 patients with long COVID who were followed up in the outpatient clinic for cardiovascular symptoms, cardiovascular disorders were present in 27% (14/52). Among them, 15% (8/52) had myocardial injury, 8% (4/52) pulmonary embolisms, and 4% (2/52) both. The incidence of a severe condition (36% [5/14] vs. 8% [3/38], p = 0.014) and in-hospital cardiac events (71% [10/14] vs. 24% [9/38], p = 0.002) was significantly higher in patients with cardiovascular disorders than in those without. A multivariate logistic regression analysis revealed that a severe condition (OR, 5.789; 95% CI 1.442-45.220; p = 0.017) and in-hospital cardiac events (OR, 8.079; 95% CI 1.306-25.657; p = 0.021) were independent risk factors of cardiovascular disorders in cardiovascular long COVID patients. Conclusions: Suspicion of cardiovascular involvement in patients with cardiovascular long COVID in this study was approximately 30%. A severe condition during hospitalization and in-hospital cardiac events were risk factors of a cardiovascular sequalae in CV long COVID patients.
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We report an autopsy case of a 69-year-old female with cervical cancer. She was given bevacizumab-containing chemotherapy for 4 months. After two years of chemotherapy, she developed congestive heart failure (CHF) with left ventricular dysfunction. Cardiac magnetic resonance (CMR) imaging revealed late gadolinium enhancement (LGE) of linear mid-wall delayed enhancement located in the basal to the mid-septal wall, suggesting bevacizumab-related cardiotoxicity. Although she was treated with cardioprotective medications and discharged, she eventually died from worsening CHF a year later, and we conducted an autopsy. Histopathological examination revealed diffuse fibrosis in the myocardium, and the area where LGE was present on CMR showed thinning and wavy changes in cardiomyocytes with diffuse interstitial fibrosis and edema.
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BACKGROUND: The clinical efficacy of the Impella for high-risk percutaneous coronary intervention (PCI) and cardiogenic shock remains under debate. We thus sought to investigate the protective effects on the heart with the Impella's early use pre-PCI using cardiac magnetic resonance imaging (CMRI). METHODS: We retrospectively evaluated the difference in the subacute phase CMR imaging results (19 ± 9 days after admission) between patients undergoing an Impella (n = 7) or not (non-Impella group: n = 18 [12 intra-aortic balloon pumps (1 plus veno-arterial extracorporeal membrane oxygenation) and 6 no mechanical circulation systems]) in broad anterior ST-elevation myocardial infarction (STEMI) cases. A mechanical circulation system was implanted pre-PCI. RESULTS: No differences were found in the door-to-balloon time, peak creatine kinase, and hospital admission days between the Impella and non-Impella groups; however, the CMRI-derived left ventricular ejection fraction was significantly greater (45 ± 13% vs. 34 ± 7.6%, P = 0.034) and end-diastolic and systolic volumes smaller in the Impella group (149 ± 29 vs. 187 ± 41 mL, P = 0.006: 80 ± 29 vs. 121 ± 40 mL, P = 0.012). Although the global longitudinal peak strain did not differ, the global radial (GRS) and circumferential peak strain (GCS) were significantly higher in the IMPELLA than non-IMPELLA group. Greater systolic and diastolic strain rates (SRs) in the Impella than non-Impella group were observed in non-infarcted rather than infarcted areas. CONCLUSIONS: Early implantation of an Impella before PCIs for STEMIs sub-acutely prevented cardiac dysfunction through preserving the GRS, GCS, and systolic and diastolic SRs in the remote myocardium. This study provided mechanistic insight into understanding the usefulness of the Impella to prevent future heart failure.
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Infarto Miocárdico de Parede Anterior , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Infarto Miocárdico de Parede Anterior/complicações , Infarto Miocárdico de Parede Anterior/diagnóstico por imagem , Infarto Miocárdico de Parede Anterior/terapia , Humanos , Imageamento por Ressonância Magnética , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/métodos , Estudos Retrospectivos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Choque Cardiogênico/diagnóstico por imagem , Choque Cardiogênico/etiologia , Volume Sistólico , Função Ventricular EsquerdaRESUMO
A few studies have reported on recurrent myocarditis occurring more than twice in one patient. In this study, we present a recurrent "third time" acute myocarditis in a young female Japanese patient with a history of a definitive diagnosis of lymphocytic myocarditis by endomyocardial biopsy, cardiac magnetic resonance imaging (CMR), and catheter examination twice in the past. Although chest pain and an increase in the cardiac enzymes were observed the third time, no significant changes were noted in the 12-lead electrocardiogram (ECG), and a definitive diagnosis could be achieved by CMR. This case suggested that in patients with a history of myocarditis, if there is chest pain and elevated cardiac enzymes even without any changes in the 12-lead ECG, acute myocarditis should be considered, and CMR is useful for the differentiation.Only four case reports including this present case were found through the previous literatures. More than two recurrent episodes of myocarditis have been extremely rare, but all cases have typical chest symptoms and a troponin level increase, leading to a relatively benign prognosis.
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Imagem Cinética por Ressonância Magnética , Miocardite/diagnóstico , Dor no Peito/etiologia , Eletrocardiografia , Feminino , Humanos , Recidiva , Adulto JovemRESUMO
Atrial fibrillation (AF) is a progressive disease that starts with structural or functional changes in the left atrium and left ventricle, and evolves from paroxysmal toward sustained forms. Early detection of structural or functional changes in the left atrium and left ventricle in the paroxysmal stage could be useful for identifying a higher risk of progression to persistent AF and future cardio-cerebrovascular events. The aim of this study was to test the hypothesis that the feature tracking (FT) left atrial (LA) strain and left ventricular (LV) extracellular volume fraction (ECV) derived from cardiovascular magnetic resonance (CMR) could detect early changes in remodeling of the left atrium and ventricle in the paroxysmal AF (PAF) stage. The participants were comprised of 106 PAF patients (age, 66.1 ± 10.7 years; 66% male) who underwent clinical CMR before pulmonary vein isolation and 20 control subjects (age, 68.3 ± 8.6 years; 55% male). The CMR-FT LA strain/phasic function and LV-ECV were compared between the PAF and control groups. The total and passive LA empty fraction (LAEF) and LA strain (corresponding to LA reservoir and conduit function) were decreased in the PAF group as compared to the control group. However, active LAEF (corresponding to the LA booster pump function) did not differ significantly between the PAF group (33.9 ± 10.9%) and control group (37.9 ± 13.3%, p = 0.15), while the active LA strain (corresponding to the LA booster pump function) was significantly decreased in the PAF group (11.4 ± 4.3 vs. 15.2 ± 5.6%, p = 0.002). The LV-ECV was significantly greater in the PAF group (28.7 ± 2.8%) than control group (26.6 ± 2.0%, p = 0.002). In the PAF group, the LV-ECV correlated significantly with the E/e' and LA volume index. Regarding the LA strain, correlations were seen between the LV-ECV and both the reservoir function and conduit function. CMR-FT LA strain in combination with the LV-ECV in a single clinical study offers a potential imaging marker that identifies LA/LV remodeling including subtle LA booster pump dysfunction undetectable by the conventional booster pump LAEF in the PAF stage.
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Fibrilação Atrial/patologia , Átrios do Coração/patologia , Remodelação Ventricular , Idoso , Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/fisiopatologia , Função do Átrio Esquerdo , Feminino , Átrios do Coração/diagnóstico por imagem , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Extent of myocardial fibrosis in hemodialysis patients has been associated with poor prognosis. Myocardial extracellular volume (ECV) quantification using contrast enhanced cardiac computed tomography (CT) is a novel method to determine extent of myocardial fibrosis. Cardiac CT-based myocardial ECV in hemodialysis patients with those of propensity-matched non-hemodialysis control subjects were compared. Twenty hemodialysis patients (mean age, 67.4 ± 9.6 years; 80% male) and 20 propensity-matched non-hemodialysis controls (mean age, 66.3 ± 9.1 years; 85% male) who underwent comprehensive cardiac CT consisted of calcium scoring, coronary CT angiography, stress perfusion CT and delayed enhancement CT were evaluated. Myocardial ECV was significantly greater in the hemodialysis group than in the control group (33.8 ± 4.7% versus 26.6 ± 2.9%; P < 0.0001). In the hemodialysis group, modest correlation was evident between myocardial ECV and left atrial volume index (r = 0.54; P = 0.01), while there was no correlation between myocardial ECV and other cardiac parameters including left ventricular mass index and severity of myocardial ischemia. Cardiac CT-based myocardial ECV may offer a potential imaging biomarker for myocardial fibrosis in HD patients.
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Fibrose/patologia , Miocárdio/patologia , Idoso , Cálcio/metabolismo , Angiografia por Tomografia Computadorizada/métodos , Meios de Contraste/metabolismo , Angiografia Coronária/métodos , Feminino , Fibrose/metabolismo , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Humanos , Masculino , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patologia , Miocárdio/metabolismo , Pacientes , Diálise Renal/métodosAssuntos
Doença da Artéria Coronariana/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Imageamento por Ressonância Magnética , Infarto do Miocárdio/diagnóstico por imagem , Idoso , Angiografia Coronária , Doença da Artéria Coronariana/terapia , Eletrocardiografia , Feminino , Humanos , Infarto do Miocárdio/terapia , Intervenção Coronária Percutânea , Valor Preditivo dos Testes , TrombectomiaRESUMO
OBJECTIVES: This study aimed to evaluate whether myocardial blood flow (MBF) quantified with dynamic computed tomography perfusion imaging (CTP) has an incremental prognostic value over coronary CT angiography (CTA) for major adverse cardiac events (MACEs) in patients with suspected coronary artery disease (CAD). BACKGROUND: The incremental prognostic value of CTP over CTA is unclear. The quantification of MBF with dynamic CTP may potentially enhance risk stratification. METHODS: A total of 332 patients (67% men; age: 67 ± 10 years) with suspected CAD who underwent CTA and dynamic CTP was analyzed. A MACE was defined as cardiac death, nonfatal myocardial infarction (MI), unstable angina, or hospitalization for congestive heart failure. A summed stress score (SSS) was calculated by adding scores of all myocardial segments according to normalized MBF values. Abnormal perfusion was defined as SSS ≥4. Obstructive CAD was defined as ≥50% stenosis in ≥1 vessel on CTA. RESULTS: During a median follow-up of 2.5 years, 19 patients had a MACE. Multivariate analysis showed that, when adjusted for obstructive CAD on CTA, abnormal perfusion was significantly associated with hazards for MACEs (hazard ratio [HR]: 5.7; 95% confidence interval [CI]: 1.9 to 16.9; p = 0.002), with a significant improvement in the prognostic value. Abnormal perfusion was an independent predictor even when adjusted for ≥70% stenosis in ≥1 vessel (HR: 5.4; 95% CI: 1.7 to 16.7; p = 0.003) or adjusted for ≥50% stenosis in ≥2 vessels (HR: 6.5; 95% CI: 2.2 to 18.9; p = 0.001). In the setting of obstructive CAD, annualized event rates showed a significant difference between the patients with and without abnormal perfusion for all events (12.2% vs. 1.5%; p = 0.002) and for cardiac death and nonfatal MI (4.2% vs. 0%; p = 0.015). CONCLUSIONS: MBF quantified with dynamic CTP has an incremental prognostic value over CTA. The addition of dynamic CTP to CTA allows improved risk stratification of patients with CTA-detected stenosis.
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Angiografia por Tomografia Computadorizada , Angiografia Coronária/métodos , Doença da Artéria Coronariana/diagnóstico por imagem , Estenose Coronária/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Imagem de Perfusão do Miocárdio/métodos , Idoso , Idoso de 80 Anos ou mais , Velocidade do Fluxo Sanguíneo , Doença da Artéria Coronariana/mortalidade , Doença da Artéria Coronariana/fisiopatologia , Circulação Coronária , Estenose Coronária/mortalidade , Estenose Coronária/fisiopatologia , Vasos Coronários/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de RiscoRESUMO
Delayed enhancement cardiac CT is a potential tool for myocardial viability assessment and is essential for extracellular volume fraction (ECV) estimation with CT. The objective of this study is to determine the optimal delay time for acquisition of delayed CT scans. Thirty-five patients with enhancement pattern typical of previous myocardial infarction on delayed CT and 17 control subjects comprised the study population. Delayed scans were acquired at 3, 5 and 7 min after contrast material injection. Image quality and estimated ECV were compared among the three time points. Delayed CT at 5 min showed the highest signal-to-noise ratio of 15.2 ± 1.0 [p < 0.0001; vs. 3 min (13.6 ± 1.0), p = 0.0015; vs. 7 min (14.9 ± 1.0)]. Contrast-to-noise ratio of infarcted and remote myocardium was highest at 7 min (6.4 ± 2.5), but was not significantly different from 5 min (6.1 ± 2.2, p = 0.08). The ECV values were constant over the three time points, although, in segments containing infarcted myocardium, trend of lower values was noted at 3 min compared to 5 and 7 min. ECV values at 5 min was 27.1% ± 2.1% in control subjects, 27.2% ± 3.0% in remote segments of patients with infarction, and 39.6% ± 5.3% in segments containing infarcted myocardium. Myocardial scars are equally best visualized with delay time of 5 and 7 min post contrast administration. No significant difference was observed in ECV of healthy myocardium or focal scars among delay time of 3, 5, and 7 min. Delay time of 5 min after contrast injection may be recommended for CT delayed enhancement imaging.
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Cicatriz/diagnóstico por imagem , Infarto do Miocárdio/diagnóstico por imagem , Miocárdio/patologia , Interpretação de Imagem Radiográfica Assistida por Computador/métodos , Tomografia Computadorizada por Raios X/métodos , Idoso , Estudos de Casos e Controles , Cicatriz/patologia , Meios de Contraste/administração & dosagem , Feminino , Humanos , Iopamidol/administração & dosagem , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/patologia , Valor Preditivo dos Testes , Fatores de Tempo , Sobrevivência de TecidosRESUMO
BACKGROUND: Recent studies using stress-rest perfusion cardiovascular magnetic resonance (CMR) demonstrated a close correlation between myocardial ischemia and reduced fractional flow reserve (FFR). However, its diagnostic concordance may be reduced in patients with multivessel disease. We sought to evaluate the concordance of adenosine stress-rest perfusion CMR for predicting reduced FFR, and to determine the additive value of measuring global coronary flow reserve (CFR) in the coronary sinus in multivessel disease. METHODS AND RESULTS: Ninety-six patients with angiographic luminal narrowing >50% underwent comprehensive CMR study and FFR measurements in 139 coronary vessels. FFR <0.80 was considered hemodynamically significant. Global CFR was quantified as the ratio of stress-rest coronary sinus flow measured by phase-contrast cine CMR. In 25 patients with single-vessel disease, visual assessment of perfusion CMR yielded high diagnostic concordance for predicting flow-limiting stenosis, with the area under receiver operating characteristic curve of 0.93 on a per-patient basis. However, in 71 patients with multivessel disease, perfusion CMR underestimated flow-limiting stenosis, resulting in the reduced area under receiver operating characteristic curve of 0.74. When CFR of <2.0 measured in the coronary sinus was considered as global myocardial ischemia, combined assessment provided correct reclassifications in 7 patients with false-negative myocardial ischemia, and improved the diagnostic concordance to 92% sensitivity and 73% specificity with the area under receiver operating characteristic curve of 0.88 (95% confidence interval, 0.80%-0.97%, P=0.002). CONCLUSIONS: Visual analysis of stress-rest perfusion CMR has limited concordance with FFR in patients with multivessel disease. Multiparametric CMR integrating stress-rest perfusion CMR and flow measurement in the coronary sinus is useful for detecting reduced FFR in multivessel disease.
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Adenosina/administração & dosagem , Cateterismo Cardíaco , Doença da Artéria Coronariana/diagnóstico por imagem , Seio Coronário/diagnóstico por imagem , Estenose Coronária/diagnóstico por imagem , Reserva Fracionada de Fluxo Miocárdico , Imagem Cinética por Ressonância Magnética , Imagem de Perfusão do Miocárdio/métodos , Vasodilatadores/administração & dosagem , Idoso , Velocidade do Fluxo Sanguíneo , Angiografia Coronária , Doença da Artéria Coronariana/fisiopatologia , Seio Coronário/fisiopatologia , Estenose Coronária/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
Alkali elements, specifically sodium (Na), are key materials to enhance the energy conversion efficiencies of chalcopyrite and related thin-film photovoltaic solar cells. Recently, the effect of potassium (K) has also attracted attention because elemental K has unique effects different from Na as well as a similar beneficial effect in improving device performance. In this study, the control of selective alkali K and Na diffusion into chalcopyrite thin-films from soda-lime glass substrates, which serve as the monolithic alkali source material and contain both K and Na, is demonstrated using ternary CuGaSe2. Elemental K is found to be incorporated in the several ten nanometer thick Cu-deficient region, which is formed on the CuGaSe2 film surface, while Na is ejected, although both K and Na diffuse from the substrate to the CuGaSe2 film surface during growth. The alkali [K]/[Na] concentration ratio in the surface region of CuGaSe2 films strongly depends on the film structure and can be controlled by growth parameters under the same substrate temperature conditions. The results we present here offer new concepts necessary to explore and develop emerging new chalcopyrite and related materials and optimize their applications.