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1.
J Mol Cell Cardiol ; 156: 7-19, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33766524

RESUMO

BACKGROUND: Heart failure (HF) is associated with highly significant morbidity, mortality, and health care costs. Despite the significant advances in therapies and prevention, HF remains associated with poor clinical outcomes. Understanding the contractile force and kinetic changes at the level of cardiac muscle during end-stage HF in consideration of underlying etiology would be beneficial in developing targeted therapies that can help improve cardiac performance. OBJECTIVE: Investigate the impact of the primary etiology of HF (ischemic or non-ischemic) on left ventricular (LV) human myocardium force and kinetics of contraction and relaxation under near-physiological conditions. METHODS AND RESULTS: Contractile and kinetic parameters were assessed in LV intact trabeculae isolated from control non-failing (NF; n = 58) and end-stage failing ischemic (FI; n = 16) and non-ischemic (FNI; n = 38) human myocardium under baseline conditions, length-dependent activation, frequency-dependent activation, and response to the ß-adrenergic stimulation. At baseline, there were no significant differences in contractile force between the three groups; however, kinetics were impaired in failing myocardium with significant slowing down of relaxation kinetics in FNI compared to NF myocardium. Length-dependent activation was preserved and virtually identical in all groups. Frequency-dependent activation was clearly seen in NF myocardium (positive force frequency relationship [FFR]), while significantly impaired in both FI and FNI myocardium (negative FFR). Likewise, ß-adrenergic regulation of contraction was significantly impaired in both HF groups. CONCLUSIONS: End-stage failing myocardium exhibited impaired kinetics under baseline conditions as well as with the three contractile regulatory mechanisms. The pattern of these kinetic impairments in relation to NF myocardium was mainly impacted by etiology with a marked slowing down of kinetics in FNI myocardium. These findings suggest that not only force development, but also kinetics should be considered as a therapeutic target for improving cardiac performance and thus treatment of HF.


Assuntos
Suscetibilidade a Doenças , Insuficiência Cardíaca Diastólica/etiologia , Insuficiência Cardíaca Diastólica/fisiopatologia , Miocárdio/metabolismo , Disfunção Ventricular Esquerda/complicações , Disfunção Ventricular Esquerda/metabolismo , Biomarcadores , Análise de Dados , Feminino , Insuficiência Cardíaca , Insuficiência Cardíaca Diastólica/diagnóstico , Insuficiência Cardíaca Diastólica/tratamento farmacológico , Testes de Função Cardíaca , Frequência Cardíaca , Humanos , Isoproterenol/farmacologia , Isoproterenol/uso terapêutico , Cinética , Masculino , Contração Miocárdica , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/tratamento farmacológico
2.
Hum Mol Genet ; 28(12): 2030-2045, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-30759207

RESUMO

Mineralocorticoid receptor (MR) drugs have been used clinically for decades to treat cardiovascular diseases. MR antagonists not only show preclinical efficacy for heart in Duchenne muscular dystrophy (DMD) models but also improve skeletal muscle force and muscle membrane integrity. The mechanisms of action of MR antagonists in skeletal muscles are entirely unknown. Since MR are present in many cell types in the muscle microenvironment, it is critical to define cell-intrinsic functions in each cell type to ultimately optimize antagonist efficacy for use in the widest variety of diseases. We generated a new conditional knockout of MR in myofibers and quantified cell-intrinsic mechanistic effects on functional and histological parameters in a DMD mouse model. Skeletal muscle MR deficiency led to improved respiratory muscle force generation and less deleterious fibrosis but did not reproduce MR antagonist efficacy on membrane susceptibility to induced damage. Surprisingly, acute application of MR antagonist to muscles led to improvements in membrane integrity after injury independent of myofiber MR. These data demonstrate that MR antagonists are efficacious to dystrophic skeletal muscles through both myofiber intrinsic effects on muscle force and downstream fibrosis and extrinsic functions on membrane stability. MR antagonists may therefore be applicable for treating more general muscle weakness and possibly other conditions that result from cell injuries.


Assuntos
Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Músculo Esquelético/patologia , Distrofia Muscular de Duchenne/patologia , Animais , Membrana Celular/efeitos dos fármacos , Membrana Celular/fisiologia , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Força Muscular/efeitos dos fármacos , Músculo Esquelético/imunologia , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/fisiopatologia , Receptores de Mineralocorticoides/genética , Receptores de Mineralocorticoides/metabolismo , Espironolactona/uso terapêutico
3.
J Mol Cell Cardiol ; 121: 81-93, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29981798

RESUMO

BACKGROUND: In patients with end-stage heart failure, the primary etiology often originates in the left ventricle, and eventually the contractile function of the right ventricle (RV) also becomes compromised. RV tissue-level deficits in contractile force and/or kinetics need quantification to understand involvement in ischemic and non-ischemic failing human myocardium. METHODS AND RESULTS: The human population suffering from heart failure is diverse, requiring many subjects to be studied in order to perform an adequately powered statistical analysis. From 2009-present we assessed live tissue-level contractile force and kinetics in isolated myocardial RV trabeculae from 44 non-failing and 41 failing human hearts. At 1 Hz stimulation rate (in vivo resting state) the developed active force was not different in non-failing compared to failing ischemic nor non-ischemic failing trabeculae. In sharp contrast, the kinetics of relaxation were significantly impacted by disease, with 50% relaxation time being significantly shorter in non-failing vs. non-ischemic failing, while the latter was still significantly shorter than ischemic failing. Gender did not significantly impact kinetics. Length-dependent activation was not impacted. Although baseline force was not impacted, contractile reserve was critically blunted. The force-frequency relation was positive in non-failing myocardium, but negative in both ischemic and non-ischemic myocardium, while the ß-adrenergic response to isoproterenol was depressed in both pathologies. CONCLUSIONS: Force development at resting heart rate is not impacted by cardiac pathology, but kinetics are impaired and the magnitude of the impairment depends on the underlying etiology. Focusing on restoration of myocardial kinetics will likely have greater therapeutic potential than targeting force of contraction.


Assuntos
Insuficiência Cardíaca/terapia , Ventrículos do Coração/fisiopatologia , Coração/fisiopatologia , Miocárdio/patologia , Adulto , Idoso , Animais , Feminino , Insuficiência Cardíaca/fisiopatologia , Transplante de Coração , Humanos , Masculino , Pessoa de Meia-Idade , Contração Miocárdica/fisiologia , Terapia de Relaxamento , Doadores de Tecidos
4.
Reprod Sci ; 31(10): 3016-3025, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39060750

RESUMO

Pregnant individuals with obesity (body mass index, BMI ≥ 30 kg/m2) are more likely to experience prolonged labor and have double the risk of cesarean compared with individuals with normal weight (BMI < 25 kg/m2). The aim of this study was to evaluate whether obesity in pregnancy is associated with reduced spontaneous and oxytocin-stimulated myometrial contractile activity using ex vivo preparations. We also assessed the relationship between maternal BMI and the expression of oxytocin (OXTR) and prostaglandin (FP) receptors in the myometrial tissue. We enrolled 73 individuals with a singleton gestation undergoing scheduled cesarean delivery at term in a prospective cohort study. This included 49 individuals with a pre-pregnancy BMI ≥ 30 kg/m2 and 24 with BMI < 25.0 kg/m2. After delivery, a small strip of myometrium was excised from the upper edge of the hysterotomy. Baseline spontaneous and oxytocin stimulated myometrial contractile activity was measured using ex vivo preparations. Additionally, expression of oxytocin and prostaglandin receptors from myometrial samples were compared using qRT-PCR and western blot techniques. Spontaneous and oxytocin-stimulated contraction frequency, duration, and force were not significantly different in myometrial samples from the obese and normal-weight individuals. Myometrial OXTR gene and protein expression was also similar in the two groups. While FP gene expression was lower in the myometrial samples from the obese group, protein expression did not differ. These data help to address an important knowledge gap related to the biological mechanisms underlying the association between maternal obesity and dysfunctional labor.


Assuntos
Índice de Massa Corporal , Miométrio , Ocitocina , Receptores de Ocitocina , Receptores de Prostaglandina , Contração Uterina , Feminino , Humanos , Gravidez , Contração Uterina/efeitos dos fármacos , Miométrio/metabolismo , Adulto , Receptores de Ocitocina/metabolismo , Receptores de Ocitocina/genética , Ocitocina/metabolismo , Receptores de Prostaglandina/metabolismo , Receptores de Prostaglandina/genética , Estudos Prospectivos , Obesidade/metabolismo , Obesidade/fisiopatologia
5.
Circ Heart Fail ; 16(3): e009871, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36695183

RESUMO

BACKGROUND: The left and right ventricles of the human heart differ in embryology, shape, thickness, and function. Ventricular dyssynchrony often occurs in cases of heart failure. Our objectives were to assess whether differences in contractile properties exist between the left and right ventricles and to evaluate signs of left/right ventricular mechanical synchrony in isolated healthy and diseased human myocardium. METHODS: Myocardial left and right ventricular trabeculae were dissected from nonfailing and end-stage failing human hearts. Baseline contractile force and contraction/relaxation kinetics of the left ventricle were compared to those of the right ventricle in the nonfailing group (n=41) and in the failing group (n=29). Correlation analysis was performed to assess the mechanical synchrony between left and right ventricular myocardium isolated from the same heart, in nonfailing (n=41) and failing hearts (n=29). RESULTS: The failing right ventricular myocardium showed significantly higher developed force (Fdev; P=0.001; d=0.98), prolonged time to peak (P<0.001; d=1.14), and higher rate of force development (P=0.002; d=0.89) and force decline (P=0.003; d=0.82) compared to corresponding left ventricular myocardium. In healthy myocardium, a strong positive relationship was present between the left and right ventricles in time to peak (r=0.58, P<0.001) and maximal kinetic rate of contraction (r=0.63, P<0.001). These coefficients were much weaker, often nearly absent, in failing myocardium. CONCLUSIONS: At the level of isolated cardiac trabeculae, contractile performance, specifically of contractile kinetics, is correlated in the nonfailing myocardium between the left and right ventricles' but this correlation is significantly weaker, or even absent, in end-stage heart failure, suggesting an interventricular mechanical dyssynchrony.


Assuntos
Insuficiência Cardíaca , Ventrículos do Coração , Humanos , Contração Miocárdica , Miocárdio , Coração
6.
J Am Heart Assoc ; 11(13): e025405, 2022 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-35730642

RESUMO

Background Because body mass index (BMI) is generally used clinically to define obesity and to estimate body adiposity, BMI likely is positively correlated with epicardial adipose tissue (EAT) level. Based on echocardiography, previous outcomes on this matter have varied from almost absent to rather strong correlations between BMI and EAT. The purpose of our study was to unambiguously examine EAT content and determine if correlations exist between EAT content and BMI, cause of heart failure, or contractile force. Methods and Results We qualitatively scored 150 human hearts ex vivo on EAT distribution. From each heart, multiple photographs of the heart were taken, and both atrial and ventricular adipose tissue levels were semiquantitatively scored. Main findings include a generally higher EAT content on nonfailing hearts compared with end-stage failing hearts (atrial adipose tissue level 5.70±0.13 vs. 5.00±0.12, P<0.001; ventricular adipose tissue level 5.14±0.16 vs. 4.57±0.12, P=0.0048). The results also suggest that EAT quantity is not strongly correlated with BMI in nonfailing (atrial adipose tissue level r=0.069, ventricular adipose tissue level r=0.14) or failing (atrial adipose tissue level r=-0.022, ventricular adipose tissue level r=0.051) hearts. Atrial EAT is closely correlated with ventricular EAT in both nonfailing (r=0.92, P<0.001) and failing (r=0.87, P<0.001) hearts. Conclusions EAT volume appears to be inversely proportional to severity of or length of time with heart failure based on our findings. Based on a lack of correlation with BMI, it is incorrect to assume high EAT volume given high body fat percentage.


Assuntos
Insuficiência Cardíaca , Miocárdio , Tecido Adiposo/diagnóstico por imagem , Insuficiência Cardíaca/diagnóstico por imagem , Ventrículos do Coração , Humanos , Obesidade/complicações , Pericárdio
7.
PLoS One ; 17(4): e0265731, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35404981

RESUMO

The relationship between hypothyroidism and the occurrence and progression of heart failure (HF) has had increased interest over the past years. The low T3 syndrome, a reduced T3 in the presence of normal thyroid stimulating hormone (TSH), and free T4 concentration, is a strong predictor of all-cause mortality in HF patients. Still, the impact of hypothyroidism on the contractile properties of failing human myocardium is unknown. Our study aimed to investigate that impact using ex-vivo assessment of force and kinetics of contraction/relaxation in left ventricular intact human myocardial muscle preparations. Trabeculae were dissected from non-failing (NF; n = 9), failing with no hypothyroidism (FNH; n = 9), and failing with hypothyroidism (FH; n = 9) hearts. Isolated muscle preparations were transferred into a custom-made setup where baseline conditions as well as the three main physiological modulators that regulate the contractile strength, length-dependent and frequency-dependent activation, as well as ß-adrenergic stimulation, were assessed under near-physiological conditions. Hypothyroidism did not show any additional significant impact on the contractile properties different from the recognized alterations usually detected in such parameters in any end-stage failing heart without thyroid dysfunction. Clinical information for FH patients in our study revealed they were all receiving levothyroxine. Absence of any difference between failing hearts with or without hypothyroidism, may possibly be due to the profound effects of the advanced stage of heart failure that concealed any changes between the groups. Still, we cannot exclude the possibility of differences that may have been present at earlier stages. The effects of THs supplementation such as levothyroxine on contractile force and kinetic parameters of failing human myocardium require further investigation to explore its full potential in improving cardiovascular performance and cardiovascular outcomes of HF associated with hypothyroidism.


Assuntos
Insuficiência Cardíaca , Hipotireoidismo , Cálcio/farmacologia , Humanos , Hipotireoidismo/complicações , Contração Miocárdica , Miocárdio , Tiroxina/farmacologia
9.
Front Physiol ; 11: 568909, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33101056

RESUMO

Duchenne muscular dystrophy (DMD) is an X-linked disorder caused by the lack of functional dystrophin protein. In muscular dystrophy preclinical research, it is pertinent to analyze the force of the muscles affected by the disease to assess pathology and potential effectiveness of therapeutic interventions. Although muscles function at sub-maximal levels in vivo, maximal tetanic contractions are most commonly used to assess and report muscle function in muscular dystrophy studies. At submaximal activation, the kinetics of contraction and relaxation are heavily impacted by the kinetics of the single twitch. However, maximal tetanic force is often the main, if not sole, outcome measured in most studies, while contractile kinetics are rarely reported. To investigate the effect of muscle disease on twitch contraction kinetics, isolated diaphragm and extensor digitorum longus (EDL) muscles of 10-, 20-week, "het" (dystrophin deficient and utrophin haplo-insufficient), and 52-week mdx (dystrophin deficient) mice were analyzed and compared to wild-type controls. We observed that twitch contractile kinetics are dependent on muscle type, age, and disease state. Specific findings include that diaphragm from wildtype mice has a greater time to 50% relaxation (RT50) than time to peak tension (TTP) compared to the het and mdx dystrophic models, where there is a similar TTP compared to RT50. Diaphragm twitch kinetics remain virtually unchanged with age, while the EDL from het and mdx mice initially has a greater RT50 than TTP, but the TTP increases with age. The difference between EDL contractile kinetics of dystrophic and wildtype mice is more prominent at young age. Differences in kinetics yielded greater statistical significance compared to previously published force measurements, thus, using kinetics as an outcome parameter could potentially allow for use of smaller experimental groups in future study designs. Although this study focused on DMD models, our findings may be applicable to other skeletal muscle conditions and diseases.

10.
ESC Heart Fail ; 7(6): 3983-3995, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32945624

RESUMO

AIMS: Duchenne muscular dystrophy (DMD) is an X-linked inherited disease due to dystrophin deficiency causing skeletal and cardiac muscle dysfunction. Affected patients lose ambulation by age 12 and usually die in the second to third decades of life from cardiac and respiratory failure. Symptomatic treatment includes the use of anti-inflammatory corticosteroids, which are associated with side effects including weight gain, osteoporosis, and increased risk of cardiovascular disease. Novel treatment options include blockade of the renin-angiotensin-aldosterone system, because angiotensin as well as aldosterone contribute to persistent inflammation and fibrosis, and aldosterone blockade represents an efficacious anti-fibrotic approach in cardiac failure. Recent preclinical findings enabled successful clinical testing of a combination of steroidal mineralocorticoid receptor antagonists (MRAs) and angiotensin converting enzyme inhibitors in DMD boys. The efficacy of MRAs alone on dystrophic skeletal muscle and heart has not been investigated. Here, we tested efficacy of the novel non-steroidal MRA finerenone as a monotherapy in a preclinical DMD model. METHODS AND RESULTS: The dystrophin-deficient, utrophin haploinsufficient mouse model of DMD was treated with finerenone and compared with untreated dystrophic and wild-type controls. Grip strength, electrocardiography, cardiac magnetic resonance imaging, muscle force measurements, histological quantification, and gene expression studies were performed. Finerenone treatment alone resulted in significant improvements in clinically relevant functional parameters in both skeletal muscle and heart. Normalized grip strength in rested dystrophic mice treated with finerenone (40.3 ± 1.0 mN/g) was significantly higher (P = 0.0182) compared with untreated dystrophic mice (35.2 ± 1.5 mN/g). Fatigued finerenone-treated dystrophic mice showed an even greater relative improvement (P = 0.0003) in normalized grip strength (37.5 ± 1.1 mN/g) compared with untreated mice (29.7 ± 1.1 mN/g). Finerenone treatment also led to significantly lower (P = 0.0075) susceptibility to limb muscle damage characteristic of DMD measured during a contraction-induced injury protocol. Normalized limb muscle force after five lengthening contractions resulted in retention of 71 ± 7% of baseline force in finerenone-treated compared with only 51 ± 4% in untreated dystrophic mice. Finerenone treatment also prevented significant reductions in myocardial strain rate (P = 0.0409), the earliest sign of DMD cardiomyopathy. Moreover, treatment with finerenone led to very specific cardiac gene expression changes in clock genes that might modify cardiac pathophysiology in this DMD model. CONCLUSIONS: Finerenone administered as a monotherapy is disease modifying for both skeletal muscle and heart in a preclinical DMD model. These findings support further evaluation of finerenone in DMD clinical trials.

11.
J Neuromuscul Dis ; 5(3): 295-306, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30010143

RESUMO

BACKGROUND: Mineralocorticoid receptor antagonists added to angiotensin converting enzyme inhibitors have shown preclinical efficacy for both skeletal and cardiac muscle outcomes in young sedentary dystrophin-deficient mdx mice also haploinsufficient for utrophin, a Duchenne muscular dystrophy (DMD) model. The mdx genotypic DMD model has mild pathology, making non-curative therapeutic effects difficult to distinguish at baseline. Since the cardiac benefit of mineralocorticoid receptor antagonists has been translated to DMD patients, it is important to optimize potential advantages for skeletal muscle by further defining efficacy parameters. OBJECTIVE: We aimed to test whether therapeutic effects of mineralocorticoid receptor antagonists added to angiotensin converting enzyme inhibitors are detectable using three different reported methods of exacerbating the mdx phenotype. METHODS: We tested treatment with lisinopril and the mineralocorticoid receptor antagonist spironolactone in: 10 week-old exercised, 1 year-old sedentary, and 5 month-old isoproterenol treated mdx mice and performed comprehensive functional and histological measurements. RESULTS: None of the protocols to exacerbate mdx phenotypes resulted in dramatically enhanced pathology and no significant benefit was observed with treatment. CONCLUSIONS: Since endogenous mineralocorticoid aldosterone production from immune cells in dystrophic muscle may explain antagonist efficacy, it is likely that these drugs work optimally during the narrow window of peak inflammation in mdx mice. Exercised and aged mdx mice do not display prolific damage and inflammation, likely explaining the absence of continued efficacy of these drugs. Since inflammation is more prevalent in DMD patients, the therapeutic window for mineralocorticoid receptor antagonists in patients may be longer.


Assuntos
Envelhecimento , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Distrofia Muscular de Duchenne/tratamento farmacológico , Condicionamento Físico Animal , Agonistas Adrenérgicos beta/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Modelos Animais de Doenças , Coração/efeitos dos fármacos , Inflamação/etiologia , Inflamação/patologia , Isoproterenol/farmacologia , Camundongos , Camundongos Endogâmicos mdx/genética , Força Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Distrofia Muscular de Duchenne/diagnóstico por imagem , Distrofia Muscular de Duchenne/patologia , Comportamento Sedentário , Espironolactona/uso terapêutico
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