University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Exp Physiol. 2021 Mar;106(3):673-682. doi: 10.1113/EP089163. Epub 2021 Jan 19.
What is the central question of this study? Prior studies failed to address the role of sex in modifying the pathophysiology and response to therapy in heart failure with preserved ejection fraction (HFpEF), potentially introducing bias into translational findings. We aimed to explore sex differences in outcomes and sought to identify the underlying mechanisms in a well-established rat model of HFpEF. What is the main finding and its importance? Male rats with HFpEF exhibited worse survival compared with females and were at a higher risk for sudden death, attributable in part to QT prolongation, autonomic dysregulation and enhanced inflammation. These data might provide the basis for the development of sex-specific interventions in HFpEF targeting these abnormalities.
Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of heart failure, and sudden death is the leading cause of mortality. We aimed to explore sex differences in outcomes in rats with HFpEF and sought to identify the underlying mechanisms. Dahl salt-sensitive rats of either sex were randomized into high-salt diet (HS diet; 8% NaCl, n = 46, 50% female) or low-salt diet (LS diet; 0.3% NaCl; n = 24, 50% female) at 7 weeks of age. After 6 and 10 weeks of LS or HS diets, the ECG, heart rate variability, cytokines and echocardiographic parameters were measured. The animals were monitored daily for development of HFpEF and survival. Over 6 weeks of HS diet, rats developed significant hypertension and signs of HFpEF. Compared with female HS diet-fed rats, males exhibited more left ventricular dilatation, a longer QT interval, and worse autonomic tone, as assessed by heart rate variability and elevated inflammatory cytokines. Ten of 23 (46%) male rats died during follow-up, compared with two of 23 (9%) female rats (P = 0.01). There were four sudden deaths in males (with ventricular tachycardia documented in one rat), whereas the females died of heart failure. In conclusion, male rats with HFpEF exhibit worse survival compared with females and are at a higher risk for sudden death, attributable in part to QT prolongation, autonomic dysregulation and enhanced inflammation. These data might provide the basis for the development of sex-specific interventions in HFpEF targeting these abnormalities.
本研究的核心问题是什么？先前的研究未能阐明性别在修饰射血分数保留的心力衰竭（HFpEF）的病理生理学和对治疗的反应中的作用，这可能会给转化研究结果带来偏差。我们旨在探讨 HFpEF 结局中的性别差异，并试图在 HFpEF 的成熟大鼠模型中确定潜在机制。主要发现及其重要性是什么？与女性相比，HFpEF 的雄性大鼠的存活率更差，并且更有可能发生猝死，部分归因于 QT 延长、自主神经调节异常和炎症增强。这些数据可能为针对这些异常的 HFpEF 特定于性别的干预措施的发展提供基础。
射血分数保留的心力衰竭（HFpEF）占心力衰竭的 50%，猝死是死亡率的主要原因。我们旨在探讨 HFpEF 大鼠结局中的性别差异，并试图确定潜在机制。7 周龄时，将雌雄两性的达尔盐敏感大鼠随机分为高盐饮食（HS 饮食；8% NaCl，n=46，50%为女性）或低盐饮食（LS 饮食；0.3% NaCl，n=24，50%为女性）。LS 或 HS 饮食 6 周和 10 周后，测量心电图、心率变异性、细胞因子和超声心动图参数。每天监测动物 HFpEF 的发展和存活情况。在 HS 饮食 6 周内，大鼠出现明显的高血压和 HFpEF 迹象。与雌性 HS 饮食喂养的大鼠相比，雄性大鼠表现出更大的左心室扩张、更长的 QT 间期和更差的自主神经张力，这通过心率变异性和升高的炎症细胞因子来评估。在随访期间，23 只雄性大鼠中有 10 只（46%）死亡，而 23 只雌性大鼠中有 2 只（9%）死亡（P=0.01）。有 4 只雄性大鼠发生猝死（其中一只大鼠有室性心动过速记录），而雌性大鼠死于心力衰竭。总之，HFpEF 的雄性大鼠与雌性大鼠相比，存活率更差，并且更有可能发生猝死，部分归因于 QT 延长、自主神经调节异常和炎症增强。这些数据可能为针对这些异常的 HFpEF 特定于性别的干预措施的发展提供基础。
