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FRIMEDBIO-Fri prosj.st. med.,helse,biol

Sex-differences in cardiac hypertrophy in pressure overload - link to heart failure with preserved ejection fraction

Awarded: NOK 3.4 mill.

Project Manager:

Project Number:

214386

Application Type:

Project Period:

2012 - 2016

Partner countries:

The Female Heart project uses a translational approach to identify ultrasound indicators of molecular and cellular changes in rodents and humans with hypertension associated with progression from compensated hypertensive heart disease to heart failure. The Project has organized annual seminars and a final workshop to provide good opportunities for networking between junior and senior researchers from the participating groups and invited expert guest lecturers in the field from Charles I University in Prague and Charite University in Berlin. Results from experimental studies in rodents and clinical studies were presented and discussed. Gene expression analyses in the first experimental study in Dahl salt sensitive rats demonstrated that males develop more reduction in myocardial contractility during chronic pressure hypertension, despite females developing the highest blood pressure on salt enriched diet. No sex difference in myocardial collagen content was found. The ultrasound images from the first Dahl SS rodent study showed no heart failure development, but compensatory cardiac hypertrophy. The blood pressure rose more in the oophorectomized rats, and the myocardial gene expression differed according to ovarial status. Preliminary data from the second rodent study focusing on influence of diet induced obesity on cardiac response using the same pressure overload model was presented. This study will be completed after the end of the Project period. Results from the clinical studies in the project have demonstrated that 1) hypertensive patients with isolated systolic hypertension have less reduction in cardiac hypertrophy and therefore cardiac benefit of antihypertensive treatment. This was primarily found in women. 2) In obese subjects, the blood pressure rise during fitness testing on treadmill is an indicator for masked hypertension, even if blood pressure is normal when measured in the doctor's office. Other results included a comparison of aortic valve stenosis progression in women and men. The progression rate was similar in both sexes, but women had lower cardiovascular morbidity and mortality during follow up, despite more women having hypertension. Of note, compared to the difference in cardiovascular disease in general population, the observed sex difference in cardiovascular event rate in the project was much less. Furthermore, results from echocardiographic studies in African patients with diabetes and hypertension were presented, and also how obesity influences cardiac function in a number of different heart diseases, irrespective of if hypertension is present. The international network developed through the FemaleHeart Project also led to publication of a joint position paper on challenges and knowledge gaps related to heart disease in women. Finally, knowledge gained from the overall Project was also utilized in writing of the book Kvinnehjerter, published 2015.

We have previously demonstrated sex-differences in cardiac hypertrophy and function in patients with chronic pressure overload using echocardiography. In particular, hypertensive women had higher prevalence of left ventricular hypertrophy, more concentri c left ventricular geometry and higher systolic function. Women also had less reduction in hypertrophy during antihypertensive treatment. In spite of this, women retained higher left ventricular systolic function independent of left ventricular geometry a nd left ventricular size. Hypertension is the most common cause of congestive heart failure in women, independent of coronary heart disease. Typically congestive heart failure in these women occurs in spite of a normal left ventricular ejection fraction, a condition referred to as Heart Failure with Preserved Ejection Fraction. The underlying molecular and cellular processes explaining these sex-differences in left ventricular structure and function in hypertension and its implication for heart failure ph enotype are still incompletely understood. Recent microarray studies in mice wirh increased left ventricular wall stress following aortic banding found a significant gender dependent difference in gene expression. In particular male hearts showed more mar ked expression of fibrosis related genes. These studies suggest that sex is important for molecular and cellular function when pathological hypertrophy develops. Furthermore, the age dependency of hypertensive heart failure suggest that decline in estroge n production following menopause may play a role. Furthermore, the modification of these mechanisms by obesity or type 2 diabetes, the most common clinical comorbidities, must be determined. The aim of this translational project is to identify new echocar diographic variables or patterns reflecting the underlying molecular and cellular mechanisms that explain the observed sex-differences in cardiac phenotype during chronic pressure overload.

Funding scheme:

FRIMEDBIO-Fri prosj.st. med.,helse,biol

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