Comprehensive Treatment of Angina in Women With Microvascular Dysfunction

Angina is the most common symptom of coronary heart disease among women but unlike men most women do not have stenosis of the coronary arteries. In a large proportion of these women, coronary microvascular dysfunction (CMD) is thought to be the cause of angina. However, CMD is also demonstrable in the asymptomatic population, and may merely be an innocent bystander related to the presence of cardiovascular risk factors rather than a cause of angina symptoms.

The aim of this study is to determine whether comprehensive intervention is feasible and results in improvement in both angina and microvascular function in these patients.

Coronary microvascular dysfunction is found to be associated with a significant adverse prognosis. The condition is strongly associated with increased future risk of major cardiovascular events, frequent hospital readmission, continued angina and loss of quality of life compared to the general population.

Pathophysiology of microvessel disease:

In the heart 95% of the blood flow is controlled by the microcirculation. When oxygen demand is increased the normal response of the microvessels is to reduce resistance in order to increase flow. When microvessels are dysfunctional the blood flow in the larger coronary vessels does not increase sufficiently to meet oxygen demand, thus leading to ischemia and pain. The main causes are thought to be dysfunction of endothelium and structural changes such as perivascular fibrosis and changes in vascular smooth muscle cells. In addition to vasodilation the endothelium plays a central role in the atherosclerotic process by generating vasoactive and anticoagulant factors that are important mediators of thrombosis. Coronary microvessel dysfunction (CMD) has been shown to be a strong predictor of poor cardiovascular prognosis in a wide group of cardiac patients.

Rationale for intervention:

In women with angina and no obstructive stenosis of the coronary vessels cardiovascular risk factors are common. Among 3000 Danish women with angina and open arteries, 12% had diabetes, 48% hypertension, 20% were smokers and the mean body mass index was 27 kg/m2. In a randomized trial among overweight patients with coronary artery disease both a large weight loss and intensive exercise training have shown to significantly improve coronary flow velocity reserve (CFVR). Small studies addressing risk factors individually suggest an effect on peripheral vascular function of exercise training, statin therapy, and weight loss. Pre-diabetes is found in eighty percent of these patients and is strongly associated to microvessel disease. Lifestyle intervention significantly reduces risk of developing diabetes. Medical treatment targeting microvessel dysfunction in patients with angina has not been systematically tested but small studies indicate an effect of beta-blockers and Angiotensin Converting Enzyme (ACE)-inhibition on coronary microvessel function. Small studies indicate effect of individual interventions but mainly on the function of peripheral vessels. A comprehensive intervention simultaneously targeting CMD and angina has not previously been attempted.

The rationale for this present intervention is to test this concept in women with angina and CMD.The study is a pilot study which, if successful, will be expanded to a multicentre, intervention trial with prognostic outcome. A large study showing improved prognosis is of crucial importance for treatment of this patient group to become part of guidelines.

Eligibility Criteria:
Inclusion Criteria:

Patients will be recruited and included from the ongoing iPower study.(the acronym iPower stands for: improving diagnosis and treatment of women with angina pectoris and microvascular disease)

* Female gender
* 40-75 years of age
* Referred to a cardiac centre for assessment with coronary angiography due to chest pain or other signs of ischemia leaving out ST-segment elevation myocardial Infarction (STEMI) or NSTEMI patients (elevated enzymes, electrocardiographic (ECG) changes/no ECG changes)
* No significant stenotic lesions at the following coronary angiography defined as \> 50% stenosis of epicardial vessels. Patients are included within 1 year after coronary angiography.

  * Angina with a symptom burden of symptoms \> monthly
  * Impaired coronary microvascular function, defined as a Transthoracic Doppler Echocardiography measured CFVR \< 2.5 with a good quality (quality index \> 3)
  * BMI \> 26 or BMI \>= 25 combined with a waist hip ratio of \>=0.8
  * Informed consent

Exclusion Criteria:

* Previously verified myocardial infarction, verified in medical records: ST-elevation myocardial infarction, elevated coronary markers or Non ST-elevation myocardial infarction
* Previous percutaneous coronary intervention or coronary artery bypass graft.
* Left ventricular ejection fraction (LVEF) \< 45% assessed by echocardiography within 6 months before inclusion
* Any allergies to the content of the low energy diet (gluten/nuts), allergy to dipyridamole, adenosine, or theophyllamine
* Significant valvular heart disease
* Congenital heart disease
* Severe asthma
* Severe chronic obstructive pulmonary disease (COPD): forced expiratory volume in 1st second (FEV1) \< 50% of predicted (age, height, ethnicity)
* Severe comorbidity with limited life-expectancy \< 1 year
* Chest pain with a strongly suspected non-ischemic etiology (e.g. pericarditis, pneumonia)
* Pregnancy
* Active cancer
* Renal (eGFR \< 30) or severe hepatic comorbidity
* Chronic alcohol abuse
* Atrial flutter or fibrillation
* Atrioventricular block \> 1st degree
* Diabetes Mellitus type II patients in treatment with Sulphonylureas
* Participation in other trials if relevant for the present study
* Language- or other barrier to giving informed consent
* Physical or mental disabilities contraindicating or hampering diet or exercise training
* Travel distance to research hospital requiring more than 3 hours of travel, making it difficult for the patient to participate

Withdrawal criteria

* Sudden unexpected serious adverse reaction or sustained side effects
* Poor compliance will lead to withdrawal from the study at the mentioned time points: Low energy diet: No weight loss within the first 3 weeks of the intervention period. Medication: \< 80% of the prescribed medicine taken within the first 3 weeks. Training: \< 50% attendance to training sessions/home training within the first 5 weeks.