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Off topic: CVD: the primary cause of death in senior women, is increasing – Nov 2012

Changing Long-Held Beliefs is Never Easy:

A Proposal for Multimodal Approaches in Female Healthcare - An Integrative View

The EPMA Journal 2012, 3:14 http://www.epmajournal.eom/content/3/14
Olga Golubnitschaja, Secretary-General of EPMA, and Vincenzo Costigliola, President of EPMA
  {EPMA = European Association for Predictive, Preventive and Personalised Medicine.}

Worldwide cardiovascular disease (CVD) is the leading cause of mortality in women: cardiovascular health in females is not improving as fast as that of males

Worldwide a third of all deaths of women and half of all deaths of women over 50 years old in developing countries are caused by CVD [1]. Several studies have been recently dedicated to the question of CVD-related death with particular focus on gender-dependent aspects. Although CVD is traditionally considered as the major health burden of male subpopulations surprising statistics have been collected for worsening the situation in females. New trends obviously demonstrate a shifting of the problem into healthcare of female populations: from 25 countries selected by World Health Organisation in the years 1990-2000, more than a half (15 countries, 60%) currently demonstrate either increase in CVD-related death in females or, even if the rates are decreased then less compared to men [2]:

  • Ukraine 63%
  • Kazakhstan 58%
  • Belarus 48 %
  • Russian Federation 33%
  • Romania 20%
  • Japan 13%
  • Mexico 2%

{ That is, male CVD death declined, but female death did not decline as much}
Norway 17% less
Germany 4% less
Hungary 4% less
Luxemburg 4% less
USA 4% less
Italy 2% less
Portugal 2% less
Armenia 1% less


Taking into consideration that from altogether 25 selected countries only 10 countries demonstrate a decrease in CVD-related death rates in women compared to men, the situation is rather worsening for female cardiovascular healthcare or - if improving then not as effectively as for males. These facts should be accepted as highly alarming for the acute reconsideration of current strategies in female cardiovascular healthcare.

Evidence-based publications indicating significant gender-related differences in CVD diagnosis, manifestation and treatments as well as particular problems shifted to the female subpopulations appeared quite recently [3-5]. Delayed recognition of the mounting problems creates a consequent delay in covering multifaceted knowledge deficits accumulated in CVD-related female healthcare which societies around the world are currently facing. Consequently there is an urgent need to elaborate the targeted measures forcing the improvement.

The logic steps might be proposed as follows:

1 identify single lacks and gaps that altogether have resulted in current unsatisfactory situation;
2 analyse rapidly worsening versus improving regional healthcare situations and identify the most specific particularities of both;
3 elaborate effective strategies for covering the recognised deficits at all levels of stakeholders that should be obligatory involved in the process of reorganisation including applicative science, social, economical and political levels;
4 consider to force the practical implementation of innovative approaches in predictive diagnostics and targeted prevention that are rapidly developing in pre-clinical trials;
5 create / readdress sufficient budgets for educational measures, training purposes and staffing the experts essentially involved in the field.


For the concrete recommendations, several crucial aspects should be properly addressed by well funded analytical studies. The most relevant aspects for their detailed analysis are summarised below.

Worldwide the leading cause of admission to hospital is CVD with consequent impacts for healthcare costs. Therefore, a precise analysis of demographic statistics is very important for the economy of CVD healthcare to cover potential deficits. Current reports [1, 6] indicate that women diagnosed with CVD suffer from

  • higher levels of discomfort
  • higher and longer pain attacks
  • significantly more of the consequent activity restrictions
  • longer disability
  • longer hospital stays

In this context it is becomes clear, why women have been reported to consume more hospital resources than men [7]. Those statistics have been collected for CVD in general but, the particular significance is reported for diagnosed atrial fibrillation, heart failure and acute myocardial infarction [7-11]. Hence, the American National Hospital Discharge Survey reports stable rates of hospital admission for men versus permanently increasing ones for the age-matched women with diagnosed heart failure [10]: the female gender-specific increase comprises about 19% in North America since 1990. Further, high risk of stroke as the secondary complication is the gender particularity acknowledged in women diagnosed with atrial fibrillation, in contrast to non of the predisposition as observed in men [8].


Consequent negative impacts of the above listed risk factors should be considered as abusing the economy of healthcare and social systems, which the contributing female fellows in active age are involved in.

"Atypical symptoms" or inadequate diagnostic approaches in females?

Just simply using a logic thinking, one can expect significant gender dependent differences in predisposition to, risk factors for and symptoms of cardiovascular disease, when anatomic, physiologic, biochemical and psychological characteristics of men and women are compared.

Deeper insights into cardiovascular-relevant gender particularities provide further strong argumentation for strictly different predisposition, manifestation and prognosis as well as targeted preventive measures and appropriate treatment modalities for both sexes. Briefly summarised female particularities are as follows:

  • Sex hormones are decisive for the sort of CVD and period of life, as well as gender-specific disease manifestation;
  • High prevalence of gender specific vascular dys-regulation is also known as "vasospastic syndrome" (VS): in premenopausal women, the prevalence can be 30% and higher, whereby VS is more characteristic for intellectual professionals. Psychosocial gender particularities, such as emotional stress, starvation to reach an extremely slim stature, etc., are strong contributors to VS worsening inadequate vaso-constriction in females. Untreated VS may predispose to a spectrum of severe CVD-related complications manifested later in life [12]. Despite high prevalence and potentially tremendous impacts for women health/care, VS has not been systematically investigated through large-scale scientific projects;
  • There is a gender specific menopausal stress of or even damage to cardiovascular system followed by post-menopausal predisposition to ageing-related CVD that is significantly higher in women compared to age-adjusted men: female hormone-related protective anti-ageing mechanisms are lost in menopause;
  • Gender specific smaller vessel lumens is the strongly contributing risk factor for poorer outcomes under both ageing-related and -unrelated ischaemic conditions as well as under invasive treatments applied to cardiovascular system in women.

Consequently, the majority of studies, e.g. dedicated to acute coronary syndrome report "atypical symptoms" in women by diagnostic procedure standardised for male patients [13-18].


There is clear evidence for urgent necessity in gender-dependent diagnostic profiles. Those profiles can be created by systematic biomedical studies considering the role of all contributing factors.

Current CVD diagnostics is elaborated for men but not for women

Despite the above listed argumentation, the symptomatology of CVD elaborates the manifestation models and patient questionnaires traditionally tailored to men as the main carriers of CVD. The absolute majority of large-scale studies dedicated to CVD symptoms include women as one tenth till maximum one quarter portion of the whole patient collective that makes any female-related particularity to non-significant variable [19]. Hence, potentially important prodromal or acute symptoms relevant for female-specific manifestation are not considered at all. Consequently, using currently practised templates, women are highly restricted in a choice defining their real CVD-related problems [13].


This leads to inaccurate description of female-specific symptoms in general and individual ones in particular -the reason, why current preventive measures are un-tailored to women, CVD manifestation is rather unexpected and frequently remains undiagnosed at early stages in female patients.

Women experience delayed care in the case of CVD emergency: Lack of knowledge or long-held beliefs to be changed?

The above given facts partially explain statistics registered worldwide [20-28] demonstrating that in the case of CVD emergency and compared to male CVD patients, women experience

  • later hospitalisation after symptom onset of acute CVD
  • longer period of time before the treatment initiation, if any provided
  • less likely intensive care settings
  • illegibility for usual therapies, due to co-morbid disorders more frequent in female CVD patients
  • less likely or delayed application of reperfusion therapy. The performed socio-demographic studies have concluded the risk factors for delayed CVD-related hospital admission as follows: female gender, older age, ethnic minorities, low income, low education level and living alone [29]. Thereby, the female gender risks carry either 1. psychological or 2. educational and/or 3. physiological character:

1. by the psychological barrier for troubling others
2. by lack of knowledge to recognise an acute emergency, e.g. in the case of heart attack
3. by physiologically higher pain threshold compared to men [30].


These risk factors should be obligatory taken in consideration to improve individual outcomes.

Women with acute myocardial infarction have higher rates of mortality than men of the same age: female-specific complications or untailored treatment approaches?

Theoretically, due to physiologically higher pain threshold compared to men, the rate of undiagnosed acute myocardial infarction and unrecognised silent infarcts is much higher in female patients [30, 31]. However, practically there are several factors contributing to higher rates of mortality of women with acute myocardial infarction. Among them are "atypical symptoms", inaccurate diagnostic approaches, untailored and delayed treatments, as summarised above. Data collected in several studies are consistent demonstrating early mortality (4-6 weeks) after acute myocardial infarction to be approximately double as high in female as in male patients [32-41]. Moreover, women below 50 years of age are of particular high risk of death related to acute myocardial infarction [1]. Thereby, in-hospital mortality was significantly higher in women across all age groups [41]. This is clear evidence for untailored treatments currently applied to female patients with acute myocardial infarction, rather than older age frequently used as the main argument to excuse higher mortality in females.


Well funded studies are essential to be carried out covering evident knowledge deficits in treatments tailored to gender-specific profiles of patients with acute myocardial infarction. There is an urgent need in creation of multi-drug cocktails considering greater burden of co-morbid diseases in women with acute myocardial infarction.

Vascular complications remain more prevalent in women undergoing coronary intervention, and female gender is an independent risk predictor of in-hospital mortality [42]. The balloon angioplasty era generally resulted in poor outcomes in women [1]. But also the improved stent-application approaches are related to the statistics unfortunate for female gender: higher procedural risk and decreased efficacy is still more typical for women. An operative mortality by artery bypass indicates 1.5-times higher risk for women compared to men [43]. Evidently gender-dependent physiological particularities play the central role: smaller vessels and lumens represent an additional technical problem for successful coronary intervention in women. Further, aggressive antic oagulation medications are more problematic for female patients suffering more from access-site haematomas and bleeding complications [44].


Innovative technical and pharmaceutical approaches are urgently needed to better satisfy gender-dependent particularities under coronary intervention in women.

Diabetes, CVD, cancer...What else? Although the coincidence is common in women, consistent data do not exist to recognise co-morbidities by patient profiling

Co-morbid diseases are frequent in women with CVD. Hence, CVD is the best acknowledged co-morbidity in diabetics. Moreover, it is well documented that female diabetics demonstrate poorer outcomes of CVD. Hence, the best recognised risk factor for high operation mortality by and low efficacy of valvular replacement is the combination of female gender and diabetes [5]. Further, cardiovascular diseased women, in particular female diabetics, have poorer prognosis of oncologic diseases [45].

The most frequent oncologic co-morbidities in female diabetics are

  • endomentrium carcinoma (4.8-times higher prevalence in type 1 diabetes and 2.2-times higher in diabetes generally)
  • ovarian carcinoma (2.42-times higher risk in female diabetics versus general female subpopulation)
  • liver cancer (2.0-times higher risk)
  • lymphoma (1.9-times higher risk)
  • uterus carcinoma (1.7-times higher risk)
  • rectum cancer (1.7-times higher risk)
  • stomach cancer (1.6-times higher risk)
  • leukaemia (1.4-times higher risk)
  • kidney cancer (1.4-times higher risk)
  • pancreatic cancer (1.3-times higher risk)
  • breast cancer (1.2-times higher risk)
  • lung cancer (1.1-times higher risk)

as documented in the literature [46].
Nevertheless, there is a significant knowledge gap concerning "typical" versus "atypical" co-morbidity profiles in females.

Women develop CVD at higher age than men, and the consensus built in literature that the factor of age is the main reason for particularly frequent manifestation of accompanying disorders and severe complications observed in the cohort of cardiovascular diseased women compared to the male patient cohort. However, due to typical for 21st century demographic trends in favour of elderly populations, co-morbidities and more complex clinical situations now should be considered as less unique cases but rather as the persistent challenge in healthcare that required new strategies for improved treatment regiments.

Common risk factors moderating the outcomes in the most frequent female pathologies, namely DM type 2, CVD and breast cancer are progressing age, overweight, poor diet, physical inactivity and depression [47-49]. Moreover, modifiable risk factors persist from childhood and adolescence into adulthood and tend to cluster with synergistic negative effects for consequent manifestation of co-morbid pathologies [47, 50-58].


Co-morbidities and complex clinical situations in elderly populations should be considered as the persistent challenge that requires new strategies in healthcare. Integrative medical approaches are strongly desirable to analyse common risk factors as well as their individual and synergistic effects. Frequent versus rare co-morbidity profiles in cardiovascular diseased patient cohorts should be created for advanced treatment regiments.

Breast cancer and CVD

In contrast to well acknowledged CVD / Diabetes link, CVD and breast cancer co-morbidity is poorly understood. This is an extremely unlucky situation, since compared to all other pathologies both co-morbidities demonstrate the highest frequency of incidence in females. The probability to identify a female postmeno-pausal patient above 55 years old diagnosed with sporadic invasive breast cancer but completely CVD-free is rather low. However, the coincidence of CVD and breast cancer in one individual, co-prevention, co-diagnosis and co-treatments are not considered at all.

What are current problems and knowledge gaps in prevention, diagnosis and treatments of breast cancer with co-morbidities?

  • Worldwide 8-12 women from 100 are diseasing on breast cancer. Around 50% of DCIS (ductal carcinoma in situ) will progress to invasive and metastasis disease if untreated, with 20% of recurring ones despite "appropriate" treatments [49].
  • Causative factors such as co-morbidities and epigenetic ones underlying recurrence of DCIS or progression to invasive disease are currently not known.
  • Currently we need to treat 50 high-risk women to prevent one breast cancer: the role of negative prediction is underestimated [49].
  • 95-98% are sporadic breast cancer cases versus 2-5% familial ones: the majority of sporadic breast cancer cases are peri- and post-menopausal women who are at significantly higher risk of CVD.
  • Co-morbidities in breast cancer are considered rather from view point of psychological aspects and palliative care but not as the realistic model to navigate biomedical research, effective diagnostic approaches and treatment multimodalities.
  • Consistent data do not exist to recognise breast cancer co-morbidities by patient profiling.
  • Cost-effective healthcare promotion in breast cancer and its common or even persistent co-morbidities such as CVD and diabetes is not provided.
  • Critical gaps between current research performance and clinically applicable results are dramatic.

Conclusions and recommendations:

If any, there is a very limited research activity around the world dedicated to integrative preventive and/or diagnostic and/or treatment approaches of both co-morbidities. The above listed challenges and knowledge gaps request a systematic reconsideration of current strategies in research and healthcare of the co-morbidities: the experts should be better motivated for really innovative integrative approaches. The most effective approach is the targeted prevention by screening for individuals at high risk followed by tailored treatments of pre-stages. Prevention by modifiable risk factors should be prioritised and forced.

Do medication strategies aim at curing the patient or treating single organs?

Since 18th century, cardiac glycosides are used to treat congestive heart failure and attrial fibrillation [59]. The natural steroid toxin Digitalis-derived cardenolides -Digitoxin and Digoxin - are the most prevalent medicaments currently used in clinical practice. The medication forces the contractility in cardiac myocytes through inhibition of the Na+/K+-ATPase that indirectly increases Ca+ concentrations. During last decade, conflicting results have been published about potentially negative side-effects of the medication. However, recent studies have clearly documented a higher rate of invasive breast cancer among ever-users of Digoxin compared to never-users [60]. The side-effect is particularly evident for postmenopausal Digitoxin users [61]. Moreover, a positive association between Digoxin usage and incident male breast cancer has been demonstrated [62].

Another example: Metformin seems to be effective against a pancreatic dysfunction in pre-diabetes and early diabetes stages. However, the application of Metformin-controlled blockade of apoptosis in young and middle-aged patients with diagnosed pre-diabetic stages should become well investigated in terms of long-term side-effects such as potential cancer development (pancreas and other organs?) later in life. Current regulations request 3-year long follow-up studies that are apparently of insufficient duration for reliable statements.

Conclusions and recommendations:

Currently the cases in medical practice are not unique anymore, when a patient is taking around 20 and more tablets prescribed for parallel treatments of single disorders, which are frequently considered as independent from each other. How much they are independent and how much overlapping within the treatment-frames? How much are single medications synergic with and contra-productive to each other? How much is multimodal medication depending on the profile of co-morbidities and on individual patient profile? All the questions should be obligatory addressed by long-term follow-up studies in accordance to reconsidered guidelines in order to avoid treatments of single organs and pathologies instead of desirable synergic multimodal approaches.


  • CVD is strongly attributable to modifiable risk factors such as life-style, predominantly sedentary behaviour, and nutrition. Unfavourable demographic and epidemiol ogic trends in childhood and adolescence may lead to high CVD-predisposition (overweight, obesity, diabetes type 2) in societies followed by unprecedented burden on healthcare systems.
  • Gender-related social and economical challenge: related to CVD, women experience longer stays in hospital, suffer greater complications and disability consuming more material and financial resources than men with same diagnosis.
  • Although CVD is the leading cause of mortality in women worldwide, cardiovascular health in females is not improving as fast as that of males.
  • Significant gender-related differences in presentation and treatment success of CVD have been recognised only recently; the consequent knowledge gap should be urgently covered in diagnostic, operation and medication technologies.
  • Current CVD diagnostics is untailored for female gender.
  • Women experience delayed care in the case of CVD emergency.
  • Women have higher in-hospital and short-term rates of mortality than men with acute myocardial infarction, and after coronary intervention.
  • Atrial fibrillation related mortality and stroke risk are higher in women than in men.
  • Heart failure associated mortality declines in men much more significantly that in women.
  • Co-morbid diseases are frequent in women with CVD: Female diabetics demonstrate poorer outcomes of CVD as well as cardiovascular diseased women have poorer prognosis of oncologic diseases.
  • Clustering of risk factors: overweight and obesity causes the leading severe diseases in women, namely diabetes type 2, CVD and breast cancer.

Desirable approaches

  • Creation of gender-specific profiles for CVD-diag-nostics and treatments by well-funded large-scale studies with parity of both sexes including "omics"-based blood analysis, molecular imaging and elaboration of gender-specific questionnaires for accurate description of prodromal and acute symptoms of CVD.
  • Consideration of CVD-specific sex-determinants such as mutated maternal mitochondrial DNA that emerges complications and fatal outcomes of CVD.
  • Performance of large-scale population studies to identify most frequent profiles of co-morbid pathologies for effective treatments suitable for corresponding combination of co-morbidities such as depression/ diabetes/CVD/breast cancer in female patients.
  • Creation of strictly individual treatment priorities and regiments request personalised medical approaches of high plasticity and new generation of multi-cocktail drug compositions.
  • New drug delivery systems that allow for targeted treatments.
  • Reasonable convergence between diagnostic and pharmaceutical industry in development of predictive/ prognostic approaches based on new multifunctional targets for diagnostic and treatment purposes.
  • Besides general prevention in populations, there is an urgent need for targeted prevention in childhood, adolescence and adulthood as the most cost-effective approach that requests complete reconsideration of current diagnostic and treatment programmes offered in healthcare systems: major CVD risk factors overweight, obesity and diabetes type 2 are the most frequent nutritional disorders in industrialised countries.
  • Creation of new programmes in healthcare systems for effective promotion of and financial motivation for healthy life-style.

Long-held beliefs are firmly embedded in formal guidelines but also in public service performance and culture. However, important is that guideline committees follow the scientific evidence supporting the process of moving away from a target-based treatment towards approaches tailored to the individual patient-profile [63].
Following approaches should be considered by healthcare-responsible organisations, research units and funding bodies to cover current knowledge deficits in the field and to introduce integrative approaches for effective prediction, prevention and tailored treatments:
1. creation of predictive molecular profiles of the disease, co-morbidities and pre-stages;
2. understanding of disease initiation: molecular, subcellular, cellular, intercellular, and single-organ levels as well as the organism as the whole;
3. disease progression should be considered as an interplay between promoters, contributors and inhibitors resulting in individual outcomes (similar to a geometric system of vectors by summarising directions and contributing power);
4. tailored treatment algorithms: specific targets, targeted pathways, multi-drug cocktails, frequent versus rare complications and co-morbidities, multi-modal approaches;
5. effective primary and secondary prevention of co-morbidities but not this of single diseases separately from each other;
7. new strategies in overall psychological supervision of individuals at high risk and patients at different disease stages;
8. new European and inter/national guidelines for population screening that would make good use of gathered knowledge to advance cost-effective healthcare and improve individual outcomes;
9. promotion of integrative (bio)medicine to force practice-oriented research and cost-effective healthcare;
10. creation of a critical mass of experts stuffing for integrative (bio)medical disciplines;
11. education at two levels, namely in professional groups and in general population;
12. elaboration of new guidelines regulating the process of the paradigm change from a treatment of targets to a treatment tailored to the person with all her (his) individual particularities taken into consideration.


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