CARDIOVASCULAR IMAGING IN WOMEN WITH HEART DISEASES, A LOCAL CLINICAL PRACTICE GUIDELINES FOR PAKISTANI POPULATION

This is the first time that a local preliminary document on gender differences in CVDs has been initiated in Pakistan. International forum has been highlighting significant gender and ethnicity in CVDs. So different countries from world took the initiative to develop their local guideline or clinical scientific statements on gender differences with different socio-cultural and educational background for their own countries. GRFW in collaboration with Scientific Council of Women with Heart Disease PCS Pakistan floated this idea to develop a local guideline in various aspects CVDs for our own women population. In this regard different topics were assigned to different groups including mostly female cardiologists, senior gynecologists/obstetricians and radiologist from all over Pakistan. Primary objectives of this write up on Cardiac Imaging in Women is to provide a local clinical practice guideline for the assessment and management of CVD that will improve and standardize the physicians’ decision making for Pakistani women population. In the setting of growing awareness of providing personalized precision medicine, addressing sex differences in CVD is a key goal.
The intention is to inform cardiologists, non-cardiologist physicians’, general practitioners, and, obstetrician/gynecologists about the reasonable use and understanding of technologies to help in proper approach to their treating women with HDs and when to send them for cardiac specialist diagnostic center. As we could not find our own local data on cardiac imaging to report at present, most recommendations on cardiac imaging used has been taken from international literatures (which we have found feasible, readily available, and some cost effective approach in our money constraint society which can be followed in our population) and also which were published within the past decade were given priority. In this document, we discuss the role of using different cardiac imaging modalities, with a focus on diseases which are unique/or occur more in women. So, five women specific topics more commonly seen in our population were selected currently, which are (stable/unstable angina and ACS, MINOCA), non-ischemic CMP, HD during pregnancy, cardio-oncology, and connective tissue diseases (CTD). In these topics we have tried to used our own local incidences and prevalence of these diseases in our community/internationally on gender basis and have highlighted the availability/limitations of cardiac imaging in our society. The updated recommendations in women have been taken from international guidelines. Graphs and tables layout has been taken from abroad literatures and made some few changes according to its use in our population. You will find this a preliminary review document which will be simple to read, have updated approach in evaluating the diagnosis of HD in women easily. For current cost effectiveness issues for our population will be taken up by PCS to Health ministries of Pakistan for its making it easily availability with cheap cost so to benefit our female (very neglected and ill informed) with CVD population.
 


Introduction
Heart disease (HD) is one of the leading cause of death for women in the USA/south Asian countries, killing 1 in 3 women in 2018. 1,2Despite understanding of CVD in men and women, recognition of sex and gender influences on the clinical care and awareness of women has been slow or absent and there are only limited numbers of sex-specific and age-balanced imaging and management guidelines for women with CVD. 1 The presentation and identification of CVD in women pose unique diagnostic challenges compared to men, and under-recognized conditions in this population may lead to clinical mismanagement.Our population especially women lack in personal care, professional health care and excess in prevalence in coronary risk factors (RFs).
We have discussed the role of using different cardiac imaging modalities, with a focus on diseases which are unique/or occur more in women population.The primary objectives of this write up is to provide a local clinical practice guideline for the assessment and management that will improve and standardize our physicians' decision making for Pakistani women population with CVD.

Coronary Heart Disease (CHD)
1.1 Introduction: This document may help informing knowledge gaps that may recommend/help clinical practice and care that will be truly tailored for our women and eventually would also help in the limited use of resources in Pakistan.Its now wellknown that anatomic differences exist between men and women which can affect diagnostic performance of cardiac imaging in women (Table 1).

Atherosclerotic Heart Disease: People of South
Asian origin, which include Pakistan also, have an increased risk of ASCVD 4 times higher than the general population in America. 1,2Women have a bad prognosis from IHD than men despite less prevalence and decrease severity of obstructive CAD.Mechanism is now well understood but over here there is much lack in awareness.We have discussed on the role of contemporary functional and anatomic imaging techniques, including ETT, echocardiography, cardiac magnetic resonance imaging (MRI), coronary computed tomographic angiography (CCTA), singlephoton emission computerized tomography (SPECT) and positron emission tomography (PET), myocardial perfusion imaging (MPI), and invasive coronary angiography (ICA) in the detection and risk assessment of the burden of ASCAD in women at risk for IHD.All these technologies with expertise are now available in major cities of Pakistan (Table 2).All the contemporary non-invasive cardiac imaging's have high sensitivity and specificity.With this table it can be helped in selecting tests which has better sensitivity and specificity in women and this can prevent us from its over and unnecessary utilization in women with IHD.

Introduction to Ischemic Heart Diseases (IHD)
in Women: It is well known by now that IHD continues to be a major threat to women across their lifespans misconception on other diseases as number one has been ruled out.Despite the progress, IHD remains the leading cause of death and disability in women all over the world and ¼ population lives in South Asia.In light of the potential sex-based differences, there have been recent efforts to adopt female-specific diagnostic paradigms for the workup of IHD. 4 The commonly used pretest probability assessment underestimate risk in women.With our improved understanding of the ischemic cascade, allow IHD to be diagnosed early and with greater accuracy.Considering the spectrum of IHD in women we encounter diagnostic challenges, it can limit the application of traditional testing strategies which, while adequate to detect obstructive epicardial CAD, may be insufficient for many women and additional investigation beyond standard stress tests is often necessary to define the etiology of symptoms in women.We have in Pakistan limited healthcare services exclusive and limited use of resources in  The advantage of CTA is its increased sensitivity and negative predictive value although exposure to radiation may attenuate its benefit in pregnant and/or young women.CT also exclude other causes of life threatening chest pain due to dissection and pulmonary embolism.CTA can also provide plaque characterizations.   and less likely to have obstructive CAD 13 Demirkiran et al. 15 showed the role of CMR if available in tissue characterization after AMI and utility of CMR in detected microvascular injury in AMI. Park et al. 16 reported on LV remodeling and functional impairment in women with non-obstructed CAD using data from the WISE-CVD study.Kanaya et al. 17 6 It is seen mostly in women a mismatch b/w the severity of obstructive CAD and the prognosis.Women have a decrease burden of obstructive CAD compared with men, but prevalence of angina and mortality from IHD is increasing for women than men.There are certain non-ischemic conditions have shown to have sex-specific differences in them in clinical presentation and occurrence.PET and CMR (these modalities are available in most part of our country and usually not utilized for such issues if we encounter in our women population) can be used to measure and quantify myocardial blood flow (MBF) and coronary flow reserve (CFR), although PET is currently considered the gold standard. 20We should be careful in using these test in pregnant women.CMR in pregnancy is helpful in documenting better diagnosis which can help management and that CMR should be offered to pregnant women when indicated.Further, CMR has been used to assess for sub-endocardial ischemia given its ability to distinguish subendocardial from epi-cardial perfusion 21 CMR not only has the advantage of lack of ionizing radiation, making it an attractive modality for women testing for myocardial ischemia, but it is a useful modality for patients who are obese.Specifically, perfusion CMR was not only feasible in more than 95% of patients with a BMI [30 kg/m 2 ], but provided good negative prognostic value in a 2-year follow-up period in women.The 2014 AHA Consensus Statement highlighted the development of novel diagnostic tools that have an expanded role in the evaluation of symptomatic female patients to detect not only focal epi-cardial coronary stenosis, but also non-obstructive atherosclerosis as well as the identification of ischemia resulting from MVD.

Referral to Cardiac Specialist from GPs and Non-cardiologists Treating Physician
1. Women with high and intermediate risk PTP. 2. Women with ACS.

Dilemma in etiology of chest pain in-stable
angina and non-responding to medical therapies or change in clinical scenario from pregnant lady with chest pain.4. Need for use of advance cardiac technologies.5. Use of diagnostic imaging is a responsibility.

CVDs during pregnancy: Prevalence of HD in pregnancy varies considerably between countries.
According to the most recent information, 1-4% of all pregnancies in industrialized countries are complicated by CVD. 22In Pakistan, 1% of all pregnancies are complicated by HD and 69% are caused by rheumatic heart disease (RHD). 23ccording to another study from Pakistan the most common cardiac disease in pregnancy is RHD.

Ionizing radiation and pregnancy:
Side effects of ionizing radiation include 1) genetic consequences 2) carcinogenesis and 3) teratogenic effects on the developing embryo or fetus.The reported dose of radiation with consequent increase incidence of birth defects or miscarriage is above 200 mSv.An important determinant of the consequence of radiation exposure in pregnancy is the stage in which the radiation exposure occurs. 26,27The accepted cumulative dose of ionizing radiation during pregnancy is 5 rad (equal to 50 mSv). 28CV diagnostic studies involving radiation do not reach these levels but should be avoided if possible.
a) Echocardiography: TTE: TTE is by far the preferred diagnostic test for cardiac imaging 29 during pregnancy, when a cardiac diagnosis is suspected.TEE: TEE is relatively safe during pregnancy 30 although its uses should be restricted to circumstances where a TEE study is necessary.Pregnant women have increased risk of vomiting and aspiration.Sedation may best be handled with the help of anesthesiologist.

b) Cardiac Magnetic Resonance (CMR) Imaging:
2][33] No untoward side effects of MRI on the fetus have been reported.CMR should be avoided in the first trimester if possible.5 Use of dobutamine stress echocardiography (DSE) during pregnancy is debatable(its use can be associated with hemodynamic complications) and can only be used for women who are unable to exercise.Dobutamine is a class B drug. 37During pregnancy DSE should be avoided, whenever possible. 32iagnosis of this entity is cornerstone for the improved outcomes of the females with HF.

Prevalence, Prognosis and Gender Differences:
Prevalence of non-ischemic CMP is different in different geographical areas, study population subtypes and the type of CMP, ranging from 2% to 15%. 39Data from Pakistan shows 1.57% prevalence of CMP with dilated CMP being the most frequent type (66%) followed by HCM (8%). 40Although CMP is found to be more common among the males but restrictive CMP is more prevalent among the females. 40Peripartum cardiomyopathy(PPCMP) is frequent CMP in females with prevalence rate of 11% among Pakistani population. 41The overall prognosis of non-ischemic CMP is better than ischemic CMP.So, the more quickly and accurate diagnosis of this entity is cornerstone for the improved outcomes of the females with HF.

Imaging Recommendation in Different Non
Ischemic CMP Sub-types: Imaging recommendation for non-ischemic CMP starts with good history taking and physical examinations.After this GPs and noncardiologist physicians can go for ECG, laboratory test (for confirming the diagnosis and exclusion of HF) Xray chest once a provisional diagnosis of HF is made, proceed to confirming the etiology/ severity.For this it needs more sophisticated imaging's for establishing the management of the patients.So GPs and noncardiologist physicians can think of referring it to cardiac centers.
X-ray: X-rays are of limited use in CMP.They are mainly performed to rule out pulmonary pathology for the symptoms.X-rays should be avoided in females whenever possible to reduce radiation exposure.
a) Dilated CMP: TTE is appropriate initial modality for the diagnosis and etiologic evaluation of female with suspected dilated CMP. 42,43Repeat TTE is appropriate in the case of change in clinical status or for the determination of therapy response. 43TTE is also appropriate before planning the device therapy in female patients with OMT of DCM. 43Stress imaging and CT are appropriate to rule out obstructive CAD in patients with intermediate pre-test probability. 43MR with gadolinium enhancement is appropriate to differentiate different etiologies and determining the prognosis of DCM. 43It is reasonable to prefer CMR in female patients on other imaging modalities requiring radiation to reduce radiation exposure. 44 TTE with strain imaging is appropriate initial test in female patients with suspected HOCM. 42,46,47epetition of TTE at periodic interval in genotype positive phenotype negative females is appropriate. 48TTE is appropriate screening tool for the first degree relatives of with HCM. 46eriodic TTE (1-2 years in adolescent and 3-5 year in adults) is appropriate for children of patients with HCM, starting from puberty or before participating in intense competitive sports or with f/o of SCD. 45 Repetition of TTE is appropriate in case of change in clinical status. 46epetition of TTE is appropriate after alcohol septal ablation or surgical myomectomy.Exercise TTE is reasonable for the quantification of dynamic LVOT obstruction in the absence of significant LVOT gradient. 44TEE is reasonable in cases of inconclusive TTE. 46CMR is appropriate in cases of inconclusive ECHO. 45CMR is reasonable for the risk stratification of SCD in cases of inconclusive conventional RFs. 45,46CMR imaging is reasonable to differentiate the different causes of hypertrophy (e.g.cardiac amyloidosis and Fabry disease) if the clinical suspicion is high. 46,47CT scan may be done in cases with high suspicion of HOCM when other tests are either inconclusive or contraindicated. 47Invasive angiography or coronary cardiac CT should be done before surgical myomectomy. 46c) Restrictive CMP: Echo with diastology is an appropriate initial modality for the diagnosis and subtype evaluation of RCM. 42,46Tissue tracking and speckle Doppler ECHO is reasonable for the diagnosis and subtype evaluation of RCM. 42,47MR is appropriate for the diagnosis and subtype evaluation in patients with inconclusive ECHO. 46MR is also appropriate to differentiate restrictive CMP from restrictive physiology cause by constrictive pericarditis in patients with inconclusive ECHO. 46CMR should be preferred over invasive imaging for hemodynamic assessment in female patient to decrease radiation exposure. 46CCT may be used to determine pericardial thickness and so to differentiate restrictive CMP from constrictive pericarditis.

d) Arrhymogenic
Right Ventricular Cardiomyopathy (ARVC): TTE is appropriate initial test in female patients with suspected ARVC.TEE is appropriate in females with suspected ARVC with inconclusive TTE.CMR is appropriate for the confirmation of echo diagnosis of ARVC or with the inconclusive ECHO in females with suspected ARVC. 44CT scan may be done in cases with high suspicion of ARVC when other tests are either inconclusive or contraindicated. 44e) Takotsubo CMP: TTE is appropriate initial modality in post-menopausal females with clinical presentation of ACS to rule out Takotsubo syndrome. 49Repeat TTE is appropriate in the case of change in clinical status or for the determination of therapy response and improvement of LV function. 47TTE is appropriate in females with Takotsubo syndrome for the evaluation of complications like LVOT obstruction and MR. 47Strain imagining is appropriate for the assessment of regional dysfunction and its recovery. 47CMR with gadolinium is reasonable to differentiate ischemic versus non-ischemic aetiology of regional wall motion abnormalities. 47CA is reasonable to rule out obstructive CAD in patients with suspected Takotsubo syndrome. 47

f)
Peripartum Cardiomyopathy (PPCMP): TTE is appropriate initial modality in female with last month of pregnancy and post-delivery for the five months if presenting with shortness of breath to rule out PPCMP. 47Repeat TTE is appropriate in the case of change in clinical status or for the determination of therapy response and improvement of LV function. 47CMR is appropriate modality for the diagnosis and differential diagnosis of PCMP in the cases with inconclusive ECHO. 47 Cardiac dysfunction is now a growing health issue during and after cancer treatment therapy.Its recommended now that it should be dealt with in some multidisciplinary center.Current advance cancer therapies have significantly improved the survival rate in cancer patients in women with breast cancer; the 5year survival for early stage breast cancer increase from 79% in 1990 to 88% in 2012. 49,50In a recent comprehensive review of breast cancer survivors, deaths due CVD is seen more in women to their chemo and radiations treatment and exceeding their risk of death from the initial cancer itself or from recurrent disease. 48,51Doxorubicin-induced cardiotoxicity is widely known to occur at cumulative doses exceeding 450 mg/m 2 however local data suggest, the incidence of subclinical cardiac dysfunction was increase with doxorubicin in the cumulative dose range of 300-450 mg/m 2 . 52,53Concomitant use of cyclophosphamide, low BMI (<20 kg/m 2 ) and preexisting cardiac disease showed a trend towards increase risk of cardiac dysfunction. 54,55Another issue we encounter is the long delay b/w exposure and clinical manifestation of HD, the use of concomitant cardiotoxic chemotherapy, continuous improvements in radiation techniques and changes in the treated population and failure to attribute cardiac disease to previous radiotherapy despite increase awareness of CV physicians of its long-term side effects.In patients with breast cancer treated in the era 1980-2000, the risk of cardiotoxicity was increase in patients treated with both left breast radiotherapy and cardiotoxic chemotherapy, suggesting a synergistic effect on cardiac risk. 48,51arked interstitial myocardial fibrosis had evidence of DD, systolic dysfunction is generally observed when radiotherapy is combined with anthracyclines.HF may aggravate with associated VHD and CAD, which may have developed later on in these treated patients.

Definition of cancer therapeutics-related cardiac dysfunction (CTRCD):
CTRCD as a decrease in the LVEF of >10 percentage points, to a value <53% (normal reference value for 2D) 2DE.The repeat study should be performed 2 to 3 weeks after the baseline diagnostic study showing the initial decrease in LVEF. 54Repeat ECHO is needed at different interval to detect LVEF decrease which may be further categorized as symptomatic or asymptomatic, or with regard to reversibility.

Vascular complications of chemotherapeutics:
The newer anti-cancer drugs which inhibit vascular endothelial growth factor signaling are also associated with CV pathology, especially HTN, thromboembolism, MI, and proteinuria. 55

Risk Assessment of Cardiac Dysfunction:
A baseline CV risk assessment is essential. 56Many strategies have had been developed in previous decades.Two of them evolved over time to be very useful: endo-myocardial biopsies and monitoring of LVEF by cardiac imaging.Echo is now widely available, cheap in Pakistan.CT is very helpful for the assessment of coronary anatomy, MRI to detected MPI abnormalities, scarring and early signs of myocardial damage such as edema and beginning fibrosis.Nuclear medicine can image perfusion abnormalities, cell death and alterations in metabolism and innervation. 57Myocardial deformation imaging S35 and 3D volumetric analysis seem to be optimal techniques to address temporal structural and functional changes during cancer therapy. 58very important that the same imaging modality should be used for all screening throughout the treatment pathway.Switching b/w modalities or assays should be avoided.
It's very important to have awareness on the cardiotoxicity effects of chemotherapeutic agents and radiation CV RFs control is important in mitigating cardiotoxicity risk in our female patients.Assessment of patient-and treatment-specific risk with appropriate CV surveillance is another key component of care.Mismatch between baseline cardiotoxicity risk and intensity of cardiotoxicity surveillance can lead to an unnecessary downstream testing, increase healthcare expenditure, and interruption or discontinuation of potentially life-saving treatment.Of those exposed, some will develop abnormalities in myocardial strain early on, and then an ↑ in extracellular volume (ECV).A subset of patients will progress to a ↓ of LVEF, and a subset of these will have a ↓ left ventricular mass with the worst outcome. 596 Valvular disease: VHD is frequently observed in patients with cancer due to radiotherapy, infective endocarditis, pre-existing valve lesion, or secondary to LV dysfunction.53,57 Approximately 10% of patient treated with radiation develop a relevant VHD during lifetime.57 In patients with Hodgkin lymphoma, a relationship b/w radiation dose to the heart and development of valvular events after treatment has been described, especially at doses >30 Gy. 60 Echo is useful modality in making its diagnosis.appears to be the most useful parameter for the prediction of cardiotoxicity, defined as a drop in LVEF or heart failure.52,60  Myocardial deformation (strain) can be measured using Doppler tissue imaging or 2D STE. GLS is the optimal parameter of deformation for the early detection of sub-clinical LV dysfunction.61,62 Other imaging modalities  CTD also called collagen vascular disorders are a heterogenous group of over 300 immunologically mediated multisystem disorders while sharing some fascinatingly common clinical dermatologic, arthritic, pulmonary and cardiac, and laboratory features.63 The relative frequency and distribution of these features divides them into some distinctive groups of conditions of arthritides namely rheumatoid arthritis, ankylosing spondylitis, vasculitides-such as mixed connective tissue disorder, dermatoses such dermatomyositis, polymyositis, progressive systemic sclerosis, and miscellaneous conditions such as Sjogren syndrome, Sarcoidosis and Systemic lupus erythematosus. 63 Th prevalence of these conditions in Pakistan is 0.55-1% according to hospital-based studies with a female preponderance and RA, SLE and PSS being the commonest.64 The ↑ frequency in women is considered to be an estrogenic effect, ↑ the CV mortality risk.65 The pathophysiology is a myriad and variable combination of direct immune/ vasculitis mediated damage to myocardium and pericardium, premature atherosclerosis-mediated myocardial damage, valvular vegetation, and PH resulting from interstitial lung disease, the end result is a HF with preserved left ventricular ejection (PLVEF) at a relatively younger age. 66The manifestations themselves and their optimum imaging are therefore complex, interrelated and overlapping.
Many modalities may be used for the purpose depending upon the clinical manifestations.Echo is often the baseline investigation utilized for the purpose of visualizing the structure of chambers, valves, origin of great arteries, wall movement, Doppler flow and EF%.Though it is operator dependent, the modality is radiation-free.Recently, s speckle-tracking strain echo technique was reported to be able to demonstrate the LV systolic dysfunction in systemic sclerosis. 67

Imaging modalities for evaluation of cardiac disease in rheumatic heart disease (RHD):
Myocardial perfusion defects presence extent and reversibility are classically studied by various kind of nuclear studies which include MPS, MIBI and Thallium SPECT.These have been utilized for evaluation of women with SLE at risk of premature atherosclerosis with success. 68Cardiac MRI (CMR) is rapidly assuming the position of one-stop solution for evaluation of myocardium, pericardium, great vessels and coronary abnormalities despite its cost.This is due to excellent tissue characterization, combined with functional and perfusion evaluation.There is a growing body of evidence that MRI provides the details of myo-pericarditis, vasculitis, CAD including spontaneous dissection, myocardial fibrosis, PH, aortic valvular and vascular lesions and HF. 66,67Even silent disease can be unraveled. 69Mapping of myocardial disease is also feasible. 70PH is basically caused by the ILD and the vasculitis.The best modality for evaluation of ILD is CT scan, particularly HRCT.Hence studies have advocated early -stage echocardiography and CT scan should be used to detect potential CV including PH in patients with CTDs. 70Premature atherosclerosis contributes to the CV morbidity risk in patients with CTD.The recommended screening modality for those with suspected atherosclerotic CAD is carotid artery Doppler ultrasound which evaluates the intimal plaques and their morphology quite nicely, predicting the risk of CAD. 71,72There is no difference in the imaging modalities used for this purpose in men and women except that evaluation of a pregnant woman would require the use of non-ionizing radiation studies such as echo and cardiac MRI.For the non-cardiologist physician, a thorough history, physical examinations, laboratory test and preliminary diagnostic picture should be obtained.Once the diagnoses of CTD is made and there is suspicion of cardiac disease, basic cardiac imaging like x-ray, and echo should be requested.For specialized imaging requirements, make a referral to specialist cardiologist or the specialized tertiary care cardiac imaging center.
The suspicious findings that need further evaluation by a specialist are presence of;  Large pleural effusion on baseline x-ray requiring drainage,  Pericardial effusion,  Acute chest pain with dyspnea that requires exclusion of pulmonary embolism and acute coronary syndrome, and  Progressive dyspnea without orthopnea, requiring HRCT for evaluation of pulmonary fibrosis or diffuse interstitial lung disease

Conclusion:
This local practice guideline document has been endorsed by Council members of GRW-P and PCS.Our intent was that this preliminary review detailed document on cardiac imaging for our local female population with HD may serve as a foundation and prototype for future local clinical practice recommendations and if possible may develop local statement guidelines.This document may help in transformation to clinical practice and care for our women and eventually would also help in the limited use of resources in Pakistan.Our next aim is to review/ and write every 1 to 2 years for adding on our own local data if available and any new data from international literatures on cardiac imaging's for women.

Figure 1 :
Figure 1: Diagnostic evaluation algorithm for women presenting with suspected IHD symptoms and intermediate IHD risk and intermediate-high IHD risk 3 . It has been broadly divided as ischemic and non-ischemic on the basis of presence or absence of obstructive CAD.Its classified as shown in figure below by ESC.38 Figure2shows the European classification of the non-ischemic CMP.

Figure 3 :Figure 4 :
Figure 3: Schematic representation of imaging guidelines in non-ischemic cardiomyopathy

4. 5
Echo evaluation of cardiac structure and function in the cancer patient: Echo is the method of choice for the evaluation of patients before, during and after cancer therapy.Calculation of LVEF ideally by 3DE, when using 2DE, the modified biplane Simpson technique is the method of choice. In the absence of global longitudinal strain (GLS) by STE, quantification of LV longitudinal function using mitral-annulus displacement by Mmode echocardiography, and/or peak systolic velocity (s') of the mitral annulus by pulsed-wave DTI is recommended. The use of myocardial contrast agents could be potentially useful in chemotherapy patients when endocardial drop out occurs. Other parameters to be measured by echocardiography are diastolic function, RV assessment, valvular pathologies, pericardial diseases like constriction, effusion and tamponade due to metastasis and radiotherapy should be addressed. Stress echocardiography may be helpful in the evaluation of patients with intermediate or high pre-test probability for CAD.

Figure 5 :undergoing anthracycline therapy 4 . 7
Figure 5: Progression in LV dysfunction in adult patients undergoing anthracycline therapy 4.7 Detection of sub-clinical LV dysfunction  LVEF assessed by 2DE, often fails to detect small changes in LV contractility. A 10% to 15% early decrease in GLS by STEappears to be the most useful parameter for the prediction of cardiotoxicity, defined as a drop in LVEF or heart failure.52,60 Myocardial deformation (strain) can be measured using Doppler tissue imaging or 2D STE. GLS is the optimal parameter of deformation for the early detection of sub-clinical LV dysfunction.61,62

Figure 6 :
Figure 6: Strategies for screening and detection of cardiotoxicity

Table 2 : Noninvasive Tests Capability to Detect Gender differences in CAD 3
women of Pakistan.Its knowledge/awareness and availability of local expertise/availability of tests will guide test selection suitable for our populations.

Table 3 : Use of Non-invasive Imaging modalities for Diagnosis and Prognostic evaluation of Women at Risk for IHD categorized according to PTP 3
1.5 Radiation-free Imaging:The 2014 AHA consensus statement have discussed the role of noninvasive testing in the clinical evaluation of women with suspected IHD and makes decision that clinicians should carefully weigh the risks and the benefits of radiation-based imaging modalities.The

8,9 b) Symptomatic Low-Risk Women: For
patients who are at low PPT of having IHD, ETT is an initial test if the ECG is interpretable, exercise stress ECHO can also be a reasonable test.However, in those patients with decrease PTP of IHD who cannot exercise, pharmacologic stress ECHO, CTA, or stress CMR are all reasonable for further workup if available in Pakistan (

Table 4 ). 8 c) Asymptomatic Intermediate-Risk Women:Table 4
10rrently, ETT is recommended in assessing CV risk for asymptomatic patients with intermediate risk, while Calcium score (CAC) by CT is better test if available.10StressECHO,

.7 Acute Coronary Syndrome (ACS): 6Table 6
19owed an interesting insight into the composition of high-intensity coronary plaques observed by CMR compared with non-high intensity plaques using optical coherence tomography (OCT).IVUS and OCT (IVUS is available in major cities of Pakistan but unfortunately being used in only 20% of cases: OCT is only available in some institutions of in Punjab) have shown to provide high image resolution of the coronary artery and can guide clinical decisionmaking in .Women presenting with ACS have different composition of atherosclerotic plaque, including decrease plaque rupture, less necrotic core, and ↓ calcium,2 making these lesions harder to detect using traditional CA.IVUS detected calcium in 73%.While in those same vessels angiography had a sensitivity of 39%.18IVUS and OCT can assess arterial wall to visualize intimal tears, intra-luminal thrombi, false lumens, and intramural hematomas, therefore can help in making correct diagnosis.Experts have recommended using IVUS and OCT to assess arterial wall integrity to improve diagnosis especially when it is uncertain in women.19

ECHO Normal Echo Abnormal Echo Other Cause Suspected Other Cause Identified No Possible Other Cause Suspected / High Clinical Suspicion of HF Further Workup Accordingly No Other Cause Identified Refer To Cardiologist 4 Use of Cardiac Imaging Techniques in Women with Cancer Treatments and Cardiovascular Toxicity
Electromagnetic interference from CMR should be kept in mind especially in patients with breast cancer in whom tissue expanders placed for breast reconstruction may represent a hazard.It is important to important to remember that the same technique should be performed for baseline assessment and follow-up studies during and after cancer treatment.CT scan if suspected metastasis or pericardial involvement.Now we have greatly advanced in developing field of cardio-oncology in Pakistan too which can provide highly sensitive methods for timely diagnosis of cardiotoxicity.Cardiac dysfunction is a growing health concern during and after well-developed cancer therapy and should be addressed in a multidisciplinary setting.Advanced modalities like myocardial deformation imaging and 3D volumetric analysis seem to be optimal techniques to address temporal structural and functional changes during cancer therapy.The intensity of echo monitoring, coordination with cardiac biomarkers monitoring, should be based on the individual risk of cardiotoxicity, all these requires collaborative evaluation by the cardio-oncology team.

Table 10
summarizes the main CV abnormalities which may be imaged in patients with CTD and the optimal imaging modality for the purpose.One potential limitation is that RA, SLE and SS have been the most studied and imaged conditions among the group and extrapolation on other less common conditions requires careful consideration of costs, risks and benefits.