Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.

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Finding the missing heritability of complex diseases

Recommendations for the evaluation of left ventricular diastolic function by echocardiography

Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography : An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging

http://www.jse.gr.jp/2016_LVDiastolicFunction.pdf

Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging

The assessment of left ventricular (LV) diastolic function should be an integral part of a routine examination, particularly in patients presenting with dyspnea or heart failure. About half of patients with new diagnoses of heart failure have normal or near normal global ejection fractions (EFs). These patients are diagnosed with “diastolic heart failure” or “heart failure with preserved EF.”1 The assessment of LV diastolic function and filling pressures is of paramount clinical importance to distinguish this syndrome from other diseases such as pulmonary disease resulting in dyspnea, to assess prognosis, and to identify underlying cardiac disease and its best treatment.

LV filling pressures as measured invasively include mean pulmonary wedge pressure or mean left atrial (LA) pressure (both in the absence of mitral stenosis), LV end-diastolic pressure (LVEDP; the pressure at the onset of the QRS complex or after A-wave pressure), and pre-A LV diastolic pressure (Figure 1).Although these pressures are different in absolute terms, they are closely related, and they change in a predictable progression with myocardial disease, such that LVEDP increases prior to the rise in mean LA pressure.



Figure 1 
The 4 phases of diastole are marked in relation to high-fidelity pressure recordings from the left atrium (LA) and left ventricle (LV) in anesthetized dogs. The first pressure crossover corresponds to the end of isovolumic relaxation and mitral valve opening. In the first phase, left atrial pressure exceeds left ventricular pressure, accelerating mitral flow. Peak mitral E roughly corresponds to the second crossover. Thereafter, left ventricular pressure exceeds left atrial pressure, decelerating mitral flow. These two phases correspond to rapid filling. This is followed by slow filling, with almost no pressure differences. During atrial contraction, left atrial pressure again exceeds left ventricular pressure. The solid arrow points to left ventricular minimal pressure, the dotted arrow to left ventricular …

https://biblio.ugent.be/publication/631868/file/631869.pdf

Background Recent studies indicate that magnetic resonance imaging (MRI) after the administration of contrast material can be used to distinguish between reversible and irreversible myocardial ischemic injury regardless of the extent of wall motion or the age of the infarct. We hypothesized that the results of contrast-enhanced MRI can be used to predict whether regions of abnormal ventricular contraction will improve after revascularization in patients with coronary artery disease. Methods Gadolinium-enhanced MRI was performed in 50 patients with ventricular dysfunction before they underwent surgical or percutaneous revascularization. The transmural extent of hyperenhanced regions was postulated to represent the transmural extent of nonviable myocardium. The extent of regional contractility at the same locations was determined by cine MRI before and after revascularization in 41 patients. Results Contrast-enhanced MRI showed hyperenhancement of myocardial tissue in 40 of 50 patients before revascularizat...

https://www.nejm.org/doi/pdf/10.1056/NEJM200011163432003

The use of contrast-enhanced magnetic resonance imaging to identify reversible myocardial dysfunction.

Underestimation of residual ischemia by 201-thallium scintigraphy after myocardial infarction.

Since myocardial 99mTc-Sestamibi uptake is closely related to coronary blood flow and the tracer does not redistribute, resting perfusion defects may be observed even in viable regions supplied by vessels with severe stenosis. The incidence and the clinical significance of 99mTc-Sestamibi uptake defects at rest were investigated in 60 men with suspected coronary artery disease and no previous myocardial infarction, in a multicenter study. Of 60 patients, 12 showed normal coronary arteries and 48 significant coronary artery disease (> 50% luminal narrowing). Based on the presence or absence of tracer uptake defects at resting planar scans, the patients were divided into Group 1 (27 patients) and Group 2 (33 patients), respectively. A greater incidence of coronary artery disease (100% versus 64%, p < 0.01) and of multivessel disease (70% versus 36%, p < 0.05) was observed in patients of Group 1. All patients underwent dipyridamole (up to 0.84 mg/kg in 10 min) 99mTc-Sestamibi scintigraphy, which more frequently induced transient 99mTc-Sestamibi uptake defects in Group 1 than in Group 2 (85% versus 42%, p < 0.001). A high incidence of resting 99mTc-Sestamibi uptake defects was observed in patients without previous myocardial infarction; this identified a subset of patients with a higher prevalence of coronary artery disease and multivessel involvement and with a greater impairment of the coronary reserve, as evidenced by a dipyridamole test.

Maldistribution of regional myocardial perfusion at rest in patients with coronary artery disease and no previous myocardial infarction, evidenced by 99mTc-Sestamibi scintigraphy.

At dipyridamole myocardial scintigraphy, perfusion defects are seldom backed up by significant ECG changes. This would suggest myocardial blood flow heterogeneity, rather than true ischaemia, as the cause of the scintigraphic abnormalities. Electrocardiographic surface mapping has been documented to be more accurate than standard 12-lead ECG in the detection of provoked ischaemia. Thus, to investigate the relationship between ECG changes and perfusion abnormalities, body surface maps were recorded during dipyridamole infusion in 55 subjects (11 normals and 44 patients with ischaemic heart disease) undergoing dipyridamole technetium-99m sestamibi single-photon emission tomography (SPET). All had a normal resting ECG. The extent and severity of the sestamibi defect were quantified. New negative areas in the isointegral maps and rest-dipyridamole map differences >2 SD from normal limits were considered abnormal. After dipyridamole in normals, neither perfusion defects nor>-1 mm ST segment depression on 12-lead ECG nor new negative areas in isointegral maps occurred. In patients, dipyridamole induced new perfusion defects in 35 (80%) but ST segment depression in only 18 (41%,P<0.001). Of the 35 patients with perfusion defects, 17 (49%, group 1) showed ST segment depression, while the other 18 (51%, group 2) did not. Abnormal body surface maps were found in 100% of group 1 and 88% of group 2 patients (NS). In group 1, the provoked hypoperfusion was of greater extent (P=0.007) and severity (P=0.01) and the onset of map abnormalities was significantly earlier (P<0.001) than in group 2; time to map abnormalities was also significantly shorter than time to ST segment depression (P=0.01). In the 35 patients with complete scintigraphic, body map and angiographic data, the severity of reversible perfusion defect proved to be the strongest correlate of ST segment depression upon logistic regression analysis. Thus, sestamibi SPET abnormalities after dipyridamole are almost always associated with electrical changes on body surface maps, suggesting myocardial ischaemia as their cause. The much less common 12-lead ECG changes are slower to appear and reflect a more severe hypoperfusion.

ECG-manifest and ECG-silent dipyridamole technetium-99m sestamibi SPET perfusion defects in patients with ischaemic heart disease.

Figure 1. Lucite-Ball Plombage. Chest discomfort and negative U waves in precordial leads V, V, and V of the electrocardiogram (black arrows) with T-wave inversion occurred after the infusion of dipyridamole in a patient with severe stenosis of the proximal left anterior descending coronary artery. These findings occurred concomitantly with severe myocardial hypoperfusion in the anteroseptal region during a thallium stress test. The area of hypoperfusion subsequently filled in (white arrows). Among the electrocardiographic signs of transient myocardial ischemia, negative U waves in the precordial leads have been reported to be very specific for coronary artery disease, especially stenosis or . . .

Images in clinical medicine. Negative U waves as an indicator of stress-induced myocardial ischemia.

Preventive intervention presupposes a threat that can be averted at an acceptable cost; in patients with stable coronary artery disease, the threat of subsequent myocardial infarction and death is generally low, and proper management can usually control symptoms and improve prognosis substantially. In general, patients who have indications for coronary angiography are also potential candidates for revascularization. The relation of typical angina to prognosis is mediated by its relation to the extent of coronary disease; since the risk of coronary occlusion is not proportional to stenosis severity, it is not surprising that treating one or more stable tight lesions does not reduce the rates of subsequent major cardiac events. Clinical evaluation, ventricular function, response to stress testing, and the extent of coronary artery disease are the key pieces of information to stratify patient risk. In subjects without a markedly positive stress test, the ischemic burden is helpful in decision-making with respect to selecting initial therapy, and contributes to risk assessment. An initial invasive strategy without prior functional testing is rarely indicated, and may only be considered for patients with severe valve disease, serious arrhythmias or when therapy has failed to control symptoms satisfactorily, with a view to revascularization. In the absence of uncontrolled symptoms, patients are potentially eligible for coronary angiography if noninvasive tests reveal a substantial area of myocardium at risk. Coronary angiography should also be undertaken in patients with moderate to severe ischemia who do not have a significant reduction of the ischemic burden with therapy, given their worse prognosis. Because the treatment of asymptomatic patients cannot improve their symptoms, recommendations for coronary angiography in this subset are weaker and limited to risk stratification in subjects with high-risk criteria. Invasive procedures require a high likelihood of success and acceptable risk of morbidity and mortality and patients should be fully informed of the risks of the therapeutic modality individually. Regardless of the treatment modality used (early invasive vs selectively invasive), noninvasive imaging of the ischemic burden may assist in both decision-making for initial therapy and determining therapeutic efficacy related to long-term outcome.

https://www.giornaledicardiologia.it/r.php?v=631&a=7374&l=10282&f=allegati/00631_2008_10/fulltext/2008-10.08 716-725.pdf

Michele Galli

Papers

Underestimation of residual ischemia by 201-thallium scintigraphy after myocardial infarction.

Maldistribution of regional myocardial perfusion at rest in patients with coronary artery disease and no previous myocardial infarction, evidenced by 99mTc-Sestamibi scintigraphy.

ECG-manifest and ECG-silent dipyridamole technetium-99m sestamibi SPET perfusion defects in patients with ischaemic heart disease.

Images in clinical medicine. Negative U waves as an indicator of stress-induced myocardial ischemia.

[Coronary angiography in stable angina: friends and foes].