One of the main advantages of cardiac MRI over other imaging modalities is its ability to qualitatively and quantitatively assess changes in myocardial tissue. For example, by using contrast-enhanced pulse sequences, cardiac MRI can be used to assess myocardial viability. Moreover, in myocarditis, this has been used to assess edema, capillary leakage, hyperemia, and, in severe cases, cellular necrosis and fibrosis. This technique has displayed high diagnostic accuracy for acute inflammatory or ischemic injury, which is significant as edema is an important hallmark of inflammatory injury. Nowadays, late gadolinium enhancement (LGE) imaging has become the primary diagnostic tool for assessment of myocardial viability in patients suffering from CAD as well as myocardial inflammation in patients with suspected myocarditis of cardiomyopathies [21]. Furthermore, cardiac stress MRI using adenosine might add a functional component to late gadolinium enhancement imaging, which detects irreversibly damaged myocardium (e.g., scar tissue) with very high accuracy. With LGE, hypo- or akinetic but still viable myocardium can be identified as dysfunctional myocardium without scar or significant remaining viable tissue (<50 % transmurality of scarring). In clinical practice, this additional information will help to decide whether or not the patient will recover after revascularization. However, different noninvasive tests provide different surrogate definitions of hibernating myocardium (e.g., metabolism, scar, or contractile reserve), and consequently the result of a given investigation may depend on the chosen imaging test.

The mechanism of LGE in acute and chronic infarction is the increase of the extracellular space caused by necrosis (loss of cell membrane integrity), resulting in a significant increase of the extracellular space of scar tissue as compared to normal myocardium. Magnetic resonance contrast agent that diffuse to the interstitial space will be resorbed into the capillary bed and undergo renal excretion. However, when the tissue is damaged, for example, due to infarction, diffuse fibrosis, or even inflammation, the resorption rate of contrast agent will be diminished. At 10–20 min after contrast injection, washout of the contrast agent will be complete in normal myocardium, in contrast to infarcted or edematous tissue. This phenomenon is the basis of “late gadolinium enhancement” imaging. Various studies have shown the relation between myocardial viability and the size of the area displaying late gadolinium enhancement. In MR images, the presence of contrast agent can be detected as a bright area on images acquired with T1-weighted MR images. Currently the principle “bright is dead,” indicating that bright areas on a late gadolinium MR image after contrast injection correspond with nonviable myocardium, is subject to a lively debate. Nevertheless, a strong correlation between the transmural extent of hyperenhancement and regional function recovery has been demonstrated in several studies, revealing LGE imaging as a powerful predictor of myocardial damage after myocardial infarction.

The mechanism in nonischemic myocardial diseases is also predominantly, if not exclusively, due to increase in the distribution volume of gadolinium, caused by an increase in the extracellular space of the myocardium. The increase in the extracellular space may be due to necrosis of myocardial cells (myocarditis), replacement of myocardial cells by fibrosis (hypertrophic cardiomyopathy), or replacement of myocardium by various infiltrates (e.g., amyloidosis, sarcoidosis), or a combination of these.

While the distribution of LGE is invariably subendocardial for ischemic disease (either acute or chronic myocardial infarction), the pattern of enhancement has a variable transmural distribution in nonischemic myocardial disease. LGE conforms to the distribution of one or more coronary arteries in ischemic heart disease, while in nonischemic myocardial disease, it does not. With nonischemic myocardial disease, the mural pattern usually can be seen midwall or subepicardial and may be spotty in multiple regions of the ventricle. The pattern of distribution in some may be almost diagnostic of a specific myocardial disease.

Within the bright LGE area of an acute myocardial infarction, microvascular obstruction (MO) or the “no-reflow” phenomenon is known as an established complication of coronary reperfusion therapy, adding another complementary “imaging biomarker” to the clinical value of LGE (Fig. 3.2) [22–24]. The phenomenon of microvascular obstruction is increasingly recognized as a poor prognostic indicator and can serve as an imaging marker of subsequent adverse LV remodeling [25]. Although MO can be assessed using various imaging modalities, evaluation by cardiac MRI is particularly useful in enhancing its detection, diagnosis, and quantification, as well as following its subsequent effects on infarct evolution and healing. MO assessment has become a routine component of the MR evaluation of acute myocardial infarction and will play an increasingly important role in therapeutic decision pathways. MO is characterized by a number of ultrastructural and functional changes at the microvascular level. Understanding these histopathophysiologic changes can enhance the approach by MRI to detecting MO, to understand the results and their subsequent clinical implications. It can also help to potentially improve how MO is assessed by CMR, which has implications with regard to the understanding of infarct evolution as well as the evaluation of the efficacy and mechanism of reperfusion treatment.

LGE and MO have been found to be predictive of clinical outcome, independently of or when adjusted for other indices such as infarct size and LV ejection fraction (EF) [26]. Many of these outcome studies showed a severe relationship between the size of LGE and/or the presence of MO and adverse LV remodeling, with reduced global systolic function and pathologically enlarged LV volumes at follow-up exams, suggesting a possible mechanism for the poor prognosis. Moreover, MO is increasingly incorporated into clinical trial methodology as a surrogate clinical outcome in studies investigating reperfusion strategies, particularly when the treatment has the potential to directly impact microvascular function.

Recent developments in tissue characterization in terms of histological differentiation, grading, but in particular immunohistochemical profiling (i.e., receptor expression) as well as genome typing, needing invasive procedures such as biopsies, have somewhat interfered with the constant ambition of establishing and optimizing imaging biomarkers for noninvasive tumor characterization. Nonetheless, relevant clinical applications focusing on perfusion-based tumor identification and characterization are being developed and constantly enhanced. One of the most important clinical applications for perfusion imaging is the characterization of hepatic nodules occurring in patients with known liver cirrhosis, fatty liver, hepatitis C, or hemochromatosis. In these cases, current diagnostic guidelines recommend a noninvasive HCC diagnosis based on the presence of typical enhancement patterns like washin and washout phenomena, in contrast-enhanced CT or MR imaging. Unfortunately, these typical qualitative enhancement patterns are not always present in HCC nodules, and potentially being missed, in particular in smaller lesions. In this clinical setting with unclear imaging results, an invasive approach, i.e., biopsy, is usually recommended. The rationale for implementing a quantitative, perfusion-based imaging biomarker of HCC and of HCC precursors is the knowledge that along the so-called multistep process of carcinogenesis, liver nodules create an arteriolar network, gradually replacing the normal sinusoidal architecture and thus becoming predominantly or exclusively supplied by arterial blood [27]. Hence, with ongoing tumor differentiation, the number of so-called non-triadal arteries is increasing which has been intensively analyzed by comparison with histology [28]. At this point, the use of perfusion imaging (e.g., perfusion CT) with the option for a separate calculation of the dual liver blood supply (arterial and portal venous blood supply) offers an ideal tool for a noninvasive classification of liver lesions [29]. Additionally, differences in the perfusion between parenchymatous organs like the liver and metastases are known to improve tumor detection both for hypervascularized and hypovascularized lesions, based on the fact that all these lesions are primarily supplied by arterial blood [30]. In several tumors, a direct correlation between them and other invasive histological biomarkers of angiogenesis like microvessel density and VEGF values has been reported [31, 32]. Despite the need for a histologic proof in the primary diagnosis, detection of tumor relapse could benefit from noninvasive imaging-based characterization, avoiding unnecessary risks related to invasive diagnosis. In particular in anatomical region like the CNS, avoidance of open biopsy has emerged to an issue of great debate. A number of studies have used perfusion CT for tumor grading showing that BF, BV, and k-trans values were higher in high-grade glioma vs. low-grade glioma [33]. Moreover, differentiation of high-grade gliomas from other brain lesions including lymphomas has been reported based on differences in BF and BV [34].

Lately, perfusion parameters have been increasingly used to predict overall survival after therapy or to predict response to different treatment regimens [35]. Some authors reported about the potential association between the degree of tumor vascularization and tumor aggressiveness [36]. An increased local failure rate was reported in squamous cell carcinoma of the head and neck presenting with low perfusion values before treatment [37]. Concordantly, a better response to both chemotherapy and radiation therapy was described in tumors exhibiting higher BF values in the baseline [38]. Early efficacy prediction of sorafenib in the treatment of hepatocellular carcinoma (HCC) could be demonstrated in rats [39]. Pretreatment perfusion values were found to be a good predictor in many other tumors undergoing antiangiogenic therapy [40].

A response biomarker may be defined as a characteristic that can be objectively measured as an indicator of pharmaceutical response. The way and magnitude by which tumor vascularization is affected by a certain drug depends both on the characteristics of the tumor’s own vessel network, that of its microenvironment as well as on the type of antitumoral agent applied. Knowledge about all these variables helps for adequate use of perfusion measurements considering any potential clinical setting. In the long term, most effective therapy regimens lead to a reduction in perfusion CT parameters. Even during standard chemotherapy, cell death is expected to be followed by a loss in angiogenic support leading to measurable hypovascularization. In particular, of interest are the angiogenesis inhibitors which in many cases are administered as monotherapy. Their antiangiogenic effects depend on the mechanism of action of the drug applied as well as on the specific tumor entity, whereas morphologic changes are generally not expected at least in the early phases of treatment. Despite concurrent imaging modalities including positron emission therapy using different radiopharmaceuticals, targeting the course of tumor vascularization seems to be the more accurate way of response assessment during antiangiogenic treatment. Moreover, perfusion parameters are also suited for confident response monitoring for both local antivascular therapies like chemoembolization and systemic treatment. Even during radiation therapy, changes in perfusion characteristics can be predictive for progressive-free survival and outcome [41]. Perfusion CT also enhances our understanding of the pharmacodynamics of novel drugs and how they should be combined with each other in order to achieve best therapeutic effects. In this respect, one good example is the class of vascular disrupting agents that target also the mature vasculature potentially impacting the arrival time and dose of other complementary-given chemotherapeutics. Using perfusion as a complementary biomarker helps for developing new more proper response criteria, avoiding confusion caused by newly described response categories like pseudoresponse, pseudostabilization, or even pseudoprogression, which severely affect patients’ management [42]. Many of the so-called targeted drugs directly or indirectly affecting the signaling pathways of angiogenesis, like EGFR, VEGFR, and PDGF inhibitors, interferon, proteasome inhibitors, and thalidomide and successor drugs, have already been extensively analyzed by means of perfusion imaging techniques [43, 44].

In conclusion, perfusion-based imaging is a potent imaging tool which requires profound understanding of tumor behavior and mechanisms of action of the drugs to be monitored. Once these aspects have been elucidated, its broad clinical use may be advocated.

Osteoarthritis is a common degenerative joint disease, affecting more than 20 million people in the USA alone. The incidence of osteoarthritis is rising, and in 2030, at least 70 million people (USA) will be affected [45]. Osteoarthritis-related costs are a relevant socioeconomic factor. The established therapy of manifest osteoarthritis is cartilage repair, cartilage transplantation, or arthroplasty, while lifestyle modification is currently the only method of potential disease prevention [46]. Disease-modifying therapies which may prevent or prolong the course of osteoarthritis have been developed and evaluated but are still not broadly approved for clinical routine.